Grading quality of evidence and strength of recommendations in clinical practice guidelines part 3 of 3. The GRADE approach to developing recommendations.

This is the third and last article in the series about the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grading the quality of evidence and the strength of recommendations in clinical practice guidelines and its application in the field of allergy. We describe the factors that influence the strength of recommendations about the use of diagnostic, preventive and therapeutic interventions: the balance of desirable and undesirable consequences, the quality of a body of evidence related to a decision, patients' values and preferences, and considerations of resource use. We provide examples from two recently developed guidelines in the field of allergy that applied the GRADE approach. The main advantages of this approach are the focus on patient important outcomes, explicit consideration of patients' values and preferences, the systematic approach to collecting the evidence, the clear separation of the concepts of quality of evidence and strength of recommendations, and transparent reporting of the decision process. The focus on transparency facilitates understanding and implementation and should empower patients, clinicians and other health care professionals to make informed choices.

Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions.

The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach provides guidance to grading the quality of underlying evidence and the strength of recommendations in health care. The GRADE system's conceptual underpinnings allow for a detailed stepwise process that defines what role the quality of the available evidence plays in the development of health care recommendations. The merit of GRADE is not that it eliminates judgments or disagreements about evidence and recommendations, but rather that it makes them transparent. This first article in a three-part series describes the GRADE framework in relation to grading the quality of evidence about interventions based on examples from the field of allergy and asthma. In the GRADE system, the quality of evidence reflects the extent to which a guideline panel's confidence in an estimate of the effect is adequate to support a particular recommendation. The system classifies quality of evidence as high, moderate, low, or very low according to factors that include the study methodology, consistency and precision of the results, and directness of the evidence.

Cyclical progestogens for heavy menstrual bleeding.

BACKGROUND: Excessively heavy menstrual bleeding (HMB) or menorrhagia is an important cause of ill health in women. Eighty per cent of women treated for HMB have no anatomical pathology, which makes medical therapy, with the avoidance of possibly unnecessary surgery, an attractive alternative. Of the wide variety of medications used to reduce heavy menstrual bleeding, oral progestogens are the most commonly prescribed. This review assesses the effectiveness of two different regimens of oral progestogens in reducing ovulatory HMB. OBJECTIVES: The primary objective of this review was to investigate the effectiveness of oral progestogen therapy taken either during the luteal phase or for a longer course of 21 days in achieving a reduction in menstrual blood loss in women of reproductive years with heavy menstrual bleeding (HMB). SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched April 2007), MEDLINE (1966 to April 2007) and EMBASE (1985 to April 2007). Attempts were also made to identify trials from citation lists of review articles. In most cases, the first author of each included trial was contacted. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of oral progestogen therapy versus placebo or other medical treatments in women of reproductive years with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic causes for their heavy menstrual blood loss. DATA COLLECTION AND ANALYSIS: Seven randomised controlled trials (RCTs) were identified that fulfilled the inclusion criteria. The review authors extracted the data independently. Odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes were estimated from the data. MAIN RESULTS: No RCTs comparing progestogen treatment with placebo were identified. Comparisons between oral progestogens and other medical therapies were assessed separately according to dosage regimen.Progestogen therapy during the luteal phase was significantly less effective at reducing menstrual blood loss when compared with tranexamic acid, danazol and the progesterone-releasing intrauterine system (IUS). Duration of menstruation was significantly longer with the progesterone IUS when compared with oral progestogen therapy but significantly shorter with danazol treatment. Adverse events were significantly more likely with danazol when compared with progestogen treatment. Progestogen therapy from day 5 to day 26 of the menstrual cycle was significantly less effective at reducing menstrual blood loss than the IUS. A significantly higher proportion of norethisterone (NET) patients taking progestogens found their treatment unacceptable compared to IUS patients. However, the adverse effects of breast tenderness and intermenstrual bleeding were more likely in women with the IUS. AUTHORS' CONCLUSIONS: Progestogens administered from day 15 or 19 to day 26 of the cycle offer no advantage over other medical therapies such as danazol, tranexamic acid, non-steroidal anti-inflammatory drugs (NSAIDs) and the IUS in the treatment of menorrhagia in women with ovulatory cycles. Progestogen therapy for 21 days of the cycle results in a significant reduction in menstrual blood loss, although women found the treatment less acceptable than intrauterine levonorgestrel. This regimen of progestogen may have a role in the short-term treatment of menorrhagia.

