Pre‐operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding
Abstract
Background
Heavy menstrual bleeding is one of the most common reasons for referral of premenopausal women to a gynaecologist. Although medical therapy is generally first line, many women eventually will require further treatment. Endometrial ablation by hysteroscopic and more recent "second‐generation" devices such as balloon, radiofrequency or microwave ablation offers a day‐case surgical alternative to hysterectomy. Complete endometrial destruction is one of the main determinants of treatment success. Surgery is most effective if undertaken when endometrial thickness is less than four millimeters. One option is to perform the surgery in the immediate postmenstrual phase, which is not always practical. The other option is to use hormonal agents that induce endometrial thinning pre‐operatively. The most commonly evaluated agents are goserelin (a gonadotrophin‐releasing hormone analogue, or GnRHa) and danazol. Other GnRH analogues and progestogens have also been studied, although fewer data are available. It has been suggested that these agents will reduce operating time, improve the intrauterine operating environment and reduce absorption of fluid used for intraoperative uterine cavity distension. They may also improve long‐term outcomes, including menstrual loss and dysmenorrhoea.
Objectives
To investigate the effectiveness and safety of pre‐operative endometrial thinning agents (GnRH agonists, danazol, estrogen‐progestins and progestogens) versus another agent or placebo when given before endometrial destruction in premenopausal women with heavy menstrual bleeding.
Search methods
The following electronic databases were searched to April 2013 for published and unpublished randomised controlled trials that met the inclusion criteria: the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsycINFO.
Other electronic sources of trials included trial registers for ongoing and registered trials; citation indexes; conference abstracts in the Web of Knowledge; the LILACS database for trials from the Portuguese‐ and Spanish‐speaking world; PubMed; and the OpenSIGLE database and Google for grey literature.
All searches were performed in consultation with the MDSG Trials Search Co‐ordinator.
Selection criteria
Randomised controlled trials (RCTs) were included if they compared the effects of these agents with one other, or with placebo or no treatment, on relevant intraoperative and postoperative treatment outcomes. Selection of trials was carried out independently by two review authors.
Data collection and analysis
Two review authors independently assessed studies for risk of bias and extracted data on surgical outcomes, effectiveness outcomes, proportion of women requiring further surgical therapy during follow‐up, endometrial outcome measures, acceptability of use outcomes and quality of life. Data were analysed on an intention‐to‐treat basis. Dichotomous data were combined for meta‐analysis with RevMan software using the Mantel‐Haenszel method to estimate pooled risk ratios (RRs). Continuous data were combined for meta‐analysis with RevMan software using an inverse variance method to estimate the pooled mean difference (MD) with 95% confidence interval (CI). The overall quality of evidence for the main findings was assessed with the use of GRADE working group methods.
Main results
Twenty studies with 1969 women were included in this review. These studies compared GnRHa, danazol and progestogens versus placebo or no treatment; GnRHa versus danazol, progestogens, GnRH antagonists or dilatation & curettage; and danazol versus progestogens. Four studies performed more than one comparison.
When compared with no treatment, GnRHa used before hysteroscopic resection were associated with a higher rate of postoperative amenorrhoea at 12 months (RR 1.6, 95% CI 1.2 to 2.0, 7 RCTs, 605 women, moderate heterogeneity; I2 = 40%) and at 24 months (RR 1.62, 95% CI 1.04 to 2.52, 2 RCTs, 357 women, no heterogeneity; I2 = 0%), a slightly shorter duration of surgery (‐3.5 minutes, 95% CI ‐4.7 to ‐2.3, 5 RCTs, 156 women, substantial heterogeneity; I2 = 72%) and greater ease of surgery (RR 0.32, 95% CI 0.22 to 0.46, 2 RCTs, 415 women, low heterogeneity; I2 = 4%). Postoperative dysmenorrhoea was reduced (RR 0.59, 95% CI 0.40 to 0.87, 2 RCTs, 133 women, no heterogeneity; I2 = 0%). The use of GnRHa had no effect on intraoperative complication rates (RR 1.47, 95% CI 0.35 to 6.06, 5 RCTs, 592 women, no heterogeneity; I2 = 0%), and participant satisfaction with this surgery was high irrespective of the use of pre‐operative endometrial thinning agents (RR 0.99, 95% CI 0.93 to 1.05, 6 RCTs, 599 women, low heterogeneity; I2 = 11%). GnRHa produced more consistent endometrial atrophy than was produced by danazol (RR 1.84, 95% CI 1.23 to 2.75, 2 RCTs, 142 women, no heterogeneity; I2 = 0%). For other intraoperative and postoperative outcomes, any differences were minimal, and no benefits of GnRHa pretreatment were noted in studies in which women underwent second‐generation ablation techniques. Both GnRHa and danazol produced side effects in a significant proportion of women, although few studies reported these in detail. Few randomised data were available to allow assessment of the effectiveness of progestogens as endometrial thinning agents. When reported, the long‐term effects of endometrial thinning agents on benefits such as postoperative amenorrhoea were reduced with time.
The main study weaknesses were that most participants received no follow‐up beyond 24 months and that the studies used a small sample size. Heterogeneity for outcomes reported ranged from none to substantial. More than half the trials had no blinding of participants or outcome assessment. Most of the trials were determined to have uncertain selection and reporting bias, as they did not report allocation concealment and evidence of selective reporting was noted. The quality of reporting of adverse events was generally poor, but, when described in the studies, they included menopausal symptoms such as hot flushes, vaginal dryness, hirsutism, decreased libido and voice changes, as well as other side effects such as headache and weight gain.
Authors' conclusions
Low‐quality evidence suggests that endometrial thinning with GnRHa and danazol before hysteroscopic surgery improves operating conditions and short‐term postoperative outcomes. GnRHa produced slightly more consistent endometrial thinning than was produced by danazol, although both achieved satisfactory results. The effect of these agents on longer‐term postoperative outcomes was reduced with time. No benefits of GnRHa pretreatment were apparent with second‐generation ablation techniques. Also, side effects were more common when these agents were used.
PICOs
Plain language summary
Pre‐operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding
Review Question
Cochrane authors reviewed evidence for the effectiveness and safety of medications used to thin the lining of the womb before surgery performed to destroy (ablate) this lining (endometrium) in premenopausal women with heavy menstrual bleeding.
Background
Heavy menstrual bleeding is one of the most common reasons why premenopausal women are referred to a gynaecologist; this condition can cause significant physical, emotional and social stress in a woman's life. Surgery to ablate the endometrium is a treatment option available for this condition that is less invasive than removal of the womb (i.e. hysterectomy). We wanted to discover whether using medications to thin the lining of the womb before endometrial destruction enhanced the effectiveness of surgery in reducing symptoms and improved operating conditions for the surgeon. We also wanted to evaluate the safety of these medications (i.e. observe whether side effects or surgical complications were increased). These medications included gonadotrophin‐releasing hormone analogues (GnRH analogues), danazol and progestogens. Endometrial destruction surgery included either the older 'hysteroscopic' technique, whereby the lining of the womb is destroyed under direct vision, or the newer second‐generation techniques, which include balloon, radiofrequency and microwave ablation.
Study Characteristics
The evidence is current to April 2013. The review included 20 randomised controlled trials with a total of 1969 premenopausal women with heavy menstrual bleeding for whom non‐surgical treatment had not worked. Studies compared GnRH analogues, danazol and progestogens versus placebo or no treatment; GnRH analogues versus danazol, progestogens, GnRH antagonists or dilatation & curettage; and danazol versus progestogens. Four studies performed more than one comparison. Three studies used the newer second‐generation surgical techniques for endometrial destruction.
Key Results
GnRH analogues and danazol used before hysteroscopic surgery improve both operating conditions for the surgeon and short‐term bleeding symptoms for women (up to 24 months after surgery). GnRH analogues thin the lining of the womb better and more consistently than danazol, although both agents produce satisfactory results. Adverse effects were more common in women taking GnRH analogues or danazol compared with no treatment, and this was especially true with danazol. Adverse effects included menopausal symptoms such as hot flushes, vaginal dryness, hirsutism, decreased libido and voice changes, as well as other side effects such as headache and weight gain. The use of medications to thin the lining of the womb before surgery does not appear to improve heavy menstrual bleeding in the long term (i.e. longer than 24 months). However, only a few small studies followed up with women for longer than 24 months. Also, medications given to thin the womb lining do not provide additional benefit when used with the newer second‐generation endometrial destruction techniques, which are being performed increasingly in hospitals.
Quality of Evidence
Overall, the quality of the evidence was very low because of risk of bias in the included studies and differences between the studies. The quality of reporting of adverse events was generally poor.
Authors' conclusions
Summary of findings
| GnRH analogues compared with placebo or no treatment for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo or no treatment | GnRH analogues | |||||
| Postoperative amenorrhoea at 12 months or less | Study population | RR 1.58 | 605 | ⊕⊝⊝⊝ | ||
| 246 per 1000 | 389 per 1000 | |||||
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1Few studies were blinded, and only one study had good quality. | ||||||
| GnRH analogues compared with danazol for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Danazol | GnRH analogues | |||||
| Postoperative amenorrhoea at 12 months or less | 348 per 1000 | 408 per 1000 | RR 1.17 | 340 | ⊕⊝⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1No trials were blinded, and only one had adequate allocation concealment. | ||||||
| GnRH analogues compared with progestogens for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Progestogens | GnRH analogues | |||||
| Postoperative amenorrhoea at 12 months or less | 258 per 1000 | 408 per 1000 | RR 1.58 | 146 | ⊕⊝⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1One trial had adequate allocation concealment, and none reported blinding. | ||||||
| GnRH analogue compared with GnRH antagonist for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| GnRH antagonist | GnRH analogue | |||||
| Postoperative amenorrhoea at 12 months or less | 840 per 1000 | 798 per 1000 | RR 0.95 | 100 | ⊕⊕⊕⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1One trial with small population. | ||||||
| GnRH analogue compared with dilatation & curettage for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Dilatation & curettage | GnRH analogue | |||||
| Postoperative amenorrhoea at 12 months or less | 0 per 1000 | 0 per 1000 | RR 20.12 | 92 | 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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1No blinding of participants; selective reporting and small sample size in only one study. | ||||||
| Danazol compared with no pretreatment for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No pretreatment | Danazol | |||||
| Postoperative amenorrhoea at 12 months or less | 517 per 1000 | 543 per 1000 | RR 1.05 | 179 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1One trial had adequate description of randomisation, the other had adequate allocation concealment, but neither reported blinding. | ||||||
| Progestogens compared with no pretreatment for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No pretreatment | Progestogens | |||||
| Postoperative amenorrhoea at 12 months or less | 520 per 1000 | 281 per 1000 | RR 0.54 | 50 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1Adequate allocation concealment but not clear if blinded. | ||||||
| Danazol compared with progestogens for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Progestogens | Danazol | |||||
| Postoperative amenorrhoea at 12 months or less | 269 per 1000 | 509 per 1000 | RR 1.89 | 103 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1Only one of two trials had adequate allocation concealment, and neither trial reported blinding. | ||||||
| GnRHa or danazol compared with no pretreatment for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No pretreatment | GnRHa or danazol | |||||
| Postoperative amenorrhoea at 12 months or less | 428 per 1000 | 483 per 1000 | RR 1.13 | 280 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1One of two trials had adequate allocation concealment, but neither trial reported blinding. | ||||||
Background
Description of the condition
Heavy menstrual bleeding or menorrhagia is one of the most common reasons why premenopausal women are referred to a gynaecologist; it is a significant cause of morbidity in these women, resulting in symptoms of anaemia and reduced quality of life. Although medical therapy is generally the first approach, many women eventually require or request further treatment, with endometrial ablation offering a less invasive surgical approach compared with hysterectomy. Each year in the UK, one in 20 women between the ages of 30 and 49 years consults her general practitioner because of menorrhagia (Grant 2000). In a 2009 study, the English rate of surgery for menorrhagia, including both hysterectomy and endometrial ablation, was shown to be 143 procedures per 100,000 women, and 40% of these procedures were hysterectomy (Cromwell 2009). The rate of hysterectomy for premenopausal women in Australia was 312 per 100,000 in 2004 to 2005, and similar numbers were reported in New Zealand during the same period (Hill 2010; McPherson 2011). A recent nationwide analysis in Germany (Stang 2011) showed that hysterectomy rates for benign reasons varied from 213.8 to 361.9 per 100,000 women. Hysterectomy is associated with a significant inpatient hospital stay and a period of recuperation that makes it an unappealing and unnecessarily invasive choice for many women. Recent studies have reported increased risk of pelvic floor prolapse and urinary stress incontinence, as well as increased association with cardiovascular disease following hysterectomy (Cooper 2011; Ingelsson 2011). Hysteroscopic endometrial ablation or resection (and more recently balloon or microwave ablation) offers a day‐case surgical alternative to hysterectomy for many of these women. In addition, studies have suggested that these procedures are more cost‐effective than hysterectomy in terms of short‐ and long‐term costs to the health system and the shortened recovery period for the woman (Hidlebaugh 1998). If effective in the long term, this procedure could result in savings in health expenditures.
Description of the intervention
A variety of endometrial ablation methods may be used to treat heavy menstrual bleeding. Neodymium‐doped yttrium aluminium garnet (Nd:YAG) laser ablation was first performed in 1981 (Goldrath 1990), and use of the resectoscope was described shortly afterwards (DeChenery 1983). Rollerball ablation was reported in 1988 (Lin 1988) in Japan, and in 1989 in Europe (Vancaillie 1989). These are known as the 'first‐generation' or the more historical hysteroscopic endometrial ablation techniques. More recently, second‐generation endometrial ablation techniques (Neuwirth 1994) have been described that produce thermal damage to the endometrium without the need for skills in operative hysteroscopy. Second‐generation endometrial ablation techniques include balloon ablation, microwave energy, bipolar radiofrequency and diffused laser energy or hot water. These 'blind' ablation techniques are technically easier to perform, take less time and achieve similar results when compared with hysteroscopic resection and ablation or first‐generation techniques (Munro 2001; Lethaby 2009), which they have largely replaced. A recent meta‐analysis has suggested that second‐generation endometrial ablation techniques such as bipolar radiofrequency (Novasure) and microwave ablative devices (Microwave Endometrial Ablation), which now are commonly used, are more effective than the thermal balloon (ThermaChoice) and free fluid ablation (Hydro ThermAblator) in the treatment of menorrhagia (Daniels 2012).
Observational follow‐up studies (Erian 1994; Krogh 2009), randomised studies (Dwyer 1993; Pinion 1994; Sesti 2011) and systematic reviews (Bhattacharya 2011) comparing these techniques with hysterectomy have reported high levels of postoperative participant satisfaction, especially with second‐generation endometrial ablation techniques. However, long‐term rates of repeat surgery needed with endometrial ablation range from 12.4% at one year to 38.2% at four years, showing that some women will experience little benefit from the procedure or will subsequently request further surgery, usually a hysterectomy, thus narrowing the cost difference over time (Longinotti 2008; Lethaby 2010). The proportion of women who experience amenorrhoea (no periods) after surgery varies in different series from 30% to 60% (Dwyer 1993; Erian 1994; Pinion 1994), although the proportion experiencing improvement in menstrual symptoms is considerably higher, ranging from 86.8% within one year to 97.3% within four years (Lethaby 2010).