Hormone replacement therapy for cognitive function in postmenopausal women.

BACKGROUND: As estrogens have been found in animal models to be associated with the maintenance and protection of brain structures, it is biologically plausible that maintaining high levels of estrogens in postmenopausal women by medication could be protective against cognitive decline. OBJECTIVES: To investigate the effect of ERT (estrogens only) or HRT (estrogens combined with a progestagen) in comparison with placebo in RCTs on cognitive function in postmenopausal women. SEARCH STRATEGY: The CDCIG Specialized Register was searched 7 March 2006. Additional searches were made of MEDLINE (1966-2006/02); EMBASE (1985-2006/02); PsycINFO (1967-2006/02) and CINAHL (1982-2006/01). SELECTION CRITERIA: All double-blind RCTs trials of the effect of ERT or HRT on cognitive function over a treatment period of at least two weeks in postmenopausal women. DATA COLLECTION AND ANALYSIS: Selection of studies, assessment of quality and extraction of data were undertaken independently by three reviewers with disagreements resolved by discussion. MAIN RESULTS: In total, 24 trials were included, but only 16 (10,114 women) had analysable data. Meta-analyses showed no effects of either ERT or HRT on prevention of cognitive impairment after five and four years of treatment, respectively (odds ratio 1.34, 95% CI 0.95 to 1.9; odds ratio 1.05, 95% CI 0.72 to 1.54 respectively) (trend favouring control in both instances). Analyses assessing the effects of treatment over time found that both ERT and HRT did not maintain or improve cognitive function and may even adversely affect this outcome (WMD = -0.45, 95% CI -0.99 to 0.09; WMD = -0.16, 95% CI -0.58 to 0.26, respectively at maximum follow up). Negative effects were found for ERT after one year and HRT after three and four years of therapy. Results from smaller trials assessing effects on individual cognitive domains mostly reported no evidence of benefit. AUTHORS' CONCLUSIONS: There is good evidence that both ERT and HRT do not prevent cognitive decline in older postmenopausal women when given as short term or longer term (up to five years) therapy. It is not known whether either specific types of ERT or HRT have specific effects in subgroups of women, although there was evidence that combined hormone therapy in similarly aged women was associated with a decrement in a number of verbal memory tests and a small improvement in a test of figural memory. There is insufficient evidence to determine whether subgroups of women using specific types of hormone therapy could benefit from treatment. It remains to be determined whether factors such as younger age (< 60 years of age), type of menopause (surgical or natural) and type of treatment (type of estrogen with or without a progestagen), mode of delivery (transdermal, oral or intramuscular) and dosage have positive effects at a clinically relevant level. In addition, whether the absence or presence of menopausal symptoms can modify treatment effects should be investigated in more detail. Large RCTs currently underway in the USA may be able to provide answers to these uncertainties by the year 2010. In the meantime, based on the available evidence, ERT or HRT cannot be recommended for overall cognitive improvement or maintenance in older postmenopausal women without cognitive impairment.

Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Nonsteroidal anti-inflammatory drugs reduce prostaglandin levels which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea. OBJECTIVES: The primary objective of this review was to investigate the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) in achieving a reduction in menstrual blood loss in women of reproductive years HMB. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched April 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2007), MEDLINE (1966 to April 2007), EMBASE (1985 to April 2007), CINAHL (1982 to April 2007), Current Contents (1993 to April 2007) and reference lists of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of individual NSAIDs with either each other, placebo or other medical treatments in women with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic (treatment induced) causes for their heavy menstrual blood loss. DATA COLLECTION AND ANALYSIS: Seventeen RCTs were identified that fulfilled the inclusion criteria for this review and data were extracted independently. Odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes were estimated from the data of nine trials. The results of the remaining seven crossover trials with data unsuitable for pooling and one trial with skewed data were described in the Other Data section. MAIN RESULTS: As a group, NSAIDs were more effective than placebo at reducing heavy menstrual bleeding but less effective than either tranexamic acid, danazol or the levonorgestrel releasing intrauterine system (LNG IUS). Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs but this did not appear to affect the acceptability of treatment. There were no statistically significant differences between NSAIDs and the other treatments (oral luteal progestogen, ethamsylate, an older progesterone releasing intra-uterine system (Progestasert), oral contraceptive pill (OCC)) but most studies were underpowered. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. AUTHORS' CONCLUSIONS: NSAIDs reduce HMB when compared with placebo but are less effective than either tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, no significant difference in efficacy was demonstrated between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCC or another type of IUS, Progestasert.

Phytoestrogens for vasomotor menopausal symptoms.

BACKGROUND: Vasomotor symptoms, such as hot flushes and night sweats, are very common during the menopausal transition. Hormone replacement therapy has traditionally been used as a very effective treatment but concerns over increased risks of some chronic diseases have markedly increased the interest of women in alternatives. Some of the most popular of these are treatments based on foods or supplements enriched with phytoestrogens, plant-derived chemicals that have oestrogenic action. OBJECTIVES: To assess the efficacy, safety and acceptability of foods and supplements based on high levels of phytoestrogens for reducing hot flushes and night sweats in postmenopausal women. SEARCH STRATEGY: Searches were undertaken of the following electronic databases: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of randomised trials, Cochrane Register of Controlled Trials (CENTRAL) (March 2007), MEDLINE (1966 to March 2007), EMBASE (1980 to March 2007), AMED (1985 to March 2007), PsycINFO (1986 to March 2007) and CINAHL (1982 to March 2007). Attempts were made to access grey literature by letters to pharmaceutical companies and searches of ongoing trial registers. Reference lists of included trials were also searched. SELECTION CRITERIA: Studies were included if they were randomised, had peri- or postmenopausal participants with vasomotor symptoms, a duration of at least 12 weeks and where the intervention was a food or supplement with high levels of phytoestrogens (and not combined with other herbal treatments). Trials of women who had breast cancer or a history of breast cancer were excluded. DATA COLLECTION AND ANALYSIS: Selection of trials, data extraction and quality assessment were undertaken by at least two authors. Most of the trials were too dissimilar to combine in meta-analysis and their results are provided in table format. Studies were grouped into broad categories: dietary soy, soy extracts, red clover extracts and other types of phytoestrogen. Five trials used Promensil, a red clover extract; these trials were combined in a meta-analysis and summary effect measures were calculated. MAIN RESULTS: Thirty trials comparing phytoestrogens with control met the inclusion criteria. Very few trials had data suitable for combining in meta-analysis. Of the five trials with data suitable for pooling that assessed daily frequency of hot flushes, there was no significant difference overall in the frequency of hot flushes between Promensil (a red clover extract) and placebo (WMD=-0.6, 95% CI -1.8 to 0.6). There was no evidence of a difference in percentage reduction in hot flushes in two trials between Promensil and placebo (WMD=20.2, 95% CI -12.1 to 52.4). Individual results from the remaining trials were compared. Some of the trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared to placebo but many of the trials were of low quality and were underpowered. There was a strong placebo effect in most trials with a reduction in frequency ranging from 1% to 59% with placebo. There was no indication that the discrepant results were due to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms or trial quality factors. There was also no evidence that the treatments caused oestrogenic stimulation of the endometrium (an adverse effect) when used for up to two years. AUTHORS' CONCLUSIONS: There is no evidence of effectiveness in the alleviation of menopausal symptoms with the use of phytoestrogen treatments.