Complete removal or destruction of the endometrium is one of the most important determinants of treatment success. The aim of endometrial ablation techniques is for the operating surgeon to remove or destroy the entire thickness of the uterine endometrium (lining of the uterus) and the basal endometrial glands present in the superficial myometrium (underlying muscle layer) (Garry 1995). During the menstrual cycle, endometrial thickness varies from as little as 1 mm in the immediate postmenstrual phase to 10 mm or greater in the late secretory phase (Weingold 1990). The radius of a standard electrosurgery loop used for endometrial resection is about 4 mm, and the depth of tissue destruction with an Nd:YAG laser or with a rollerball electrode is 4 to 6 mm (Goldrath 1990; Duffy 1992; El‐Nashar 2009). Best results with ablation can be achieved if the endometrium is first rendered thin and inactive, either during the immediate postmenstrual phase or with administration of hormonal agents that induce endometrial thinning or atrophy, to increase the likelihood that ablation will include the basal layer of the endometrium, which can lie 4 to 6 mm beneath the surface, depending on the phase of the cycle.
How the intervention might work
Difficulty in timing surgery for the immediate postmenstrual phase and the unpredictable thickness of the unprepared endometrium have resulted in a focus on the use of endometrial thinning agents before surgery. A number of randomised studies have been undertaken to compare different hormonal agents with one other or with no pre‐operative treatment or placebo. Agents studied include goserelin (a gonadotrophin‐releasing hormone (GnRH) analogue), danazol, progestogens, estrogen‐progestin contraceptives and other GnRH agonists.
It has been suggested that use of these agents, particularly GnRH analogues, reduces operating time, improves the intrauterine operating environment and reduces distension medium absorption (this is the fluid used to distend the uterine cavity during surgery). Greater improvements in long‐term outcomes such as menstrual blood loss and dysmenorrhoea may be achieved (Donnez 2001). An improved operating environment might also reduce the rate of complications associated with the procedure. Improved postoperative outcomes might increase patient satisfaction and reduce the proportion of women undergoing subsequent hysterectomy.
These agents add a significant additional cost to any hysteroscopic procedure. However, if they have any effect on the proportion of women undergoing a second procedure (usually hysterectomy), then the additional costs and potential for uncomfortable side effects associated with these agent are likely to be outweighed by the advantages they offer (Banu 2005).
Why it is important to do this review
The aim of this review is to evaluate evidence from randomised controlled trials to assess whether endometrial thinning agents have a beneficial effect on postoperative and long‐term outcomes of endometrial resection and ablation, and to determine whether their use significantly improves the intrauterine operating environment. Endometrial ablation agents have the potential to improve both short‐ and long‐term effectiveness of endometrial ablation in women with heavy menstrual bleeding, thus reducing the number of women requiring further surgery and possibly improving the cost‐to‐benefit ratio. It is important to do this review because the evidence gathered will evaluate whether endometrial thinning agents should be used more consistently in clinical practice.
Objectives
To investigate the effectiveness and safety of pre‐operative endometrial thinning agents (GnRH agonists, danazol, estrogen‐progestins and progestogens) versus another agent or placebo when given before endometrial destruction in premenopausal women with heavy menstrual bleeding.
Methods
Criteria for considering studies for this review
Types of studies
Both published and unpublished randomised controlled trials were considered for inclusion in this review.
Types of participants
Premenopausal women with heavy menstrual bleeding undergoing endometrial resection or ablation with first‐generation or hysteroscopic techniques (i.e. resectoscope, rollerball diathermy, Nd:YAG laser) or any second‐generation technique (i.e. bipolar radiofrequency, balloon ablation, diffused laser energy, free fluid ablation, microwave ablation).
Types of interventions
Studies comparing the effects of the following interventions before endometrial resection or ablation with any of the first‐ or second‐generation techniques used for heavy menstrual bleeding were considered suitable for inclusion in this review.
1. Any medical therapy (GnRH analogues, danazol, estrogen‐progestin contraceptives or progestogens) compared with placebo or no treatment.
2. Any specific type of medical therapy (GnRH analogues, danazol, estrogen‐progestin contraceptives or progestogens) compared with any other specific type of medical therapy (GnRH analogues, danazol, estrogen‐progestin contraceptives or progestogens).
Types of outcome measures
Outcome measures were divided into primary and secondary outcomes for the purposes of the review.
Studies were considered suitable for inclusion in this review if they evaluated any of the following outcome measures.
Primary outcomes
1. Number of complications during surgery.
2. Proportion of women with amenorrhoea (no periods) postoperatively, at 12 months or less and at 24 months or longer.
3. Proportion of women requiring or requesting further surgical therapy during follow‐up.
Secondary outcomes
4. Endometrial outcome measures
a. Endometrial thickness after therapy (ultrasound or histological measurement or other type of measurement).
b. Cavity length of the uterus after therapy (ultrasound or hysteroscopic measurement at the time of surgery).
5. Acceptability of use of endometrial thinning agents
a. Continuation of treatment with endometrial thinning agent before endometrial resection or ablation surgery and participation levels.
b. Antiestrogenic and androgenic side effects (e.g. hot flushes, oily skin).
c. Other side effects.
6. Other surgical/post‐operative outcome measures
a. Duration of operation.
b. Proportion of procedures during which operative difficulty was encountered.
c. Distension medium absorption during surgery.
d. Blood loss during surgery.
e. Postoperative blood loss (measured objectively or subjectively).
f. Proportion of women with dysmenorrhoea (painful periods) postoperatively.
7. Proportion of women expressing satisfaction with surgery, with quality of life scores on validated scales.
Search methods for identification of studies
We searched for all published and unpublished randomised controlled trials that met the inclusion criteria, with no language restriction, in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co‐ordinator.
Electronic searches
We searched the following electronic databases for trials meeting the inclusion criteria: Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of Controlled Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsycINFO.
Other electronic sources of trials included the following.
-
Trial registers for ongoing and registered trials.
-
Citation indexes.
-
Conference abstracts in the Web of Knowledge.
-
LILACS database, for trials from the Portuguese‐ and Spanish‐speaking world.
-
PubMed.
-
OpenSIGLE database and Google for grey literature.
The search strategies used for these searches are itemised in Appendix 1.
Searching other resources
We handsearched reference lists of articles retrieved by the search and contacted experts in the field to obtain additional data. We also handsearched relevant journals and conference abstracts that were not covered in the MDSG register, in liaison with the Trials Search Co‐ordinator.
Data collection and analysis
Selection of studies
After an initial screen of the titles and abstracts retrieved by the search, which was conducted independently by two review authors (YHT and AL), the full texts of all potentially eligible studies were retrieved. Two review authors (YHT and AL) independently examined the full‐text articles for compliance with the inclusion criteria and selected eligible studies for inclusion in this review. We corresponded with study investigators as required to clarify study eligibility. No disagreements arose as to study eligibility. The selection process was documented with a 'PRISMA' flow chart (Figure 1).
Study flow diagram for 2002 to 2013 searches.
Data extraction and management
Two review authors (YHT and AL) independently extracted data from eligible studies using a data extraction form designed and pilot‐tested by the review authors, in accordance with Cochrane guidelines. Disagreements were resolved by discussion. When necessary, we corresponded with the principal study investigators of eligible trials to ask for further data on trial methodology or actual trial data. When studies were the subject of multiple publications, the main trial report was used as the reference, and additional details were derived from secondary papers. Included trials were analysed for the following quality criteria and methodological details.
Trial characteristics
1. Method of randomisation.
2. Multi‐centre or single‐centre design.
3. Presence or absence of blinding to treatment allocation.
4. Numbers of women randomly assigned, excluded or lost to follow‐up.
5. Whether an 'intention‐to‐treat' analysis was done.
6. The presence of a power calculation.
7. Duration, timing and location of the study.
8. Sources of funding.
Characteristics of study participants
1. Age and any other recorded characteristics of the women in the study.
2. Methods used to define heavy menstrual bleeding.
3. Exclusion criteria.
4. Type of hysteroscopic surgery performed.
Interventions used
1. Types of therapeutic agents used.
2. Dose, duration and timing of administration of therapeutic agents.
Outcomes
1. Intraoperative and postoperative outcome measures, as defined above.
2. Methods used to evaluate postoperative symptoms and patient satisfaction.
3. Methods used to measure postoperative menstrual blood loss.
We extracted data in the most accurate way possible. In cases for which results were presented in graphs, and no actual data were given, the data were extracted from the graphs.
Assessment of risk of bias in included studies
Two review authors (YHT and AL) independently assessed the included studies for risk of bias using the Cochrane 'Risk of bias assessment tool' (www.cochrane‐handbook.org) to assess selection bias (random sequence generation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective outcome reporting); and other sources of bias. Disagreements were resolved by discussion. We fully described all judgements and presented conclusions in the 'Summary of risk of bias' (Figure 2).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Each domain was scored as follows:
-
'Low risk' of bias;
-
'High risk' of bias; or
-
'Unclear risk' of bias.
Scoring of each domain was assessed in conjunction with The Cochrane Collaboration's tool for assessing risk of bias.
Measures of treatment effect
For dichotomous data, we used the numbers of events in the control and intervention groups of each study to calculate Mantel‐Haenszel risk ratios (RRs) with 95% confidence intervals (CIs). For continuous data, if all studies reported exactly the same outcomes, we calculated the mean difference (MD) between treatment groups. If similar outcomes were reported on different scales, we calculated the standardised mean difference (SMD). We reversed the direction of effects of individual studies, if required, to ensure consistency across trials. When ordinal data were used to measure outcomes, for example, satisfaction rates, the categories were collapsed and the data dichotomised and presented as RRs with 95% CIs. When data needed to calculate RRs or MDs were not available, we used the most detailed numerical data provided, such as test statistics or P values, to facilitate similar analyses of included studies. We compared the magnitude and direction of effects reported by studies with how they were presented in the review, while taking account of legitimate differences.
Dealing with missing data
The data were analysed as far as possible on an intention‐to‐treat basis. When data for eligible outcomes were missing from the publications, we attempted to contact authors of the trials for clarification. When these data could not be obtained, imputation of individual values was undertaken for the primary outcomes only. For other outcomes, only available data were analysed. When studies reported details sufficient for calculating the MD but did not provide information on the associated standard deviation (SD), the outcome was assumed to have an SD equal to the highest SD reported by other studies within the same analysis.
Assessment of heterogeneity
We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta‐analysis to provide a clinically meaningful summary. Included studies were carefully inspected for evidence of clinical heterogeneity in characteristics of participants, interventions provided, outcomes or trial duration. We assessed statistical heterogeneity by using the I2 statistic to determine the percentage of total variation across studies that was due to heterogeneity rather than to chance. An I2 measurement greater than 50% was taken to indicate substantial heterogeneity (Higgins 2003). In cases in which extreme statistical heterogeneity could not be explained by differences between studies, the estimates were not pooled in the meta‐analyses. We considered any statistical heterogeneity when interpreting the results, especially if any variation in the direction of effect was noted.
Assessment of reporting biases
In view of the difficulty of detecting and correcting for publication bias and other reporting biases, the review authors aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by staying alert for duplication of data. We planned to assess publication bias by constructing funnel plots when 10 or more studies were identified for outcomes. However, fewer than 10 studies were identified for all outcomes, so funnel plots were not presented.
Data synthesis
Outcome data were pooled in a meta‐analysis when no significant clinical heterogeneity and no evidence of any major skew were found. In studies with evidence of major skew, outcome data were not included in the main meta‐analyses. However, we assessed the outcome data when evidence of major skew was noted, and we commented narratively on the results.
Dichotomous data were combined for meta‐analysis with RevMan software using the Mantel‐Haenszel method to estimate pooled risk ratios. For negative outcomes (e.g. proportion requiring further surgery), an increase in the risk of a particular outcome for the experimental group is displayed graphically in the meta‐analyses to the right of the centre‐line, and a decrease in the risk of an outcome is displayed graphically to the left of the centre‐line. For positive outcomes (e.g. satisfaction with treatment), an increase in risk is shown on the reverse axis. Graphs were labelled for ease of interpretation.
Continuous data were combined for meta‐analysis with RevMan software using an inverse variance method to estimate the pooled MD with 95% CI. Fixed‐effect models were used in the meta‐analyses, but when evidence indicated I2 > 50%, results were compared with those obtained using a random‐effects model, which produced a more conservative estimation of the summary effect measure.
A 'Summary of findings' table was generated with the use of GRADEPRO software. This table evaluated the overall quality of the body of evidence for main review outcomes by using GRADE criteria (study limitations, i.e. risk of bias, consistency of effect, imprecision, indirectness and publication bias). Judgements about evidence quality (high, moderate or low) for each comparison were justified, documented and incorporated into reporting of results for the primary outcome of postoperative amenorrhoea.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis was undertaken according to:
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months of pretreatment with thinning agents (i.e. one month, two months, three months or more than three months of treatment); and
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first‐ or second‐generation endometrial ablation.
Sensitivity analysis
We planned to perform sensitivity analyses for the following quality features.
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Adequate allocation concealment versus all included trials.
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A placebo group as the control group versus all included trials, with a no pretreatment group as the control.
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Dropouts < 20% versus all included trials.
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Pharmaceutical funding excluded.
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Continuous outcomes for which no estimation of variance has had to be made for pooling in the meta‐analysis versus all included trials (for MD).
However, the number of identified studies was insufficient to allow performance of the above prespecified sensitivity analyses.
Overall quality of the body of evidence: Summary of findings tables
We generated Summary of findings tables with the use of GRADEPRO software. These tables evaluated the overall quality of the body of evidence for main review outcomes, when data were available, by using GRADE criteria (study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness and publication bias). Judgements about evidence quality (high, moderate or low) were justified, documented and incorporated into reporting of results for each outcome.
Results
Description of studies
Results of the search
For the initial publication of the review in 1998, a total of 17 trials were identified that evaluated the use of potential endometrial thinning agents administered before endometrial resection or rollerball/laser ablation. The review in 2001 included 12 trials that met the inclusion criteria (Sutton 1994; Fraser 1996; Garry 1996; Romer 1996; Taskin 1996; Vercellini 1996; Donnez 1997;Sorensen 1997; Sowter 1997; Lissak 1999; Rai 2000; Kriplani 2001). The updated search in 2013 located an additional 11 studies that appeared to meet the inclusion criteria, of which eight trials were included in this review (English 1998; Taskin 1998; Alborzi 2002; Kriplani 2002; Shawki 2002; Jack 2005; Bhatia 2008; Vilos 2010). Twenty studies (31 articles) were suitable for inclusion in the review and were retrieved in full text. Four studies were followed by more than one publication reporting on follow‐up after treatment (Donnez 1997; Jack 2005; Romer 1996; Vercellini 1996). Five publications, which are awaiting classification, were identified as conference abstracts, and the authors were contacted (Gannon 1994; Mayonda 1994; McDonald 1994; Nagele 1995; Watermeyer 2005). No replies have been received. No trials still in progress were identified. See study tables: Characteristics of included studies, Characteristics of excluded studies, Characteristics of studies awaiting classification.
The search process is documented by a PRISMA flow chart (Figure 1).
Included studies
Study design and setting
Twenty parallel‐design randomised controlled trials were included in the review. Sixteen studies were single‐centre studies. One Australian study had two centres, two studies had three centres (one in Egypt and two in the United States for one study, and three centres in Italy for the other study) and one study was a multi‐centre study (37 centres in 12 countries, from Europe, South Africa, the UK and Canada).