Danazol for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in pre menopausal women. Medical therapy, with the avoidance of possibly unnecessary surgery is an attractive treatment option, but there is considerable variation in practice and uncertainty about the most effective therapy. Danazol is a synthetic steroid with anti-oestrogenic and anti progestogenic activity, and weak androgenic properties. Danazol suppresses oestrogen and progesterone receptors in the endometrium, leading to endometrial atrophy (thinning of the lining of the uterus) and reduced menstrual loss and to amenorrhoea in some women. OBJECTIVES: To determine the effectiveness and tolerability of Danazol when used for heavy menstrual bleeding in women of reproductive years. SEARCH STRATEGY: We searched the Menstrual Disorders and Subfertility Group's Specialised Register (April 2007). We also searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 2, 2007), MEDLINE (1966 to April 2007), EMBASE (1980 to April 2007, CINAHL (1982 to April 2007). Attempts were also made to identify trials from citation lists of included trials and relevant review articles. SELECTION CRITERIA: Randomised controlled trials of Danazol versus placebo, any other medical (non-surgical) therapy or Danazol in different dosages for heavy menstrual bleeding in women of reproductive age with regular HMB measured either subjectively or objectively. Trials that included women with post menopausal bleeding, intermenstrual bleeding and pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Nine RCTs, with 353 women, were identified that fulfilled the inclusion criteria. Quality assessment and data extraction were performed independently by two reviewers. The main outcomes were menstrual blood loss, the number of women experiencing adverse effects, weight gain, withdrawals due to adverse effects and dysmenorrhoea. If data could not be extracted in a form suitable for meta-analysis, they were presented in a descriptive format. MAIN RESULTS: Most data were not in a form suitable for meta analysis, and the results are based on a small number of trials, all of which are under-powered. Danazol appears to be more effective than placebo, progestogens, NSAIDs and the OCP at reducing MBL, but confidence intervals were wide. Treatment with Danazol caused more adverse events than NSAIDs (OR 7.0; 95% CI 1.7 to 28.2) and progestogens (OR 4.05, 95% CI 1.6 to10.2). Danazol was shown to significantly lower the duration of menses when compared with NSAIDs (WMD -1.0; 95% CI -1.8 to -0.3) and a progesterone releasing IUD (WMD -6.0; 95% CI -7.3 to -4.8). There were no randomised trials comparing Danazol with tranexamic acid or the levonorgestrel-releasing intrauterine system. AUTHORS' CONCLUSIONS: Danazol appears to be an effective treatment for heavy menstrual bleeding compared to other medical treatments. The use of Danazol may be limited by its side effect profile, its acceptability to women and the need for continuing treatment. The small number of trials, and the small sample sizes of the included trials limit the recommendations for clinical care. Further studies are unlikely in the future and this review will not be updated unless further studies are identified.

Local oestrogen for vaginal atrophy in postmenopausal women.