Participants
The studies included a total of 1969 women. In all, 1029 women were randomly assigned to an intervention group and 940 women to control groups. All were premenopausal women with dysfunctional uterine bleeding not responding to medical treatment. Three studies including 345 women used second‐generation endometrial ablation techniques.
Interventions
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Ten studies compared GnRH analogues versus placebo or no treatment; 722 women (Romer 1996; Taskin 1996; Vercellini 1996; Donnez 1997; Sorensen 1997; Sowter 1997; English 1998; Taskin 1998; Lissak 1999; Rai 2000).
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Seven studies compared GnRH analogues versus danazol; 511 women (Sutton 1994; Fraser 1996; Garry 1996; Romer 1996; English 1998; Rai 2000; Shawki 2002).
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Three studies compared GnRH analogues versus progestogens; 146 women (Romer 1996; Rai 2000; Shawki 2002).
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Four studies compared danazol versus placebo or no treatment; 228 women (Romer 1996; English 1998; Rai 2000; Kriplani 2002).
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Three studies compared progestogens versus no pretreatment; 120 women (Romer 1996; Rai 2000; Kriplani 2001).
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Three studies compared danazol versus progestogens; 123 women (Romer 1996; Rai 2000; Shawki 2002).
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Two studies compared GnRH analogues or danazol versus no pretreatment; 300 women (Alborzi 2002; Jack 2005).
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One study compared GnRH analogues versus GnRH antagonist; 106 women (Bhatia 2008).
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One study compared GNRH analogues versus dilatation & curettage; 105 women (Vilos 2010).
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Four studies included more than one comparison (Romer 1996; English 1998; Rai 2000; Shawki 2002).
Outcomes
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Thirteen studies reported duration of operation (Alborzi 2002; Bhatia 2008; Donnez 1997; English 1998; Fraser 1996; Garry 1996; Jack 2005; Kriplani 2002; Shawki 2002; Sorensen 1997; Taskin 1996; Taskin 1998; Vercellini 1996).
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Three studies reported proportion in which operative difficulty was encountered (Donnez 1997; Vercellini 1996).
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Eight studies reported distension medium absorption (Bhatia 2008; English 1998; Fraser 1996; Garry 1996; Kriplani 2002; Sorensen 1997; Taskin 1996; Vercellini 1996).
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Six studies reported intraoperative complications (Bhatia 2008; Donnez 1997; English 1998; Sorensen 1997; Sowter 1997; Vercellini 1996).
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Three studies reported postoperative dysmenorrhoea (Bhatia 2008; Sorensen 1997; Sowter 1997).
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Fifteen studies reported proportion with postoperative amenorrhoea at 12 month or less (Alborzi 2002; Bhatia 2008; Donnez 1997; Fraser 1996; Garry 1996; Jack 2005; Kriplani 2002; Lissak 1999; Rai 2000; Romer 1996; Shawki 2002; Sorensen 1997; Sowter 1997; Vercellini 1996; Vilos 2010).
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Four studies reported proportion with postoperative amenorrhoea at 24 months or longer (Bhatia 2008; Donnez 1997; Kriplani 2002; Romer 1996).
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Seven studies reported postoperative blood loss (Donnez 1997; Fraser 1996; Garry 1996; Romer 1996; Sorensen 1997; Sowter 1997; Sutton 1994).
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Ten studies reported proportion requiring further surgery or treatment during follow‐up (Bhatia 2008; Donnez 1997; Jack 2005; Kriplani 2002; Lissak 1999; Romer 1996; Sorensen 1997; Sowter 1997; Sutton 1994; Vilos 2010).
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Eight studies reported on endometrial thickness after therapy (ultrasound or histological measurement or other measure) (Bhatia 2008; Donnez 1997; Garry 1996; Jack 2005; Kriplani 2002; Rai 2000; Romer 1996; Sutton 1994).
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Eight studies reported on side effects with therapy (Bhatia 2008; Donnez 1997; English 1998; Fraser 1996; Garry 1996; Jack 2005; Sutton 1994; Vilos 2010).
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Eleven studies reported on proportion satisfied with outcome (Bhatia 2008; Donnez 1997; Garry 1996; Jack 2005; Lissak 1999; Rai 2000; Sorensen 1997; Sowter 1997; Sutton 1994; Vercellini 1996; Vilos 2010).
Excluded studies
Sixteen studies were excluded from the review, for the following reasons.
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Seven of 16 were not randomised controlled trials.
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Nine of 16 did not meet the inclusion criteria for participants or treatment groups or outcome measures.
Risk of bias in included studies
Allocation
Eleven studies were at low risk of selection bias related to sequence generation, as they used computer randomisation or a random numbers table (Fraser 1996; Taskin 1996; Vercellini 1996; Donnez 1997; Sorensen 1997; Taskin 1998; Lissak 1999; Kriplani 2001; Kriplani 2002; Jack 2005; Bhatia 2008). The other nine studies did not describe the randomisation method used and were at unclear risk of this bias (Sutton 1994; Garry 1996; Romer 1996; Sowter 1997; English 1998; Rai 2000; Alborzi 2002; Shawki 2002; Vilos 2010).
Seven studies were at low risk of selection bias related to allocation concealment, as they used opaque sealed envelopes or a centralised telephone system (Vercellini 1996; Donnez 1997; English 1998; Rai 2000; Jack 2005; Bhatia 2008; Vilos 2010). The other 13 studies did not describe the method used and were at unclear risk of this bias.
Blinding
We did not consider that blinding was likely to have a major influence on findings for most of the surgical outcomes (duration of operation, distension medium absorption during surgery, blood loss during surgery, number of complications during surgery, proportion of women with dysmenorrhoea postoperatively) or on endometrial outcome measures (endometrial thickness, proportion of women with atrophic endometrial glands). For the outcome of proportion in which operative difficulty was encountered, potential for performance bias depended on how operative difficulty was defined, especially if the surgeon was not blinded to the interventions (Vercellini 1996). However, for the other outcomes (proportion of women with amenorrhoea postoperatively at 12 months or less, proportion of women with amenorrhoea postoperatively, at 24 months or longer, postoperative blood loss, proportion of women requiring further treatment at follow‐up, proportion with optimal endometrial thinning by operator assessment, side effects, proportion of women satisfied with outcome), blinding status could potentially affect findings.
Five studies were deemed to be at low risk of performance bias, as they described a placebo identical to the intervention or treatment that was administered by staff who were not involved in the surgery or in the analysis of results (Taskin 1996; Donnez 1997; English 1998; Taskin 1998; Bhatia 2008). Thirteen studies were deemed to be at high risk of performance bias, as they were open studies that did not involve a placebo and that used different treatment protocols. Two studies were single‐blinded and so were at unclear risk of this bias.
Five studies were deemed to be at low risk of detection bias, as they were double‐blinded with blinding of outcome assessors (Taskin 1996; Donnez 1997; English 1998; Taskin 1998;Bhatia 2008). Twelve studies were assessed to be at high risk of detection bias, as they did not have blinding of outcome assessors, or they were open studies with different treatment protocols. Three studies did not mention whether outcome assessors were blinded and so were at unclear risk of detection bias.
Incomplete outcome data
Fifteen studies were at low risk of attrition bias, as all or most (> 95%) women who were randomly assigned were analysed. Two studies were deemed to be at high risk of attrition bias, as withdrawals were not balanced between the two groups or women were not analysed in their randomly assigned groups (Sutton 1994; Sorensen 1997). Three studies were considered to be at unclear risk of attrition bias, as reasons for dropouts were not given.
Selective reporting
Two studies were considered to be at low risk of reporting bias, as all prespecified outcomes were reported. Two studies were deemed to be at high risk of reporting bias, as they failed to report on outcomes that had been looked at (Alborzi 2002; Vilos 2010). Sixteen studies were at unclear risk of reporting bias, as prior published protocols were not available or investigators did not fully report on all prespecified outcomes.
Other potential sources of bias
Five studies were considered to be at low risk of other bias, as they were balanced at baseline with no other potential sources of bias identified. Fifteen studies were at unclear risk of bias, as it was unclear whether the groups were balanced at baseline, whether participants were not evenly distributed amongst the groups or whether the study was funded by a pharmaceutical company.
Risk of bias for all studies is summarised in Figure 2 and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Effects of interventions
See: Summary of findings for the main comparison GnRH analogues compared with placebo or no treatment for heavy menstrual bleeding; Summary of findings 2 GnRH analogues compared with danazol for heavy menstrual bleeding; Summary of findings 3 GnRH analogues compared with progestogens for heavy menstrual bleeding; Summary of findings 4 GnRH analogue compared with GnRH antagonist for heavy menstrual bleeding; Summary of findings 5 GnRH analogue compared with dilatation & curettage for heavy menstrual bleeding; Summary of findings 6 Danazol compared with no pretreatment for heavy menstrual bleeding; Summary of findings 7 Progestogens compared with no pretreatment for heavy menstrual bleeding; Summary of findings 8 Danazol compared with progestogens for heavy menstrual bleeding; Summary of findings 9 GnRHa or danazol compared with no pretreatment for heavy menstrual bleeding
1. Comparison of GnRH analogues versus placebo or no treatment
Primary outcomes
1.1 Surgical outcome measures
These included number of complications during surgery (Vercellini 1996; Donnez 1997; Sorensen 1997; Sowter 1997; English 1998).
Five studies reported on intraoperative complications (Vercellini 1996; Donnez 1997; Sorensen 1997; Sowter 1997; English 1998). Three uterine perforations were reported in the 306 women who received GnRH analogues, and one perforation was decribed in the 286 women who had received no treatment or had been given placebo (RR 1.47, 95% CI 0.35 to 6.06, 5 RCTs, 592 women, I2 = 0%) (Figure 4).
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.1 Intraoperative complications—uterine perforation.
1.2 Effectiveness of endometrial thinning agents on outcome of endometrial resection or ablation as a surgical treatment for menorrhagia
These outcomes included the following.
1.2 Women with amenorrhoea within 12 months (Romer 1996; Vercellini 1996; Donnez 1997; Sorensen 1997; Sowter 1997; Lissak 1999; Rai 2000).
The estimated overall proportion of women with amenorrhoea in the GnRH analogue group within 12 months was significantly greater than in the control group when data from one and two months of therapy were combined (RR 1.6, 95% CI 1.2 to 2.0, 7 RCTs, 605 women, I2 = 40%) (Figure 5). The risk difference for this outcome is 0.14 (95% CI 0.06 to 0.21), giving a number needed to treat to produce one additional case of amenorrhoea of 7.1. The number of women receiving only one month of therapy is probably too small to determine whether the duration of therapy has any effect on the proportion of women with postoperative amenorrhoea.
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.2 Postoperative amenorrhoea at 12 months or less.
1.3 Women with amenorrhoea at 24 or more months
Two studies report amenorrhoea rates at 24 months or longer postsurgery (Donnez 1997; Romer 1996). The benefits of GnRH analogue administration appear to be reduced (RR 1.62, 95% CI 1.04 to 2.52, 2 RCTs, 357 women, I2 = 0%) (Figure 6). No benefit of GnRH analogue pretreatment was found in the single small study in which balloon (second‐generation) ablation was used (Lissak 1999).
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.3 Postoperative amenorrhoea at 24 months or longer.
1.4 Women requiring or requesting further surgical therapy during follow‐up
These outcomes included the following.
1.4 Women requiring further surgery within 12 months of follow‐up (Donnez 1997; Sorensen 1997; Sowter 1997; Lissak 1999).
1.5 Women requiring surgery at 24 or more months of follow‐up (Donnez 1997; Romer 1996)
The number of women undergoing further surgery within 12 months of follow‐up in the four studies that reported this was 17 of the 241 women followed up who were given GnRH analogues, and 18 in the 247 women given placebo or no treatment (RR 0.99, 95% CI 0.53 to 1.86, 4 RCTs, 488 women, I2 = 0%) (Figure 7). These figures do not suggest that treatment with GnRH analogues reduces the proportion of women who will subsequently request further surgery. This is confirmed by two studies in follow‐up greater than 24 months (RR 1.51, 95% CI 0.97 to 2.35, 2 RCTs, 319 women, moderate quality evidence) (Figure 8).
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.4 Requiring further surgery within 12 months of follow‐up.
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.5 Requiring further surgery ≥ 24 months of follow‐up.
The duration of follow‐up in these studies ranges from six months (Romer 1996; Donnez 1997) to 12 months (Sorensen 1997; Sowter 1997) or longer (Romer 1996; Donnez 1997).
Secondary outcomes
1.6 Endometrial outcome measures
These outcomes included the following.
1.6 Endometrial thickness (ultrasound) (Romer 1996).
1.7 Endometrial thickness (descriptive data) (Donnez 1997; Rai 2000).
Donnez 1997 showed a significant reduction in endometrial thickness on ultrasound measurement when GnRH analogue rather than placebo was used (1.61 mm vs 3.53 mm; estimated ratio 0.46; 95% CI 0.41 to 0.52), and this is confirmed by Rai 2000. These results are reported in the 'Other data' section of the review. A similar result was reported by Romer 1996 in the meta‐analysis (MD ‐2.7 mm, 95% CI ‐3.5 to ‐1.9, 1 RCT, 20 women).
1.8 Proportion with atrophic endometrial glands (Romer 1996; Vercellini 1996; Donnez 1997; Rai 2000)
GnRHa pretreatment effectively induced atrophic endometrial glands when compared with either placebo or no pretreatment (RR 6.02, 95% CI 4.11 to 8.81, 4 RCTs, 483 women, I2 = 68%, moderate quality evidence).
1.9 Proportion with optimal endometrial thinning by operator assessment (Romer 1996)
In one small study (Romer 1996), nine out of ten women given triptorelin had optimal endometrial preparation (as assessed by the operating surgeon) compared with six out of ten who had received no treatment, although this was not a significant difference (RR 6.0, 95% CI 0.87 to 41.21, 1 RCT, 20 women).
1.10 Acceptability of use of endometrial thinning agents
Outcomes assessed included the following.
1.10 Side effects (Donnez 1997; English 1998). However, English 1998 reported side effects only for women receiving GnRH analogues. Donnez 1997 reported that a significantly higher proportion of women receiving GnRH analogues experienced hot flushes, sweating and headaches than those receiving placebo, although only one woman withdrew (out of 174) because of treatment side effects (headache).
1.11 Other surgical/postoperative outcome measures
These included the following.
1.11 Duration of operation (minutes) (Taskin 1996; Vercellini 1996; Donnez 1997; Sorensen 1997; English 1998; Taskin 1998).
The duration of surgery (in minutes) was shorter in the GnRH analogue (GnRHa) group in all included studies that evaluated this outcome, although this finding did not reach significance in two small studies (Vercellini 1996; English 1998). In two other studies included in the meta‐analysis (Sorensen 1997; English 1998), standard deviations were not available and estimates of variation were imputed, with the highest SD value from other included studies used in the analysis. The data reported in Donnez 1997 as a geometric range have been converted and an SD found. The difference in mean operating times in the meta‐analysis varied from two minutes (Vercellini 1996) to 14 minutes (Sorensen 1997). When the data for all studies were combined, the pooled estimate for the mean difference is ‐3.5 minutes (95% CI ‐4.7 to ‐2.3, 5 RCTs, 156 women, I2 = 72%) in favour of GnRH analogues. In these studies, the mean duration of operation in the GnRHa group ranged from 12.1 to 32.8 minutes, and the mean duration of operation in the placebo group ranged from 14.6 to 46.4 minutes, thus showing that the studies had significant heterogeneity and that the mean difference of ‐3.5 minutes may not be clinically significant.
1.12 Procedures in which operative difficulty was encountered (Vercellini 1996; Donnez 1997).
The degree of operative difficulty was graded by two studies either as the proportion of operations reported as more difficult than usual (Donnez 1997) or on an ordinal scale from none to severe difficulty (Vercellini 1996). The data have been combined as the proportion of procedures in which some difficulty or more difficulty than usual was encountered. In these studies, GnRH analogues significantly reduced the proportion of procedures in which difficulty was encountered (RR 0.32, 95% CI 0.22 to 0.46, 2 RCTs, 415 women, I2 = 4%).
1.13 Procedures with distension medium absorption during surgery (Taskin 1996; Vercellini 1996; Sorensen 1997; English 1998).
The volume of distension medium absorbed was lower in the GnRH analogue group in the studies that measured this outcome, although the differences were relatively small (MD ‐154.5, 95% CI ‐211.4 to ‐97, 4 RCTs, 137 women, I2 = 0%). These differences reached statistical significance in three of the studies, although the authors commented that the differences probably were not clinically significant. Only in one study (Sorensen 1997) did a woman suffer from fluid overload, and this occurred in the no treatment group. Standard deviations were imputed for two studies as above, as these were not available from the publications or from the study authors.
1.14 Procedures with distension medium absorption during surgery (descriptive data) (Donnez 1997).
One study (Donnez 1997) reported distension medium absorption during surgery as median fluid absorption with no range, and this is reported in the 'Other data' section of this review.
From these studies, it seems likely that treatment with GnRH analogues will reduce distension medium absorption, although the treatment effect is small.
1.15 Procedures with postoperative blood loss (Romer 1996; Donnez 1997; Sorensen 1997; Sowter 1997).
No objective measures were used to assess menstrual blood loss postoperatively. The combined estimate of four studies suggested that women were more likely to report reduced menstrual loss and were less likely to report moderate or heavy menstrual bleeding if given GnRH analogues (RR 0.74, 95% CI 0.59 to 0.92, 4 RCTs, 480 women, I2 = 39%, moderate quality evidence).
1.16 Women with dysmenorrhoea (painful periods) postoperatively (Donnez 1997; Sorensen 1997; Sowter 1997).
Dysmenorrhoea was reduced by surgery in both treated and untreated women in the three studies that recorded this (Donnez 1997; Sorensen 1997; Sowter 1997). Data were combined in meta‐analysis for two studies as the proportion of women experiencing any postoperative dysmenorrhoea (Sorensen 1997; Sowter 1997). This shows a significant difference in favour of GnRH analogues (RR 0.59, 95% CI 0.40 to 0.87, 2 RCTs, 133 women, I2 = 0%). However, these data should be treated cautiously, as by far the largest study (Donnez 1997) showed no difference in postoperative pain scores between women given GnRH analogues and those given placebo, although no actual patient data were reported. It is likely that any reduction in postoperative dysmenorrhoea is small.
1.17 Quality of life
The outcome assessed was proportion of women satisfied with outcome (Vercellini 1996; Donnez 1997; Sorensen 1997; Sowter 1997; Lissak 1999; Rai 2000). Participant satisfaction was high in both groups. When data were combined, no difference was seen between women treated with GnRH analogues and those given no treatment or placebo (RR 0.99, 95% CI 0.93 to 1.05, 6 RCTs, 599 women, I2 = 11%).
2. Comparison of GnRH analogues with danazol
Primary outcomes
2.1 Surgical outcome measures
None of the studies have described any intraoperative complications. It is not possible to comment on whether GnRH analogues or danazol is associated with a lower complication rate during surgery.
2.2 Effectiveness of endometrial thinning agents on outcome of endometrial resection or ablation as a surgical treatment for menorrhagia
These outcomes included the following.
2.2 Women with amenorrhoea within 12 months (Fraser 1996; Garry 1996; Romer 1996; Rai 2000; Shawki 2002).
2.3 Women with amenorrhoea at 24 or more months (Romer 1996).
The proportion of women experiencing postoperative amenorrhoea after two months of GnRH analogues was significantly higher in one study (Garry 1996), significantly lower in another study (Rai 2000) and not significantly different in the other three studies, regardless of duration of pretreatment (Fraser 1996; Romer 1996; Shawki 2002). Sutton 1994 assessed only whether there had been an overall improvement in menstrual symptoms at three months. When data are combined, no significant difference in the postoperative amenorrhoea rate is apparent when GnRH analogues rather than danazol are used. For postoperative amenorrhoea at 12 months or less, the RR is 1.17 (95% CI 0.90 to 1.52, 5 RCTs, 340 women, I2 = 52%) (Figure 9). In Romer 1996, an identical amenorrhoea rate was reported in the two groups at three‐year follow up (RR 1.00, 95% CI 0.49 to 2.05, 1 RCT, 20 women) (Analysis 2.3).
Forest plot of comparison: 2 GnRH analogues versus danazol, outcome: 2.2 Postoperative amenorrhoea at 12 months or less.
2.4 Women requiring or requesting further surgical therapy during follow‐up
This included women requiring further surgery during follow‐up (Sutton 1994; Romer 1996). No evidence suggested a significant difference between the number of women requiring further surgery in the small Romer 1996 study, which was included in the meta‐analysis (RR 0.33, 95% CI 0.02 to 7.32, 1 RCT, 20 women). Follow‐up ranged from three months (Sutton 1994) to 24 months (Romer 1996).
Secondary outcomes
2.5 Endometrial outcome measures
Outcomes included the following.
2.5 Endometrial thickness (ultrasound) (Romer 1996).
2.6 Endometrial thickness (descriptive data) (Sutton 1994; Garry 1996; Rai 2000).
Median endometrial thickness on ultrasound measurement or histology after GnRH analogues compared with danazol therapy was significantly lower in one study (Sutton 1994) and similar in the other three studies (Garry 1996; Romer 1996; Rai 2000). Combining data on endometrial thickness was not possible, so data have been presented as medians with no useable measure of variance in the 'Other data' section of the review for three of the four studies.
2.7 Women with atrophic endometrial glands (Sutton 1994; Garry 1996; Romer 1996; Rai 2000)
Four studies compared the proportion of women in each group with atrophic endometrial glands on histology. Two of the four studies reported that the proportion of women with atrophic or inactive endometrial glands or stroma was greater in the GnRH analogue–treated group (Sutton 1994;Garry 1996). These studies reported their histology slightly differently. Garry 1996 makes no distinction between inactive and atrophic glands, and data have been combined using the proportion of women with inactive glands for one study (Garry 1996) and with atrophic glands for the other (Sutton 1994). Garry 1996 also makes no distinction between one and two months of therapy in reporting endometrial histology. Two other studies reported similar proportions in each group. When data are combined, the overall proportion of women with atrophic or inactive glands appears to be greatest in women treated with GnRH analogues (RR 1.28, 95% CI 1.03 to 1.58, 4 RCTs, 318 women, I2 = 43%).
2.8 Women with satisfactory thinning at hysteroscopy (Garry 1996; Romer 1996)
2.9 Women with optimal endometrial thinning by operator assessment (Romer 1996)
2.10 Women with complete atrophy at hysteroscopy
A subjective hysteroscopic assessment of either the degree of endometrial atrophy (Sutton 1994; Fraser 1996) or how satisfactory endometrial suppression appeared (Sutton 1994; Garry 1996; Romer 1996) was made in four studies. When reported data have been combined for the former outcome, the meta‐analysis suggests that on hysteroscopic assessment, the proportion of women with complete endometrial atrophy or with a very thin endometrium is slightly greater with GnRH analogues than with danazol (RR 1.84, 95% CI 1.23 to 2.75, 2 RCTs, 142 women, I2 = 0%). The proportion of cases in which satisfactory suppression is obtained is slightly greater with GnRH analogues, but the differences are likely to be minimal (RR 1.09, 95% CI 1.00 to 1.19, 2 RCTs, 165 women, I2 = 0%). An identical rate of optimal endometrial thinning was noted in the two groups (RR 1.00, 95% CI 0.49 to 2.05, 1 RCT, 20 women).
2.11 Acceptability of use of endometrial thinning agents
Outcomes included the following.
2.11 Side effects (Sutton 1994; Fraser 1996; Garry 1996). The spectrum of side effects reported reflects the different modes of action of these two drugs, and no study used a psychometric scale to evaluate the impact of these side effects on "quality of life", so only the proportion of women experiencing each particular side effect can be reported. Garry 1996 has not reported side effects in sufficient detail for results to be combined with those of any other study, but the proportion of women reporting various side effects is shown for Fraser 1996 and Sutton 1994. Hot flushes, reduced libido, depression, headaches and vaginal dryness were significantly more common with GnRHa.
A greater proportion of women withdrew from the studies because of side effects from danazol (RR 0.08 favouring GnRHa, 95% CI 0.01 to 0.59, 3 RCTs, 285 women, I2 = 0%). However, this apparent difference should be treated with caution because once inserted, GnRH analogues cannot be removed, ensuring complete compliance unless side effects within the first few weeks of therapy are intolerable.
2.12 Weight gain was more common with danazol.
2.13 Other surgical/postoperative outcome measures
Outcomes included the following.
2.13 Duration of operation (Fraser 1996; Garry 1996; English 1998; Shawki 2002).
Operating time was not significantly different in three studies (Sutton 1994—no data given; Fraser 1996—data obtained from author; and English 1998) and was significantly reduced in favour of GnRH analogues in two other studies (Garry 1996; Shawki 2002). Data were combined for four studies (Fraser 1996; Garry 1996; English 1998; Shawki 2002) for one, two and three months of therapy and showed a reduction in operating time in favour of GnRH analogues (MD ‐5.02, 95% CI ‐6.25 to ‐3.78, 4 RCTs, 325 women, I2 = 42%). This result should be treated cautiously, as results were inconsistent between trials, and data were not available from Sutton 1994.
2.14 Procedures in which operative difficulty was encountered (Fraser 1996).
In the two studies in which a subjective assessment of operative difficulty was made (Sutton 1994; Fraser 1996), no significant difference was noted in the proportion of women in whom operative difficulty was encountered. Complete data were available only for Fraser 1996 (RR 0.68, 95% CI 0.35 to 1.51, 1 RCT, 56 women) for GnRHa compared with danazol (i.e. a non‐significant difference).
2.15 Distension medium absorption during surgery (Fraser 1996; Garry 1996; English 1998).
A similar pattern was seen for distension medium absorption, although the reported data were heterogeneous, and no difference in fluid absorption is apparent when data are combined (MD ‐22.38, 95% CI ‐87.07 to 42.32, 3 RCTs, 223 women, I2 = 78%). A more useful measure might be the proportion of women with any distension medium absorption in each group. This has been reported by Garry 1996, where 54% of women who had received danazol had distension medium absorption compared with 32% of women who had received GnRH analogues.
2.16 Postoperative blood loss measured objectively (Fraser 1996) or assessed subjectively (Sutton 1994; Garry 1996; Romer 1996).
The only study that objectively measured postoperative blood loss (Fraser 1996) showed at both three and six months postoperatively a significantly lower mean loss and a shorter duration of bleeding in women given GnRH analogues compared with those given danazol (MD ‐6.40, 95% CI ‐9.19 to ‐3.61, 1 RCT, 56 women). However, it is a small study, and results should be interpreted cautiously.
2.17 Quality of life
The outcome assessed is proportion satisfied with outcome (Sutton 1994; Garry 1996; Rai 2000). Participant satisfaction after endometrial resection was high in all these studies, and although one study reported a significant difference between groups, the overall combined estimate was non‐significant (RR 0.94, 95% CI 0.82 to 1.08, 3 RCTs, 286 women, I2 = 61%) (Analysis 2.17).
3. Comparison of GnRH analogues with progestogens
Primary outcomes
3.1 Surgical outcome measures
Intraoperative complications were not assessed in these studies.
3.2 Effectiveness of endometrial thinning agents on outcome of endometrial resection or ablation as a surgical treatment for menorrhagia
These outcomes included the following.
3.2 Women with amenorrhoea within 12 months (Romer 1996; Rai 2000; Shawki 2002).
3.3 Women with amenorrhoea at 24 or more months (Romer 1996).
No evidence of a significant difference in postoperative amenorrhoea rates up to 12 months after surgery was found between groups either in individual trial results or overall (combining one, two and three months of pretreatment with GnRHa), although the summary effect estimate was close to the cutoff P value for significance overall, in favour of GnRHa pretreatment (RR 1.58, 95% CI 0.96 to 2.61, 3 RCTs, 146 women, I2 = 0%). No evidence of a significant difference in these amenorrhoea rates was noted at longer follow‐up, two years after surgery, in a very small trial (Romer 1996) (RR 3.00, 95% CI 0.79 to 11.44, 1 RCT, 20 women) (Figure 10).
Forest plot of comparison: 3 GnRH analogues versus progestogens, outcome: 3.2 Postoperative amenorrhoea at 12 months or less.
3.4 Proportion of women requiring or requesting further surgical therapy during follow‐up
This included the outcome of proportion of women requiring further surgery during follow‐up (Romer 1996). No evidence of differences between groups was found in the requirement for further surgical intervention up to two years after surgery (RR 0.33, 95% CI 0.02 to 7.32, 1 RCT, 20 women) (Analysis 3.4).
Secondary outcomes
3.5 Endometrial outcome measures
Outcomes included the following.
3.5 Endometrial thickness (ultrasound) (Romer 1996).
3.6 Endometrial thickness (descriptive data) (Rai 2000).
Romer 1996 reported a significant difference in the thickness of the endometrium (MD ‐2.8 mm, 95% CI ‐3.6 to ‐2.0, 1 RCT, 20 women), but this was not confirmed by another small trial, for which results are described in narrative form with median and range (Rai 2000 in 'Other data' section of the review).
3.7 Women with atrophic endometrium on histology (Romer 1996; Rai 2000)
3.8 Women with optimal endometrial thinning by operator assessment (Romer 1996).
GnRHa pretreatment was associated with a greater likelihood of endometrial atrophy (as measured by histology) compared with progestogen pretreatment when the effects of one and two months of treatment were combined (RR 2.25, 95% CI 1.13 to 4.49, 2 RCTs, 70 women, I2 = 0%). No evidence indicated a significant difference in the proportion with optimal endometrial thinning as measured by operator assessment (RR 3.00, 95% CI 0.79 to 11.44, 1 RCT, 20 women).
Acceptability of use of endometrial thinning agents
Side effects were not measured in these studies.
3.9 Other surgical/postoperative outcome measures
Outcomes included duration of operation (Shawki 2002). Proportion of procedures in which operative difficulty was encountered, distension medium absorption during surgery, postoperative blood loss and postoperative dysmenorrhoea were not looked at in these studies.
The duration of surgery was significantly shorter after GnRHa pretreatment for one and three months before surgery in Shawki 2002 (one month MD ‐15 minutes, 95% CI ‐19.44 to ‐10.56, 1 RCT, 50 women; three months MD ‐17 minutes, 95% CI ‐20.90 to ‐13.10, 1 RCT, 53 women).