BACKGROUND: Vaginal atrophy is a frequent complaint of postmenopausal women; symptoms include vaginal dryness, itching, discomfort and painful intercourse. Systemic treatment for these symptoms in the form of oral hormone replacement therapy is not always necessary. An alternative choice is oestrogenic preparations administered vaginally (in the form of creams, pessaries, tablets and the oestradiol-releasing ring). OBJECTIVES: The objective of this review was to compare the effectiveness, safety and acceptability of oestrogenic preparations for women who suffer from vaginal atrophy. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Register of trials (searched January 2006), The Cochrane Library (2006,Issue 2), MEDLINE (1966 to January 2006), EMBASE (1980 to January 2006), Current Contents (1993 to January 2006, Biological Abstracts (1969 to 2006), Social Sciences Index (1980 to January 2006), PsycINFO (1972 to February 2006), CINAHL (1982 to January 2006) and reference list of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of oestrogenic preparations administered intravaginally in postmenopausal women for the treatment of symptoms resulting from vaginal atrophy or vaginitis. DATA COLLECTION AND ANALYSIS: Thirty-seven trials were identified: of these 18 were excluded. Included trials were assessed for quality and two reviewer authors extracted data independently. The ratios for dichotomous outcomes and means for continuous outcomes were calculated. The outcomes analysed were categorised under the headings of: efficacy, safety and acceptability. MAIN RESULTS: Nineteen trials with 4162 women were included in this review. The overall quality of the studies was good, although not all trials measured the same outcomes. All trials measured efficacy, with various outcome measures. When comparing the efficacy of different oestrogenic preparations (in the form of creams, pessaries, tablets and the oestradiol-releasing vaginal ring) in relieving the symptoms of vaginal atrophy, results indicated significant findings favouring the cream, ring, and tablets when compared to placebo and non-hormonal gel. Fourteen trials compared safety. Four looked at hyperplasia, four looked at endometrial overstimulation and seven looked at adverse effects. One trial showed significant adverse effects of the cream (conjugated equine oestrogen) when compared to tablets (oestradiol) which included uterine bleeding, breast pain and perineal pain (1 RCT; OR 0.18, 95% CI 0.07 to 0.50). Two trials showed significant endometrial overstimulation as evaluated by a progestagen challenge test with the cream (conjugated equine oestrogen) group when compared to the ring (OR 0.29, 95% CI 0.11 to 0.78). Although not statistically significant there was a 2% incidence of simple hyperplasia in the ring group when compared to the cream (conjugated equine oestrogen) and 4% incidence of hyperplasia (one simple, one complex) in the cream group (conjugated equine oestrogen) when compared to the tablet (oestradiol). Eleven studies compared acceptability to the participants by comparing: comfort of product use, ease of use, overall product rating, delivery system and satisfaction. Results showed a significant preference for the oestradiol-releasing vaginal ring. AUTHORS' CONCLUSIONS: Creams, pessaries, tablets and the oestradiol vaginal ring appeared to be equally effective for the symptoms of vaginal atrophy. One trial found significant side effects following cream (conjugated equine oestrogen) administration when compared to tablets causing uterine bleeding, breast pain and perineal pain. Another trial found significant endometrial overstimulation following use of the cream (conjugated equine oestrogen) when compared to the ring. As a treatment choice women appeared to favour the oestradiol-releasing vaginal ring for ease of use, comfort of product and overall satisfaction.

Progesterone for Premenstrual Syndrome.

BACKGROUND: Premenstrual Syndrome (PMS) is the term for severe symptoms experienced by about 5% of menstruating women up to two weeks before their menstrual periods, but not at other times. Treatment with progesterone may restore a deficiency, or balance the level of progesterone with other menstrual hormones. Progesterone therapy may reduce the effects of falling progesterone levels on the brain or on electrolytes in the blood. OBJECTIVES: The objectives were to determine if progesterone has been found to be an effective treatment for all or some premenstrual symptoms, and if adverse events associated with this treatment have been reported. SEARCH STRATEGY: We last searched the Cochrane Menstrual Disorders and Subfertility Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2005), MEDLINE (1966 to 2005) and EMBASE (1980 to 2005) in March 2005, and PsycINFO (1806 to 2006) in April 2006. We contacted pharmaceutical companies for information about unpublished trials. SELECTION CRITERIA: We included randomised double-blind, placebo-controlled trials of progesterone on women with PMS diagnosed by at least two prospective cycles, without current psychiatric disorder. DATA COLLECTION AND ANALYSIS: Two reviewers (BM and OF) extracted data independently, and decided on the trials to be included. OF wrote to the trial investigators to ask for missing data. MAIN RESULTS: We considered 17 studies. We included two trials totaling 280 participants aged from 18 to 45 years. Of these 115 yielded analysable results. Both studies measured outcomes using subjective scales of symptom severity but made calculations as if they were interval data. The two studies differed in design, participants, dose of progesterone, how and when the dose was administered and in outcome measures. It was impossible to combine data in a meta-analysis. Adverse events which may or may not have been the side effects of the treatment, were generally described as mild. Both trials intended to exclude women whose symptoms continued after their periods; unfortunately the larger multicentre study had some ineligible participants. Overall, participants benefited more from progesterone than placebo. This was statistically significant in per protocol analysis but not in the intention-to-treat analysis, except for the first cycle. The smaller, crossover study found no statistically significant difference between oral progesterone, vaginally absorbed progesterone and placebo. AUTHORS' CONCLUSIONS: We could not say that progesterone helped women with PMS, nor that it was ineffective. Neither trial distinguished a subgroup of women who benefited.