3.10 Quality of life
Outcomes assessed include proportion of women satisfied with outcome (Rai 2000). Participants were less likely to be satisfied (pleased or very pleased) with the outcome if they had undergone GnRHa pretreatment when compared with progestogen pretreatment (RR 0.8, 95% CI 0.65 to 0.99, 1 RCT, 20 women).
4. Comparison of GnRH analogues with GnRH antagonists
Primary outcomes
4.1 Surgical outcome measures
Intraoperative complications were assessed (Bhatia 2008).
The same number of intraoperative complications was reported for the two groups (Analysis 4.1).
4.2 Effectiveness of endometrial thinning agents on outcome of endometrial resection or ablation as a surgical treatment for menorrhagia
These outcomes included the following.
4.2 Women with amenorrhoea within 12 months (Bhatia 2008).
4.3 Women with amenorrhoea and/or hypomenorrhoea at 12 months or less (Bhatia 2008).
No statistically significant difference was noted between the two groups in terms of the proportion of women with amenorrhoea within 12 months of treatment (RR 0.95, 95% CI 0.79 to 1.14, 1 RCT, 100 women) (Analysis 4.3) or the proportion of women with amenorrhoea and/or hypomenorrhoea within 12 months of treatment (RR 0.94, 95% CI 0.83 to 1.06, 1 RCT, 100 women) (Analysis 4.3).
4.4 Proportion of women requiring or requesting further surgical therapy during follow‐up
This included the outcome of proportion of women requiring further surgery during follow‐up (Bhatia 2008). No statistically significant difference was noted between the two groups in terms of proportion of women requiring further surgery at six‐month follow‐up (RR 1.33, 95% CI 0.31 to 5.65, 1 RCT, 100 women) (Analysis 4.4).
Secondary Outcomes
4.5 Endometrial outcome measures
Outcomes included endometrial thickness (ultrasound) (Bhatia 2008). Proportion with atrophic endometrium on histology and proportion with optimal endometrial thinning by operator assessment were not assessed.
The endometrium was significantly thinner after GnRH analogue pretreatment than after GnRH antagonist pretreatment, both when hyperplasia was included (MD 0.54 mm, 95% CI 0.17 to 0.91, 1 RCT, 88 women) and when hyperplasia was excluded (MD 0.53 mm, 95% CI 0.22 to 0.84, 1 RCT, 83 women).
4.6 Acceptability of use of endometrial thinning agents
Side effects were measured in one study (Bhatia 2008). More episodes of hot flushes were reported in the GnRH analogue group (15/50) than in the GnRH anatagonist group (6/50), and this was statistically significant (RR 0.40, 95% CI 0.17 to 0.95, 1 RCT, 100 women). Differences between the groups in terms of skin irritation and non‐specific adverse effects were not statistically significant.
4.7 Other surgical/postoperative outcomes measures
Outcomes included the following.
4.7 Duration of operation (Bhatia 2008).
No significant difference was noted in the duration of operation between GnRH analogues compared with GnRH antagonists (MD 2.26, 95% CI ‐1.11 to 5.63, 1 RCT, 100 women).
4.8 Distension medium absorption during surgery (Bhatia 2008).
Distension medium absorption during surgery was provided as median values with a range, and no significant difference was noted between the two treatments.
4.9 Procedures with good operative view (Bhatia 2008).
No significant difference was noted in the proportion of women with a good operative view between the two treatments (RR 0.96, 95% CI 0.89 to 1.04, 1 RCT, 100 women).
4.10 Women with postoperative dysmenorrhoea (Bhatia 2008). Postoperative blood loss was not assessed.
The same proportion with postoperative dysmenorrhoea was reported in both groups.
4.11 Quality of life
Outcomes assessed include proportion of women satisfied with outcome (Bhatia 2008). No statistically significant difference was noted between the two groups in terms of the proportion of women satisfied with outcome (RR 0.93, 95% CI 0.81 to 1.07, 1 RCT, 100 women). Follow‐up was provided at six months after surgery.
5. Comparison of GnRH analogues with dilatation & curettage
Primary outcomes
5.1 Surgical outcome measures
Intraoperative complications were not looked at in these studies.
5.2 Effectiveness of endometrial thinning agents on outcome of endometrial resection or ablation as a surgical treatment for menorrhagia
These outcomes included the following.
5.2 Women with normal bleeding or less at 12 months (Vilos 2010).
5.3 Women with amenorrhoea at 12 months or less (Vilos 2010).
Evidence shows that an increased number of women in the GnRH analogue group had amenorrhoea at 12 months or less (RR 20.13, 95% CI 1.21 to 333.63, 1 RCT, 92 women, low quality evidence) (Analysis 5.3). No evidence of a significant difference between groups was found for the proportion of women with normal bleeding or less at 12 months (RR 1.03, 95% CI 0.91 to 1.16, 1 RCT, 92 women).
5.4 Proportion of women requiring or requesting further surgical therapy during follow‐up
This included the outcome of proportion of women requiring further surgery within 12 months of follow‐up (Vilos 2010). No evidence of a significant difference was found between groups for this outcome (RR 0.75, 95% CI 0.18 to 3.18, 1 RCT, 100 women) (Analysis 5.4).
Secondary outcomes
5.5 Endometrial outcome measures
Endometrial thickness, proportion with atrophic endometrium on histology and proportion with optimal endometrial thinning by operator assessment were not assessed.
5.6 Acceptability of use of endometrial thinning agents
The proportion of women with premenstrual syndrome (PMS) symptoms was assessed, and no evidence of a statistically significant difference between the two groups was found in Vilos 2010 (RR 1.03, 95% CI 0.67 to 1.58, 1 RCT, 93 women).
5.7 Other surgical/postoperative outcome measures
Outcomes assessed included proportion with postoperative dysmenorrhoea (Vilos 2010). Duration of operation, distension medium absorption during surgery postoperative blood loss and proportion of procedures with good operative view were not looked at.
No statistically significant difference was reported between the two pretreatment groups in terms of the proportion of women with postoperative dysmenorrhoea (RR 1.00, 95% CI 0.66 to 1.52, 1 RCT, 92 women).
5.8 Quality of life
Outcomes assessed include proportion of women satisfied with outcome (Vilos 2010). No statistically significant difference in this outcome was observed between the two groups (RR 0.94, 95% CI 0.83 to 1.05, 1 RCT, 92 women).
6. Comparison of danazol with placebo or no pretreatment
Primary outcomes
6.1 Surgical outcome measures
Intraoperative complications were not assessed in these studies.
6.2 Effectiveness of endometrial thinning agents on outcome of endometrial resection or ablation as a surgical treatment for menorrhagia
These outcomes included the following.
6.2 Women with amenorrhoea at 12 months or less (Rai 2000; Kriplani 2002).
No evidence of a significant difference was noted between groups for proportion of women with amenorrhoea at 12 months or less (RR 1.05, 95% CI 0.80 to 1.39, 2 RCTs, 179 women, I2 = 14%) (Figure 11).
Forest plot of comparison: 6 Danazol versus no pretreatment, outcome: 6.2 Postoperative amenorrhoea at 12 months or less.
6.3 Women with amenorrhoea at two years or more (Romer 1996; Kriplani 2002).
Findings were similar for proportions of women with amenorrhoea at two years or more (RR 1.27, 95% CI 0.79 to 2.04, 2 RCTs, 81 women, I2 = 55%) (Figure 12).
Forest plot of comparison: 6 Danazol versus no pretreatment, outcome: 6.3 Postoperative amenorrhoea at two years or more.
6.4 Proportion of women requiring or requesting further surgical therapy during follow‐up
This included the outcome of proportion of women requiring further surgery at two years or more (Romer 1996; Kriplani 2002). No evidence revealed a significant difference between the two groups for proportion of women requiring further surgery at two years or more (RR 1.37, 95% CI 0.28 to 6.69, 2 RCTs, 152 women, I2 = 0%) (Figure 13).
Forest plot of comparison: 6 Danazol versus no pretreatment, outcome: 6.4 Requiring further surgery at two years or more.
Secondary outcomes
6.5 Endometrial outcome measures
6.5 Endometrial thickness (by ultrasound) (Romer 1996; Kriplani 2002).
6.6 Endometrial thickness (descriptive data) (Rai 2000).
All studies separately reported a significantly thinner endometrium after danazol pretreatment compared with no pretreatment (trials unable to be pooled because of extreme heterogeneity and non‐normal distribution of data) with differences between groups ranging between 0.5 mm and 8 mm.
6.7 Women with atrophic endometrial glands (Romer 1996; Rai 2000)
Participants taking danazol pretreatment were more likely to have atrophic endometrial glands (RR 3.15, 95% CI 1.46 to 6.80, 2 RCTs, 70 women, I2 = 63%).
6.8 Women with optimal endometrial thinning by operator assessment (Romer 1996)
A trend towards greater optimal endometrial thinning (by operator assessment) was observed in this one small study (RR 6.00, 95% CI 0.87 to 41.21, 1 RCT, 20 women).
6.9 Acceptability of use of endometrial thinning agents
Side effects were not assessed.
6.10 Other surgical/postoperative outcome measures
Outcomes assessed included the following.
6.10 Duration of operation (English 1998; Kriplani 2002).
With overall results pooling, duration of surgery was significantly shorter with danazol pretreatment but with significant heterogeneity (MD ‐6.84 minutes, 95% CI ‐7.97 to ‐5.72, 2 RCTs, 157 women, I2 = 94%).
6.11 Distension medium absorption during surgery (English 1998; Kriplani 2002).
Overall benefit was noted for danazol in fluid absorption during surgery (MD‐109.45 mL, 95% CI ‐193.3 to ‐25.7, 2 RCTs, 156 women, I2 = 0%).
Proportion of procedures with good operative view, proportion with postoperative dysmenorrhoea and postoperative blood loss were not assessed.
6.12 Quality of life
Outcomes assessed include proportion of women satisfied with outcome (Rai 2000). No statistically significant difference in this outcome was noted between the two groups (RR 1.00, 95% CI 0.93 to 1.08, 1 RCT, 50 women).
7. Comparison of progestogens with placebo or no pretreatment
Primary outcomes
7.1 Surgical outcome measures
Intraoperative complications were not assessed in the included studies.
7.2 Effectiveness of endometrial thinning agents on outcome of endometrial resection or ablation as a surgical treatment for menorrhagia
These outcomes included the following.
7.2 Women with amenorrhoea at 12 months or less (Rai 2000).
7.3 Women with postoperative amenorrhoea at two to four years (Romer 1996; Kriplani 2001).
No evidence of a significant difference was seen between groups in either of the above outcomes—proportion of women with amenorrhoea at 12 months or less (RR 0.54, 95% CI 0.26 to 1.12, 1 RCT, 50 women) (Analysis 7.3) and proportion of women with amenorrhoea at two to four years (RR 0.75, 95% CI 0.36 to 1.54, 2 RCTs, 70 women, I2 = 0%) (Figure 14).
Forest plot of comparison: 7 Progestogens versus no pretreatment, outcome: 7.3 Postoperative amenorrhoea at two to four years.
7.4 Proportion of women requiring or requesting further surgical therapy during follow‐up
This included the outcome of proportion of women requiring further surgery at two to four years of follow‐up (Romer 1996; Kriplani 2001). No evidence of a significant difference between groups was noted for this outcome (RR 3.00, 95% CI 0.50 to 17.95, 2 RCTs, 70 women, I2 = 0.23) (Figure 15).
Forest plot of comparison: 7 Progestogens versus no pretreatment, outcome: 7.4 Requiring further surgery at two to four years.
Secondary outcomes
7.5 Endometrial outcome measures
7.5 Endometrial thickness (by ultrasound) (Romer 1996).
7.6 Endometrial thickness (descriptive data) (Rai 2000).
7.7 Women with atrophic endometrial glands (Romer 1996; Rai 2000).
7.8 Women with optimal endometrial thinning by operator assessment (Romer 1996).
These were assessed, and no evidence was found of a significant difference in any of the endometrial outcome measures.
7.9 Acceptability of use of endometrial thinning agents
Side effects were not assessed.
7.10 Other surgical/postoperative outcomes
None of the included studies assessed any of these outcomes.
7.11 Quality of life
Outcome assessed was women satisfied with outcome (Rai 2000). No statistically significant difference in this outcome was noted between the two groups (RR 1.00, 95% CI 0.93 to 1.08, 1 RCT, 50 women).
8. Comparison of danazol with progestogens
Primary outcomes
8.1 Surgical outcome measures
Intraoperative complications were not looked at.
8.2 Effectiveness of endometrial thinning agents on outcome of endometrial resection or ablation as a surgical treatment for menorrhagia
These outcomes included the following.
8.2 Women with amenorrhoea at 12 months or less (Rai 2000; Shawki 2002).
Participants having danazol pretreatment were more likely to have amenorrhoea up to 12 months after surgery (RR 1.89, 95% CI 1.12 to 3.18, 2 RCTs, 103 women, I2 = 16%) (Figure 16).
Forest plot of comparison: 8 Danazol versus progestogens, outcome: 8.2 Postoperative amenorrhoea at 12 months or less.
8.3 Women with postoperative amenorrhoea at two years (Romer 1996).
One small study showed no evidence of a significant difference between the two groups for proportion of women with postoperative amenorrhoea at two years (RR 3.00, 95% CI 0.79 to 11.44, 1 RCT, 20 women) (Figure 17).
Forest plot of comparison: 9 GnRHa or danazol versus no pretreatment, outcome: 9.2 Postoperative amenorrhoea at 12 months or less.
8.4 Proportion of women requiring or requesting further surgical therapy during follow‐up
This included the outcome of proportion of women requiring further surgery at two years of follow‐up (Romer 1996). No evidence of a significant difference between groups for this outcome was found in one small study (RR 1.00, 95% CI 0.07 to 13.87, 1 RCT, 20 women) (Analysis 8.3).
Secondary outcomes
8.5 Endometrial outcome measures
8.5 Endometrial thickness (by ultrasound) (Romer 1996).
8.6 Endometrial thickness (descriptive data) (Rai 2000).
The endometrium was significantly thinner after danazol pretreatment when compared with after progestogen pretreatment in one very small study (Romer 1996) (MD ‐3.00, 95% CI ‐3.76 to ‐2.24, 1 RCT, 20 women), but this was not confirmed by another study (Rai 2000), with data showing no significant difference (in the 'Other data' section of the review).
8.7 Women with atrophic endometrial glands (Romer 1996; Rai 2000)
Participants given danazol pretreatment were more likely to have atrophic endometrial glands than those given progestogen pretreatment (RR 2.50, 95% CI 1.27 to 4.92, 2 RCTs, 70 women, I2 = 0%).
8.8 Women with optimal endometrial thinning by operator assessment (Romer 1996)
No evidence indicated that optimal endometrial thinning rates differed between groups in one very small trial (RR 3.00, 95% CI 0.79 to 11.44, 1 RCT, 20 women).
8.9 Acceptability of use of endometrial thinning agents
Side effects were not assessed.
8.10 Other surgical/postoperative outcomes
Outcomes assessed included duration of operation (Shawki 2002).
Distension medium absorption during surgery, proportion of procedures with good operative view, proportion with postoperative dysmenorrhoea and postoperative blood loss were not assessed.
Duration of surgery was significantly shorter after danazol pretreatment for three months than after progestogen pretreatment (MD ‐11.00, 95% CI ‐14.59 to ‐7.41, 1 RCT, 53 women).
8.11 Quality of life
Outcomes assessed include proportion of women satisfied with outcome (Rai 2000). No statistically significant difference in this outcome was noted between the two groups (RR 1.00, 95% CI 0.93 to 1.08, 1 RCT, 50 women).
9. Comparison of GnRH analogues or danazol with placebo or no pretreatment
Primary outcomes
9.1 Surgical outcome measures
Intraoperative complications were not looked at.
9.2 Effectiveness of endometrial thinning agents on outcome of endometrial resection or ablation as a surgical treatment for menorrhagia
These outcomes included the following.
9.2 Women with amenorrhoea at 12 months or less (Alborzi 2002; Jack 2005).
9.3 Women with postoperative amenorrhoea at five years (Jack 2005).
No significant difference was noted in the proportion of women with postoperative amenorrhoea at 12 months or less (RR 1.13, 95% CI 0.89 to 1.43, 2 RCTs, 280 women, I2 = 0%) (Analysis 9.3) or in the proportion with postoperative amenorrhoea at five years (RR 1.05, 95% CI 0.91 to 1.20, 1 RCT, 154 women) between women given a GnRH analogue or danazol versus no pretreatment (Analysis 9.3).
9.4 Improvement at five years (Jack 2005)
No difference between groups was observed in the proportion of women with bleeding improvement (light bleeding/amenorrhoea) at five years (RR 1.01, 95% CI 0.98 to 1.05, 1 RCT, 154 women).
9.5 Proportion of women requiring or requesting further surgical therapy during follow‐up
This included the following.
9.5 Women requiring further surgery at one‐year follow‐up (Jack 2005).
9.6 Women requiring further surgery at five‐year follow‐up (Jack 2005). No evidence showed a significant difference between groups for proportion of women requiring further surgery at one year (RR 0.97, 95% CI 0.06 to 15.29, 1 RCT, 197 women) (Analysis 9.5) or for proportion of women requiring further surgery at five years (RR 0.73, 95% CI 0.32 to 1.65, 1 RCT, 197 women) (Analysis 9.6).
Secondary outcomes
9.7 Endometrial outcome measures
Endometrial thickness (by ultrasound) (Jack 2005) was assessed. Proportion with atrophic endometrial glands and proportion with optimal endometrial thinning by operator assessment were not assessed.
The endometrium was significantly thinner after GnRH analogues or danazol pretreatment than with no pretreatment (MD ‐1.9 mm, 95% CI ‐2.54 to ‐1.26, 1 RCT, 197 women).
9.8 Acceptability of use of endometrial thinning agents
Side effects, including hot flushes, nausea, rashes or itch and weight gain, were assessed (Jack 2005). Side effects were significantly more likely with endometrial thinning treatment with danazol or GnRH analogue than with no pretreatment.
9.9 Other surgical/postoperative outcome measures
Outcomes assessed included the following.
9.9 Duration of operation (Alborzi 2002; Jack 2005).
Duration of surgery was compared in subgroups according to whether first‐ or second‐generation ablation was undertaken. In the trial in which women underwent TCRE and rollerball surgery, participants given pretreatment with GnRH analogues or danazol had significantly shorter surgery than those not given pretreatment (MD ‐15 minutes, 95% CI ‐16.87 to ‐13.13, 1 RCT, 90 women). In the trial in which women underwent microwave surgery, no significant difference in procedure time was noted between groups (MD 0.40 minutes, 95% CI ‐0.89 to 1.69, 1 RCT, 197 women).
9.10 Postoperative blood loss at five years (Jack 2005).
No difference was noted between groups in the proportion of women with postoperative menorrhagia (RR 0.81, 95% CI 0.22 to 2.93, 2 RCTs, 280 women, I2 = 0%).
Distension medium absorption during surgery, proportion of procedures with good operative view and proportion with postoperative dysmenorrhoea were not assessed.
9.11 Quality of life
Outcomes assessed included the following.
9.11 Women satisfied with outcome at 12 months (Jack 2005).
9.12 Women satisfied with outcome at five years of follow‐up (Jack 2005).
No statistically significant difference in this outcome was observed between the two groups at 12 months (RR 0.96, 95% CI 0.87 to 1.05, 1 RCT, 188 women) or at five years (RR 0.94, 95% CI 0.83 to 1.06, 1 RCT, 154 women).
Sensitivity Analysis
Sensitivity analysis could not be performed because insufficient studies were entered into the meta‐analyses. As the review is updated with additional trials, it may be possible in the future to assess the robustness of the results by sensitivity analysis.
Discussion
Summary of main results
We are unable to determine whether the use of pre‐operative endometrial thinning agents reduces the risk of complications, as the complication risk, specifically, uterine perforation, is so uncommon that further randomised trials would have to be of an unfeasibly large size to demonstrate any small differences. Useful information can be drawn from the MISTLETOE study, the largest published audit of more than 10,000 endometrial resections (Overton 1997), in which the use of endometrial thinning agents was not associated with any reduction in complication rates.
One possible advantage of being able to operate with a consistently thinned endometrium is a more reliable postoperative result. Combining the results of all postoperative outcome measures is difficult because several methods of evaluating postoperative results have been used, and some studies have not reported non‐significant data in any detail. However, postoperative amenorrhoea is one measure of postoperative outcome that has been consistently reported by different studies, irrespective of the method used to evaluate postoperative menstrual loss. Good evidence suggests that administration of GnRH analogues before surgery results in higher rates of postoperative amenorrhoea at 12 and 24 months compared with placebo or no treatment. Whether this difference is maintained after two or three years is uncertain, as few women taking part in randomised trials have been followed up for this length of time.
Analysis of the randomised controlled trials included in this review shows that use of GnRH analogues before endometrial destruction surgery results in slightly shorter operating time and a reduction in intraoperative distension medium absorption. The reduction in operating time is relatively small in terms of the effect it may have on the cost of the procedure (i.e. mean reduction of 3.5 minutes) and may not be clinically significant, but it is a reflection of the increased ease of surgery produced by the use of GnRH analogues. The use of GnRH analogues also more reliably results in a thinner endometrium than when surgery is timed to the immediate postmenstrual phase of the menstrual cycle.
Using GnRH analogues rather than no therapy also reduces the proportion of women who continue to experience heavy menstrual loss postoperatively. It is interesting to note that these postoperative differences are not apparent when participant satisfaction rates are compared. This may be true because the proportion of women expressing satisfaction with the surgery is high, irrespective of whether endometrial preparation is used, or because the determinants of participant satisfaction are rather more complex than just amenorrhoea alone. Similarly, the proportion of women undergoing further surgery seems to be unaffected by the use of GnRH analogues. More long‐term follow up studies are needed to assess the effects of endometrial thinning with GnRH analogues on outcomes after three years.
Only published trials of small sample sizes have compared danazol with no pretreatment or placebo, as its value can be assessed only from trials that have compared it with GnRH analogues. In these comparisons, some differences are seen in favour of GnRH analogues, but their clinical significance is small. More consistent induction of endometrial atrophy is seen, although this does not appear to have any great impact on operating time, distension medium absorption, the proportion of procedures in which difficulty is encountered or participant satisfaction. GnRH analogues are shown to increase the proportion of women with postoperative amenorrhoea to a greater extent than danazol, but, as previously mentioned, the study populations for danazol are small, and it is uncertain whether further trials with larger populations will show danazol to be equivalent to GnRH analogues in increasing postoperative amenorrhoea.
Given these small differences, compliance, side effects and costs may be more important. Depot preparations of GnRH analogues are certainly associated with better patient compliance, although this is at least in part a reflection of the impossibility of removing them, whereas an oral preparation can be easily discontinued. Women should be advised that although the spectrum of side effects will vary, both GnRH analogues and danazol are likely to produce side effects in a significant proportion of women, particularly if used for two months. As GnRH analogue use appears to be beneficial, add‐back estrogen therapy may have a role in enabling women to tolerate the side effects of GnRH analogues. Danazol appears to have a worse side effect profile than GnRH analogues. Evidence for the use of GnRH analogues is more substantial and is of better quality than evidence for any of the other medications that have been looked at in this review.
Cost would be one factor that would make the use of progestogens attractive, as they are significantly cheaper than both GnRH analogues and danazol. However, pretreatment with lynestrenol or MPA had no beneficial effects on thinning of the endometrium or on postoperative amenorrhoea or satisfaction rates in this review. Few data are available from randomised trials to support their use, and no trial, either unpublished or in progress, is evaluating their use. Observational studies that have included women treated with progestogens have reported disappointing effects. If progestogens are to be used at all, this should occur only within the context of a trial undertaken to formally evaluate them. No studies have investigated estrogen‐progestin contraception as a pre‐operative endometrial thinning agent; a future trial could be considered to evaluate this.
Only 3 studies with a total of 345 women used second‐generation endometrial ablation techniques; although the study sizes were small, the results suggest that pre‐operative endometrial thinning agents given before second‐generation endometrial ablation techniques are performed do not significantly reduce operation time or the proportion of women with postoperative amenorrhoea. This is important, as many hospitals are moving towards these techniques for endometrial ablation rather than using the hysteroscopic techniques.
Overall completeness and applicability of evidence
Overall, the included studies addressed the review question, which was to look at effectiveness and safety of pre‐operative endometrial thinning agents (GnRH agonists, danazol, estrogen‐progestin contraceptives and progestogens) versus another agent or versus placebo before endometrial destruction in premenstrual women with heavy menstrual bleeding. All studies included relevant participants, interventions and outcomes. Current practice and guidelines do not recommend routine use of pre‐operative endometrial thinning agents before endometrial destruction. The findings of this review show that the use of GnRH analogues and danazol before endometrial resection and ablation can improve the intrauterine operating environment and postoperative amenorrhoea at 12 and 24 months, but that their benefits in the long term are less certain, and side effects may limit their usefulness. Use of these agents should be assessed on a case‐by‐case basis by the clinician involved in the care of the woman. This review should inform future practice and guidelines. Insufficient studies on progestogens were identified, and no studies on the estrogen‐progestin contraceptive were found; thus, there is room to further update this review in the future.
Quality of the evidence
Low‐quality evidence from clinical trials shows the effects of GnRH analogues used before endometrial thinning, as outlined above, as more than half the trials included no blinding of participants or outcome assessment. Most of the trials had uncertain selection and reporting bias, as they did not report allocation concealment and had selective reporting. Moderate heterogeneity was noted across the studies, and only one trial was of good quality. No RCTs of any significant size have compared danazol with no treatment versus placebo; this reduces the quality of evidence obtained when danazol was looked at as pretreatment. Substantial heterogeneity was observed in the studies that included danazol as pretreatment. Studies looking at progestogens as pretreatment were not of significant size, and none of the studies were blinded or reported blinding; thus, evidence was of low quality. Two studies reported a pharmaceutical company as a source of funding, and this was an uncertain source of bias.
Potential biases in the review process
No potential biases were identified in the review process, as any disagreements between the two review authors (YHT and AL) involved in screening and analysing studies were resolved by discussion.
Agreements and disagreements with other studies or reviews
This updated review agrees with the previous version of the same review published in 2002 but with some additional conclusions. However, larger studies with longer‐term follow‐up than three years could make a difference in the results of this review in the future.
Study flow diagram for 2002 to 2013 searches.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.1 Intraoperative complications—uterine perforation.
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.2 Postoperative amenorrhoea at 12 months or less.
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.3 Postoperative amenorrhoea at 24 months or longer.
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.4 Requiring further surgery within 12 months of follow‐up.
Forest plot of comparison: 1 GnRH analogues versus placebo or no treatment, outcome: 1.5 Requiring further surgery ≥ 24 months of follow‐up.
Forest plot of comparison: 2 GnRH analogues versus danazol, outcome: 2.2 Postoperative amenorrhoea at 12 months or less.
Forest plot of comparison: 3 GnRH analogues versus progestogens, outcome: 3.2 Postoperative amenorrhoea at 12 months or less.
Forest plot of comparison: 6 Danazol versus no pretreatment, outcome: 6.2 Postoperative amenorrhoea at 12 months or less.
Forest plot of comparison: 6 Danazol versus no pretreatment, outcome: 6.3 Postoperative amenorrhoea at two years or more.
Forest plot of comparison: 6 Danazol versus no pretreatment, outcome: 6.4 Requiring further surgery at two years or more.
Forest plot of comparison: 7 Progestogens versus no pretreatment, outcome: 7.3 Postoperative amenorrhoea at two to four years.
Forest plot of comparison: 7 Progestogens versus no pretreatment, outcome: 7.4 Requiring further surgery at two to four years.
Forest plot of comparison: 8 Danazol versus progestogens, outcome: 8.2 Postoperative amenorrhoea at 12 months or less.
Forest plot of comparison: 9 GnRHa or danazol versus no pretreatment, outcome: 9.2 Postoperative amenorrhoea at 12 months or less.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 1 Intraoperative complications—uterine perforation.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 2 Postoperative amenorrhoea at 12 months or less.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 3 Postoperative amenorrhoea at 24 months or longer.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 4 Requiring further surgery within 12 months of follow‐up.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 5 Requiring further surgery ≥ 24 months of follow‐up.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 6 Endometrial thickness (ultrasound, mm).
| Study | GnRHa | Control | Mann‐Whitney U test |
| two months of therapy | |||
| Donnez 1997 | n=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 2000 | n=25 Median: 1.5 mm Range: 1 ‐ 4 | n=25 Median:2 mm Range: 0.5 ‐ 4 | p=0.02 |
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 7 Endometrial thickness (descriptive data).
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 8 Atrophic endometrial glands.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 9 Optimal endometrial thinning (operator assessment).
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 10 Side effects.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 11 Duration of operation (minutes).
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 12 Where operative difficulty encountered.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 13 Distension medium absorption during surgery.
| Study | GnRHa | Placebo or no treatment | Test results |
| two months of therapy | |||
| Donnez 1997 | n=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 1 GnRH analogues versus placebo or no treatment, Outcome 14 Distension medium absorption during surgery (descriptive data).
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 15 Women with moderate/heavy postoperative blood loss.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 16 Postoperative dysmenorrhoea.
Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 17 Satisfaction with outcome.
Comparison 2 GnRH analogues versus danazol, Outcome 2 Postoperative amenorrhoea at 12 months or less.
Comparison 2 GnRH analogues versus danazol, Outcome 3 Postoperative amenorrhoea at 24 months.
Comparison 2 GnRH analogues versus danazol, Outcome 4 Requesting further surgery during follow‐up.
Comparison 2 GnRH analogues versus danazol, Outcome 5 Endometrial thickness (ultrasound).
| Study | GnRHa | Danazol | Test results |
| one month of therapy | |||
| Garry 1996 | n=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 1996 | n=38 Median: 0.5 mm Range: 0.5‐1.5 | n=32 Median: 0.5 Range 0.4‐1.5 | Results not reported |
| Rai 2000 | n=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 1994 | n=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 2 GnRH analogues versus danazol, Outcome 6 Endometrial thickness (descriptive data).
Comparison 2 GnRH analogues versus danazol, Outcome 7 Atrophic endometrial glands.
Comparison 2 GnRH analogues versus danazol, Outcome 8 Satisfactory thinning (hysteroscopy).