Cost-effectiveness analysis of levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding.

OBJECTIVE: To compare the cost-effectiveness of levonorgestrel intrauterine system (LNG-IUS) (Mirena; Schering Co., Turku, Finland) and thermal balloon ablation (Thermachoicetrade mark; Gynecare Inc., Menlo Park, CA, USA) for the treatment of heavy menstrual bleeding. DESIGN: An open, pragmatic, prospective randomised trial. SETTING: A menstrual disorders clinic at National Women's Hospital, Auckland, New Zealand. POPULATION: Seventy-nine women with self-defined heavy menstrual bleeding randomised to the LNG-IUS (40 women) or the thermal balloon ablation (39 women). METHODS: Decision tree modelling using primary source data was used to identify the incremental cost-effectiveness of the two treatments. MAIN OUTCOME MEASURES: Direct and indirect costs of medical treatment, including treatment costs, subsequent medical procedures, lost income and medical treatment for failed procedures. The change in quality of life as assessed by the Short Form-36 (SF-36) measured between time of treatment and 24 months was the primary outcome measure. Economic modelling examined the expected cost and outcome for a woman entering each treatment. Sensitivity analysis explored the robustness of the results. RESULTS: The expected cost of treatment was $NZ1241 ($US869) for the LNG-IUS and $NZ2418 ($US1693) for the thermal balloon ablation. The LNG-IUS was associated with an increase of 15 points on the SF-36 scale, compared with 12 points for the thermal balloon ablation. Sensitivity analysis indicates that the results are robust to a 25% decrease in the price of the primary cost drivers and to variations in the rates of failed treatment between the conditions. CONCLUSION: The LNG-IUS would appear to be cost-effective when compared with the thermal balloon ablation for treatment of heavy menstrual bleeding.

Surgical approach to hysterectomy for benign gynaecological disease.

BACKGROUND: There are three approaches to hysterectomy for benign disease - abdominal hysterectomy (AH), vaginal hysterectomy (VH) and laparoscopic hysterectomy (LH). Laparoscopic hysterectomy has three further subdivisions - laparoscopic assisted vaginal hysterectomy (LAVH) where a vaginal hysterectomy is assisted by laparoscopic procedures that do not include uterine artery ligation, laparoscopic hysterectomy (which we will abbreviate to LH(a)) where the laparoscopic procedures include uterine artery ligation, and total laparoscopic hysterectomy (TLH) where there is no vaginal component and the vaginal vault is sutured laparoscopically. OBJECTIVES: To assess the most appropriate surgical approach to hysterectomy. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders & Subfertility Group's Specialised Register of controlled trials (searched 23 March 2004), CENTRAL (The Cochrane Library Issue 1, 2004), MEDLINE (1966 to Mar 2004), EMBASE (1985 to Mar 2004), Biological Abstracts (1968 to Mar 2004), the National Research Register and relevant citation lists. SELECTION CRITERIA: Only randomised trials comparing one surgical approach to hysterectomy with another were included. DATA COLLECTION AND ANALYSIS: Twenty-seven trials that included 3643 participants were included. Independent selection of trials and data extraction were employed following Cochrane guidelines. MAIN RESULTS: The benefits of VH versus AH were shorter duration of hospital stay (WMD 1.0 day, 95%CI 0.7 to 1.2 days), speedier return to normal activities (WMD 9.5 days, 95%CI 6.4 to 12.6 days), fewer unspecified infections or febrile episodes (OR 0.42, 95%CI 0.21 to 0.83). The benefits of LH versus AH were lower intraoperative bloodloss (WMD 45.3 mls, 95%CI 17.9 to 72.7 mls) and a smaller drop in haemoglobin level (WMD 0.55g/L, 95%CI 0.28 to 0.82g/L), shorter duration of hospital stay (WMD 2.0 days, 95%CI 1.9 to 2.2 days), speedier return to normal activities (WMD 13.6 days, 95%CI 11.8 to 15.4 days), fewer wound or abdominal wall infections (OR 0.32, 95%CI 0.12 to 0.85), fewer unspecified infections or febrile episodes (OR 0.65, 95%CI 0.49 to 0.87), at the cost of longer operating time (WMD 10.6 minutes, 95%CI 7.4 to 13.8 minutes) and more urinary tract (bladder or ureter) injuries (OR 2.61, 95%CI 1.22 to 5.60). There was no evidence of benefits of LH versus VH and the operating time was increased (WMD 41.5 minutes, 95%CI 33.7 to 49.4 minutes). There was no evidence of benefits of LH(a) versus LAVH and the operating time was increased for LH(a) (WMD 25.3 minutes, 95%CI 10.0 to 40.6 minutes). There was statistical heterogeneity in many of the outcome measures when randomised trials were pooled for meta-analysis. No other statistically significant differences were found. However, for some important outcomes, the analyses were underpowered to detect important differences, or they were simply not reported in trials. Data were notably absent for many important long-term outcome measures. AUTHORS' CONCLUSIONS: Significantly improved outcomes suggest VH should be performed in preference to AH where possible. Where VH is not possible, LH may avoid the need for AH, however the length of the surgery increases as the extent of the surgery performed laparoscopically increases, particularly when the uterine arteries are divided laparoscopically and laparoscopic approaches require greater surgical expertise. The surgical approach to hysterectomy should be decided by a woman in discussion with her surgeon in light of the relative benefits and hazards. Further research is required with full reporting of all relevant outcomes, particularly important long-term outcomes, in large RCTs, to minimise the possibility of reporting bias. Further research is also required to define the role of the newer approaches to hysterectomy such as TLH.