Comparison 2 GnRH analogues versus danazol, Outcome 9 Optimal endometrial thinning (operator assessment).
Comparison 2 GnRH analogues versus danazol, Outcome 10 Complete atrophy (hysteroscopy).
Comparison 2 GnRH analogues versus danazol, Outcome 11 Side effects.
Comparison 2 GnRH analogues versus danazol, Outcome 12 Weight gain.
Comparison 2 GnRH analogues versus danazol, Outcome 13 Duration of operation (minutes).
Comparison 2 GnRH analogues versus danazol, Outcome 14 Where operative difficulty encountered.
Comparison 2 GnRH analogues versus danazol, Outcome 15 Distension medium absorption during surgery.
Comparison 2 GnRH analogues versus danazol, Outcome 16 Postoperative blood loss—objective.
Comparison 2 GnRH analogues versus danazol, Outcome 17 Satisfaction with outcome.
Comparison 3 GnRH analogues versus progestogens, Outcome 2 Postoperative amenorrhoea at 12 months or less.
Comparison 3 GnRH analogues versus progestogens, Outcome 3 Postoperative amenorrhoea at 24 months.
Comparison 3 GnRH analogues versus progestogens, Outcome 4 Requiring further surgery at two years of follow‐up.
Comparison 3 GnRH analogues versus progestogens, Outcome 5 Endometrial thickness (ultrasound).
| Study | GnRHa | Progestogens | Mann‐Whitney U test |
| two months of therapy | |||
| Rai 2000 | n=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 3 GnRH analogues versus progestogens, Outcome 6 Endometrial thickness (descriptive data).
Comparison 3 GnRH analogues versus progestogens, Outcome 7 Endometrial atrophy (histology).
Comparison 3 GnRH analogues versus progestogens, Outcome 8 Optimal endometrial thinning (operator assessment).
Comparison 3 GnRH analogues versus progestogens, Outcome 9 Duration of operation (minutes).
Comparison 3 GnRH analogues versus progestogens, Outcome 10 Satisfaction with outcome.
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 1 Intraoperative complications.
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 2 Postoperative amenorrhoea at 12 months or less.
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 3 Postoperative amenorrhoea and/or hypomenorrhoea at 12 months or less.
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 4 Requiring further surgery within 12 months of follow‐up.
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 5 Endometrial thickness (ultrasound).
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 6 Side effects.
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 7 Duration of operation (minutes).
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 8 Good operative view.
| Study | GnRH antagonist | GnRH analogue | Mann‐Whitney U test |
| Bhatia 2008 | n=50 Median: 300 mL Range 0 to 2000 | n=50 Median: 250 mL Range 0 to 2000 | Mann‐Whitney test P = 0.641 |
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 9 Distension medium absorption during surgery.
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 10 Postoperative dysmenorrhoea.
Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 11 Satisfaction with outcome.
Comparison 5 GnRH analogue versus dilatation & curettage, Outcome 2 Normal bleeding or less at 12 months.
Comparison 5 GnRH analogue versus dilatation & curettage, Outcome 3 Postoperative amenorrhoea at 12 months or less.
Comparison 5 GnRH analogue versus dilatation & curettage, Outcome 4 Requiring further surgery within 12 months of follow‐up.
Comparison 5 GnRH analogue versus dilatation & curettage, Outcome 6 Side effects—presence of PMS symptoms.
Comparison 5 GnRH analogue versus dilatation & curettage, Outcome 7 Postoperative dysmenorrhoea.
Comparison 5 GnRH analogue versus dilatation & curettage, Outcome 8 Satisfaction with outcome.
Comparison 6 Danazol versus no pretreatment, Outcome 2 Postoperative amenorrhoea at 12 months or less.
Comparison 6 Danazol versus no pretreatment, Outcome 3 Postoperative amenorrhoea at two years or more.
Comparison 6 Danazol versus no pretreatment, Outcome 4 Requiring further surgery at two years or more.
Comparison 6 Danazol versus no pretreatment, Outcome 5 Endometrial thickness (ultrasound).
| Study | Danazol | Control | Mann‐Whitney U test |
| two months of therapy | |||
| Rai 2000 | n=25 Median: 1.5 mm Range: 1 ‐ 3.5 | n=25 Median: 2 mm Range: 0.5 ‐ 4 | p=0.02 |
Comparison 6 Danazol versus no pretreatment, Outcome 6 Endometrial thickness (descriptive data).
Comparison 6 Danazol versus no pretreatment, Outcome 7 Atrophic endometrial glands.
Comparison 6 Danazol versus no pretreatment, Outcome 8 Optimal endometrial thinning (operator assessment).
Comparison 6 Danazol versus no pretreatment, Outcome 10 Duration of operation (minutes).
Comparison 6 Danazol versus no pretreatment, Outcome 11 Distension medium absorption during surgery (mL).
Comparison 6 Danazol versus no pretreatment, Outcome 12 Satisfaction with outcome.
Comparison 7 Progestogens versus no pretreatment, Outcome 2 Postoperative amenorrhoea at 12 months or less.
Comparison 7 Progestogens versus no pretreatment, Outcome 3 Postoperative amenorrhoea at two to four years.
Comparison 7 Progestogens versus no pretreatment, Outcome 4 Requiring further surgery at two to four years.
Comparison 7 Progestogens versus no pretreatment, Outcome 5 Endometrial thickness (ultrasound).
| Study | Progestogens | No treatment | Mann‐Whitney U test |
| two months of therapy | |||
| Rai 2000 | n=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 7 Progestogens versus no pretreatment, Outcome 6 Endometrial thickness (descriptive data).
Comparison 7 Progestogens versus no pretreatment, Outcome 7 Atrophic endometrial glands.
Comparison 7 Progestogens versus no pretreatment, Outcome 8 Optimal endometrial thinning (operator).
Comparison 7 Progestogens versus no pretreatment, Outcome 11 Satisfaction with outcome.
Comparison 8 Danazol versus progestogens, Outcome 2 Postoperative amenorrhoea at 12 months or less.
Comparison 8 Danazol versus progestogens, Outcome 3 Postoperative amenorrhoea at two years.
Comparison 8 Danazol versus progestogens, Outcome 4 Requiring further surgery at two years of follow‐up.
Comparison 8 Danazol versus progestogens, Outcome 5 Endometrial thickness (ultrasound).
| Study | Danazol | Progestogens | Mann‐Whitney U test |
| two months of therapy | |||
| Rai 2000 | n=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 8 Danazol versus progestogens, Outcome 6 Endometrial thickness (descriptive data).
Comparison 8 Danazol versus progestogens, Outcome 7 Atrophic endometrial glands.
Comparison 8 Danazol versus progestogens, Outcome 8 Optimal endometrial thinning (operator).
Comparison 8 Danazol versus progestogens, Outcome 10 Duration of operation (minutes).
Comparison 8 Danazol versus progestogens, Outcome 11 Satisfaction with outcome.
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 2 Postoperative amenorrhoea at 12 months or less.
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 3 Amenorrhoea at five years.
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 4 Improvement (light bleeding/amenorrhoea) at five years.
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 5 Requiring further surgery at one year.
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 6 Requiring further surgery at five years.
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 7 Endometrial thickness (mm).
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 8 Side effects.
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 9 Duration of operation (minutes).
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 10 Postoperative menorrhagia.
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 11 Satisfaction with outcome at 12 months of follow‐up.
Comparison 9 GnRHa or danazol versus no pretreatment, Outcome 12 Satisfaction with outcome at five years.
| GnRH analogues compared with placebo or no treatment for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo or no treatment | GnRH analogues | |||||
| Postoperative amenorrhoea at 12 months or less | Study population | RR 1.58 | 605 | ⊕⊝⊝⊝ | ||
| 246 per 1000 | 389 per 1000 | |||||
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1Few studies were blinded, and only one study had good quality. | ||||||
| GnRH analogues compared with danazol for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Danazol | GnRH analogues | |||||
| Postoperative amenorrhoea at 12 months or less | 348 per 1000 | 408 per 1000 | RR 1.17 | 340 | ⊕⊝⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1No trials were blinded, and only one had adequate allocation concealment. | ||||||
| GnRH analogues compared with progestogens for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Progestogens | GnRH analogues | |||||
| Postoperative amenorrhoea at 12 months or less | 258 per 1000 | 408 per 1000 | RR 1.58 | 146 | ⊕⊝⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1One trial had adequate allocation concealment, and none reported blinding. | ||||||
| GnRH analogue compared with GnRH antagonist for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| GnRH antagonist | GnRH analogue | |||||
| Postoperative amenorrhoea at 12 months or less | 840 per 1000 | 798 per 1000 | RR 0.95 | 100 | ⊕⊕⊕⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1One trial with small population. | ||||||
| GnRH analogue compared with dilatation & curettage for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Dilatation & curettage | GnRH analogue | |||||
| Postoperative amenorrhoea at 12 months or less | 0 per 1000 | 0 per 1000 | RR 20.12 | 92 | 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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1No blinding of participants; selective reporting and small sample size in only one study. | ||||||
| Danazol compared with no pretreatment for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No pretreatment | Danazol | |||||
| Postoperative amenorrhoea at 12 months or less | 517 per 1000 | 543 per 1000 | RR 1.05 | 179 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1One trial had adequate description of randomisation, the other had adequate allocation concealment, but neither reported blinding. | ||||||
| Progestogens compared with no pretreatment for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No pretreatment | Progestogens | |||||
| Postoperative amenorrhoea at 12 months or less | 520 per 1000 | 281 per 1000 | RR 0.54 | 50 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1Adequate allocation concealment but not clear if blinded. | ||||||
| Danazol compared with progestogens for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Progestogens | Danazol | |||||
| Postoperative amenorrhoea at 12 months or less | 269 per 1000 | 509 per 1000 | RR 1.89 | 103 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1Only one of two trials had adequate allocation concealment, and neither trial reported blinding. | ||||||
| GnRHa or danazol compared with no pretreatment for heavy menstrual bleeding | ||||||
| Patient or population: women with heavy menstrual bleeding | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No pretreatment | GnRHa or danazol | |||||
| Postoperative amenorrhoea at 12 months or less | 428 per 1000 | 483 per 1000 | RR 1.13 | 280 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1One of two trials had adequate allocation concealment, but neither trial reported blinding. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Intraoperative complications—uterine perforation Show forest plot | 5 | 592 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.47 [0.35, 6.06] |
| 2 Postoperative amenorrhoea at 12 months or less Show forest plot | 7 | 605 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.58 [1.24, 2.01] |
| 2.1 one month of therapy | 3 | 89 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.80 [0.95, 3.40] |
| 2.2 two months of therapy | 4 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.54 [1.19, 2.01] |
| 3 Postoperative amenorrhoea at 24 months or longer Show forest plot | 2 | 357 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.62 [1.04, 2.52] |
| 3.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.79, 11.44] |
| 3.2 two months of therapy | 1 | 337 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.50 [0.94, 2.41] |
| 4 Requiring further surgery within 12 months of follow‐up Show forest plot | 4 | 488 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.53, 1.86] |
| 4.1 one month of therapy | 2 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.21, 1.97] |
| 4.2 two months of therapy | 2 | 419 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.20 [0.55, 2.61] |
| 5 Requiring further surgery ≥ 24 months of follow‐up Show forest plot | 2 | 319 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [0.97, 2.35] |
| 5.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 two months of therapy | 1 | 299 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [0.97, 2.35] |
| 6 Endometrial thickness (ultrasound, mm) Show forest plot | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐2.70 [‐3.49, ‐1.91] |
| 6.1 one month of therapy | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐2.70 [‐3.49, ‐1.91] |
| 7 Endometrial thickness (descriptive data) Show forest plot | Other data | No numeric data | ||
| 7.1 two months of therapy | Other data | No numeric data | ||
| 8 Atrophic endometrial glands Show forest plot | 4 | 483 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.02 [4.11, 8.81] |
| 8.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 15.0 [0.97, 231.84] |
| 8.2 two months of therapy | 3 | 463 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.84 [3.97, 8.58] |
| 9 Optimal endometrial thinning (operator assessment) Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.0 [0.87, 41.21] |
| 9.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.0 [0.87, 41.21] |
| 10 Side effects Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 10.1 hot flushes | 1 | 346 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.16 [2.24, 4.45] |
| 10.2 sweating | 1 | 346 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.08 [1.50, 6.32] |
| 10.3 headaches | 1 | 346 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.46 [1.02, 2.08] |
| 10.4 withdrawal from treatment due to side effects | 2 | 372 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.20 [0.35, 29.75] |
| 11 Duration of operation (minutes) Show forest plot | 6 | 502 | Mean Difference (IV, Fixed, 95% CI) | ‐3.62 [‐4.76, ‐2.49] |
| 11.1 one month of therapy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐13.60 [‐19.44, ‐7.76] |
| 11.2 two months of therapy | 5 | 463 | Mean Difference (IV, Fixed, 95% CI) | ‐3.23 [‐4.39, ‐2.07] |
| 12 Where operative difficulty encountered Show forest plot | 2 | 415 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.22, 0.46] |
| 12.1 one month of therapy | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 12.2 two months of therapy | 2 | 415 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.22, 0.46] |
| 13 Distension medium absorption during surgery Show forest plot | 4 | 137 | Mean Difference (IV, Fixed, 95% CI) | ‐154.53 [‐211.41, ‐97.65] |
| 13.1 one month of therapy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐149.0 [‐291.32, ‐6.68] |
| 13.2 two months of therapy | 3 | 98 | Mean Difference (IV, Fixed, 95% CI) | ‐155.59 [‐217.64, ‐93.53] |
| 14 Distension medium absorption during surgery (descriptive data) Show forest plot | Other data | No numeric data | ||
| 14.1 two months of therapy | Other data | No numeric data | ||
| 15 Women with moderate/heavy postoperative blood loss Show forest plot | 4 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.59, 0.92] |
| 15.1 one month of therapy | 2 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.22, 1.51] |
| 15.2 two months of therapy | 2 | 421 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.60, 0.94] |
| 16 Postoperative dysmenorrhoea Show forest plot | 2 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.40, 0.87] |
| 16.1 one month of therapy | 1 | 58 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.25, 1.07] |
| 16.2 two months of therapy | 1 | 75 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.63 [0.41, 0.98] |
| 17 Satisfaction with outcome Show forest plot | 6 | 599 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.93, 1.05] |
| 17.1 one month of therapy | 2 | 68 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.71, 1.16] |
| 17.2 two months of therapy | 4 | 531 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.94, 1.06] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2 Postoperative amenorrhoea at 12 months or less Show forest plot | 5 | 340 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.90, 1.52] |
| 2.1 one month of therapy | 2 | 91 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.60 [0.83, 3.11] |
| 2.2 two months of therapy | 3 | 174 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.78, 1.47] |
| 2.3 three months of therapy | 1 | 41 | Risk 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 | 1 | 34 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.42, 2.74] |
| 3 Postoperative amenorrhoea at 24 months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.49, 2.05] |
| 4 Requesting further surgery during follow‐up Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.02, 7.32] |
| 4.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.02, 7.32] |
| 5 Endometrial thickness (ultrasound) Show forest plot | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐0.46, 0.86] |
| 5.1 one month of therapy | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐0.46, 0.86] |
| 6 Endometrial thickness (descriptive data) Show forest plot | Other data | No numeric data | ||
| 6.1 one month of therapy | Other data | No numeric data | ||
| 6.2 two months of therapy | Other data | No numeric data | ||
| 7 Atrophic endometrial glands Show forest plot | 4 | 318 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.28 [1.03, 1.58] |
| 7.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.53, 1.46] |
| 7.2 two months of therapy | 3 | 298 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [1.06, 1.67] |
| 8 Satisfactory thinning (hysteroscopy) Show forest plot | 2 | 165 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [1.00, 1.19] |
| 8.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.75, 1.34] |
| 8.2 two months of therapy | 1 | 145 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [1.00, 1.21] |
| 9 Optimal endometrial thinning (operator assessment) Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.49, 2.05] |
| 9.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.49, 2.05] |
| 10 Complete atrophy (hysteroscopy) Show forest plot | 2 | 142 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.84 [1.23, 2.75] |
| 10.1 two months of therapy | 2 | 142 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.84 [1.23, 2.75] |
| 11 Side effects Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.1 hot flushes | 2 | 168 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.99 [1.50, 2.64] |
| 11.2 vaginal dryness | 2 | 168 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.16 [1.30, 3.59] |
| 11.3 depression | 2 | 168 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.89, 1.97] |
| 11.4 voice changes | 2 | 168 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.37, 1.65] |
| 11.5 hirsutism | 2 | 168 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.29, 2.08] |
| 11.6 decrease in libido | 2 | 168 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.15 [1.08, 4.28] |
| 11.7 headaches | 1 | 110 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.89 [1.23, 2.91] |
| 11.8 withdrawal from treatment due to side effects | 3 | 285 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.08 [0.01, 0.59] |
| 12 Weight gain Show forest plot | 1 | 58 | Mean Difference (IV, Fixed, 95% CI) | ‐2.3 [‐3.70, ‐0.90] |
| 13 Duration of operation (minutes) Show forest plot | 4 | 325 | Mean Difference (IV, Fixed, 95% CI) | ‐5.02 [‐6.25, ‐3.78] |
| 13.1 one month of therapy with GnRHa and danazol | 1 | 74 | Mean Difference (IV, Fixed, 95% CI) | ‐6.40 [‐9.16, ‐3.64] |
| 13.2 two months of therapy with GnRHa and danazol | 3 | 150 | Mean Difference (IV, Fixed, 95% CI) | ‐3.78 [‐5.92, ‐1.64] |
| 13.3 three months of therapy with GnRHa and danazol | 1 | 52 | Mean Difference (IV, Fixed, 95% CI) | ‐6.0 [‐8.24, ‐3.76] |
| 13.4 three months of danazol and one month of GnRHa | 1 | 49 | Mean Difference (IV, Fixed, 95% CI) | ‐4.0 [‐7.08, ‐0.92] |
| 14 Where operative difficulty encountered Show forest plot | 1 | 56 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.31, 1.51] |
| 14.1 two months of therapy | 1 | 56 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.31, 1.51] |
| 15 Distension medium absorption during surgery Show forest plot | 3 | 223 | Mean Difference (IV, Fixed, 95% CI) | ‐22.38 [‐87.07, 42.32] |
| 15.1 one month of therapy | 1 | 74 | Mean Difference (IV, Fixed, 95% CI) | ‐504.0 [‐776.80, ‐231.20] |
| 15.2 two months of therapy | 3 | 149 | Mean Difference (IV, Fixed, 95% CI) | 6.32 [‐60.27, 72.92] |
| 16 Postoperative blood loss—objective Show forest plot | 1 | 56 | Mean Difference (IV, Fixed, 95% CI) | ‐6.4 [‐9.19, ‐3.61] |
| 16.1 two months of therapy | 1 | 56 | Mean Difference (IV, Fixed, 95% CI) | ‐6.4 [‐9.19, ‐3.61] |
| 17 Satisfaction with outcome Show forest plot | 3 | 286 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.83, 1.01] |
| 17.1 one month of therapy | 1 | 71 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.90, 1.13] |
| 17.2 two months of therapy | 3 | 215 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.78, 1.01] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2 Postoperative amenorrhoea at 12 months or less Show forest plot | 3 | 146 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.58 [0.96, 2.61] |
| 2.1 one month of therapy | 2 | 57 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.84 [0.85, 3.98] |
| 2.2 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.57, 2.91] |
| 2.3 three months of therapy | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.55, 5.03] |
| 3 Postoperative amenorrhoea at 24 months Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.79, 11.44] |
| 3.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.79, 11.44] |
| 4 Requiring further surgery at two years of follow‐up Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.02, 7.32] |
| 4.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.02, 7.32] |
| 5 Endometrial thickness (ultrasound) Show forest plot | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐2.80 [‐3.59, ‐2.01] |
| 5.1 one month of therapy | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐2.80 [‐3.59, ‐2.01] |
| 6 Endometrial thickness (descriptive data) Show forest plot | Other data | No numeric data | ||
| 6.1 two months of therapy | Other data | No numeric data | ||
| 7 Endometrial atrophy (histology) Show forest plot | 2 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.25 [1.13, 4.49] |
| 7.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.5 [0.95, 12.90] |
| 7.2 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.83 [0.80, 4.19] |
| 8 Optimal endometrial thinning (operator assessment) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.79, 11.44] |
| 8.2 two months of therapy | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Duration of operation (minutes) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 9.1 one month of therapy | 1 | 50 | Mean Difference (IV, Fixed, 95% CI) | ‐15.0 [‐19.44, ‐10.56] |
| 9.2 three months of therapy | 1 | 53 | Mean Difference (IV, Fixed, 95% CI) | ‐17.0 [‐20.90, ‐13.10] |
| 10 Satisfaction with outcome Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.65, 0.99] |
| 10.1 one month of therapy | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 10.2 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.65, 0.99] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Intraoperative complications Show forest plot | 1 | 300 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.25, 3.92] |
| 1.1 uterine perforation | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.13, 71.92] |
| 1.2 traumatic dilatation of cervix | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.99] |
| 1.3 fluid deficit > 1500 mL | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.15, 6.82] |
| 2 Postoperative amenorrhoea at 12 months or less Show forest plot | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.79, 1.14] |
| 2.1 six months after surgery | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.79, 1.14] |
| 3 Postoperative amenorrhoea and/or hypomenorrhoea at 12 months or less Show forest plot | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.83, 1.06] |
| 3.1 six months after surgery | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.83, 1.06] |
| 4 Requiring further surgery within 12 months of follow‐up Show forest plot | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.31, 5.65] |
| 4.1 at six months of follow‐up | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.31, 5.65] |
| 5 Endometrial thickness (ultrasound) Show forest plot | 1 | 171 | Mean Difference (IV, Fixed, 95% CI) | 0.53 [0.29, 0.77] |
| 5.1 hyperplasia included | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | 0.54 [0.17, 0.91] |
| 5.2 hyperplasia excluded | 1 | 83 | Mean Difference (IV, Fixed, 95% CI) | 0.53 [0.22, 0.84] |
| 6 Side effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 hot flushes | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.4 [0.17, 0.95] |
| 6.2 skin irritation | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.67 [0.75, 9.47] |
| 6.3 nonspecific adverse effects | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.15, 6.82] |
| 7 Duration of operation (minutes) Show forest plot | 1 | 100 | Mean Difference (IV, Fixed, 95% CI) | 2.26 [‐1.11, 5.63] |
| 8 Good operative view Show forest plot | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.89, 1.04] |
| 9 Distension medium absorption during surgery Show forest plot | Other data | No numeric data | ||
| 10 Postoperative dysmenorrhoea Show forest plot | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.48, 2.09] |
| 11 Satisfaction with outcome Show forest plot | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.81, 1.07] |
| 11.1 at six months of follow‐up | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.81, 1.07] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2 Normal bleeding or less at 12 months Show forest plot | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.91, 1.16] |
| 2.1 at 12 months of follow‐up | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.91, 1.16] |
| 3 Postoperative amenorrhoea at 12 months or less Show forest plot | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 20.13 [1.21, 333.63] |
| 3.1 at 12 months of follow‐up | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 20.13 [1.21, 333.63] |
| 4 Requiring further surgery within 12 months of follow‐up Show forest plot | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.18, 3.18] |
| 4.1 at one year of follow‐up | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.18, 3.18] |
| 6 Side effects—presence of PMS symptoms Show forest plot | 1 | 93 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.67, 1.58] |
| 6.1 at one year of follow‐up | 1 | 93 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.67, 1.58] |
| 7 Postoperative dysmenorrhoea Show forest plot | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.66, 1.52] |
| 7.1 at one year of follow‐up | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.66, 1.52] |
| 8 Satisfaction with outcome Show forest plot | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.83, 1.05] |
| 8.1 at 12 months of follow‐up | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.83, 1.05] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2 Postoperative amenorrhoea at 12 months or less Show forest plot | 2 | 179 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.80, 1.39] |
| 2.1 one month of therapy | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.68, 1.34] |
| 2.2 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.82, 2.08] |
| 3 Postoperative amenorrhoea at two years or more Show forest plot | 2 | 81 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.79, 2.04] |
| 3.1 one month of therapy | 2 | 81 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.79, 2.04] |
| 4 Requiring further surgery at two years or more Show forest plot | 2 | 152 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.37 [0.28, 6.69] |
| 4.1 one month of therapy | 2 | 152 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.37 [0.28, 6.69] |
| 5 Endometrial thickness (ultrasound) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5.1 one month of therapy | 2 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Endometrial thickness (descriptive data) Show forest plot | Other data | No numeric data | ||
| 6.1 two months of therapy | Other data | No numeric data | ||
| 7 Atrophic endometrial glands Show forest plot | 2 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.15 [1.46, 6.80] |
| 7.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 17.0 [1.11, 259.87] |
| 7.2 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.0 [0.89, 4.49] |
| 8 Optimal endometrial thinning (operator assessment) Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.0 [0.87, 41.21] |
| 8.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.0 [0.87, 41.21] |
| 10 Duration of operation (minutes) Show forest plot | 2 | 157 | Mean Difference (IV, Fixed, 95% CI) | ‐6.84 [‐7.97, ‐5.72] |
| 10.1 one month of therapy | 1 | 132 | Mean Difference (IV, Fixed, 95% CI) | ‐7.90 [‐9.13, ‐6.67] |
| 10.2 two months of therapy | 1 | 25 | Mean Difference (IV, Fixed, 95% CI) | ‐1.30 [‐4.12, 1.52] |
| 11 Distension medium absorption during surgery (mL) Show forest plot | 2 | 156 | Mean Difference (IV, Fixed, 95% CI) | ‐109.45 [‐193.25, ‐25.65] |
| 11.1 one month of therapy | 1 | 132 | Mean Difference (IV, Fixed, 95% CI) | ‐119.90 [‐209.00, ‐28.80] |
| 11.2 two months of therapy | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | ‐52.0 [‐265.65, 161.65] |
| 12 Satisfaction with outcome Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.93, 1.08] |
| 12.1 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.93, 1.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2 Postoperative amenorrhoea at 12 months or less Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.54 [0.26, 1.12] |
| 2.1 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.54 [0.26, 1.12] |
| 3 Postoperative amenorrhoea at two to four years Show forest plot | 2 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.36, 1.54] |
| 3.1 one month of therapy | 2 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.36, 1.54] |
| 4 Requiring further surgery at two to four years Show forest plot | 2 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.50, 17.95] |
| 4.1 one month of therapy | 2 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.50, 17.95] |
| 5 Endometrial thickness (ultrasound) Show forest plot | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.78, 0.98] |
| 5.1 one month of therapy | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.78, 0.98] |
| 6 Endometrial thickness (descriptive data) Show forest plot | Other data | No numeric data | ||
| 6.1 two months of therapy | Other data | No numeric data | ||
| 7 Atrophic endometrial glands Show forest plot | 2 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.53, 3.25] |
| 7.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.0 [0.27, 92.62] |
| 7.2 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.37, 2.68] |
| 8 Optimal endometrial thinning (operator) Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.0 [0.21, 18.69] |
| 8.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.0 [0.21, 18.69] |
| 11 Satisfaction with outcome Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.93, 1.08] |
| 11.1 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.93, 1.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2 Postoperative amenorrhoea at 12 months or less Show forest plot | 2 | 103 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.89 [1.12, 3.18] |
| 2.1 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.43 [1.23, 4.81] |
| 2.2 three months of therapy | 1 | 53 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.58, 3.06] |
| 3 Postoperative amenorrhoea at two years Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.79, 11.44] |
| 3.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.79, 11.44] |
| 4 Requiring further surgery at two years of follow‐up Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.07, 13.87] |
| 4.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.07, 13.87] |
| 5 Endometrial thickness (ultrasound) Show forest plot | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐3.00 [‐3.76, ‐2.24] |
| 5.1 one month of therapy | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐3.00 [‐3.76, ‐2.24] |
| 6 Endometrial thickness (descriptive data) Show forest plot | Other data | No numeric data | ||
| 6.1 two months of therapy | Other data | No numeric data | ||
| 7 Atrophic endometrial glands Show forest plot | 2 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.5 [1.27, 4.92] |
| 7.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.0 [1.11, 14.35] |
| 7.2 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.0 [0.89, 4.49] |
| 8 Optimal endometrial thinning (operator) Show forest plot | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.79, 11.44] |
| 8.1 one month of therapy | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.79, 11.44] |
| 10 Duration of operation (minutes) Show forest plot | 1 | 53 | Mean Difference (IV, Fixed, 95% CI) | ‐11.0 [‐14.59, ‐7.41] |
| 10.1 three months of therapy | 1 | 53 | Mean Difference (IV, Fixed, 95% CI) | ‐11.0 [‐14.59, ‐7.41] |
| 11 Satisfaction with outcome Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.93, 1.08] |
| 11.1 two months of therapy | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.93, 1.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2 Postoperative amenorrhoea at 12 months or less Show forest plot | 2 | 280 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.89, 1.43] |
| 3 Amenorrhoea at five years Show forest plot | 1 | 154 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.91, 1.20] |
| 4 Improvement (light bleeding/amenorrhoea) at five years Show forest plot | 1 | 154 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.98, 1.05] |
| 5 Requiring further surgery at one year Show forest plot | 1 | 197 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.06, 15.29] |
| 6 Requiring further surgery at five years Show forest plot | 1 | 197 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.32, 1.65] |
| 7 Endometrial thickness (mm) Show forest plot | 1 | 197 | Mean Difference (IV, Fixed, 95% CI) | ‐1.9 [‐2.54, ‐1.26] |
| 8 Side effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 hot flushes | 1 | 197 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.95 [2.02, 4.31] |
| 8.2 nausea | 1 | 197 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.06 [1.22, 3.48] |
| 8.3 rashes/itch | 1 | 197 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.88 [1.34, 11.19] |
| 8.4 weight gain | 1 | 197 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.36 [1.42, 3.94] |
| 9 Duration of operation (minutes) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 9.1 TCRE + rollerball | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐15.0 [‐16.87, ‐13.13] |
| 9.2 microwave | 1 | 197 | Mean Difference (IV, Fixed, 95% CI) | 0.40 [‐0.89, 1.69] |
| 10 Postoperative menorrhagia Show forest plot | 2 | 280 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.22, 2.93] |
| 11 Satisfaction with outcome at 12 months of follow‐up Show forest plot | 1 | 188 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.87, 1.05] |
| 12 Satisfaction with outcome at five years Show forest plot | 1 | 154 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.83, 1.06] |