Surgery versus medical therapy for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) significantly impairs the quality of life of many otherwise healthy women. Perception of HMB is subjective and management usually depends upon what symptoms are acceptable to the individual. Medical treatment options include oral medication and a hormone-releasing intrauterine system (LNG-IUS). Surgical options include conservative surgery (uterine resection or ablation) and hysterectomy. OBJECTIVES: To compare the effectiveness, safety and acceptability of surgery versus medical therapy for HMB. SEARCH STRATEGY: In September 2005 we searched the Cochrane Menstrual Disorders and Subfertility Group trials register Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2005), MEDLINE EMBASE, Current Contents, Biological Abstracts, PsycINFO, and CINAHL. We also searched reference lists of articles retrieved and contacted pharmaceutical companies and experts in the field. SELECTION CRITERIA: Controlled randomised trials comparing conservative surgery or hysterectomy versus medical therapy (oral or intrauterine) for HMB DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trials for quality and extracted data . MAIN RESULTS: The eight included trials randomised 821 women. In comparisons of oral medication versus surgery, 58% of women randomised to medical treatment had received surgery by two years. Compared to oral medication, endometrial resection was significantly more effective in controlling bleeding (at four months: OR 10.62, 95% CI 5.30 to 21.27) and significantly less likely to cause side effects (at four months: OR 0.15, 95% CI 0.07 to 0.31) and hysterectomy resulted in significantly greater improvements in mental health (at six months p = 0.04). In comparisons of LNG-IUS versus conservative surgery or hysterectomy, at one year there was no statistically significant difference in satisfaction rates or quality of life, though adverse effects were significantly less likely with conservative surgery (OR 0.24, 95% CI 0.11 to 0.49). Two trials found conservative surgery significantly more effective than LNG-IUS in controlling bleeding at one year (OR 3.99, 95% CI 1.53 to 10.38). Two other small trials with longer follow-up found no difference or favoured LNG-IUS - however in both these studies the data were skewed and fewer than two thirds of participants were analysed. Hysterectomy stopped all bleeding but caused serious complications for some women. AUTHORS' CONCLUSIONS: Surgery, especially hysterectomy, reduces menstrual bleeding at one year more than medical treatments but LNG-IUS appears equally effective in improving quality of life. The evidence for longer term comparisons is weak and inconsistent. Oral medication suits a minority of women long term.

Total versus subtotal hysterectomy for benign gynaecological conditions.

BACKGROUND: Hysterectomy using an abdominal approach removes either the uterus alone (subtotal hysterectomy) or both the uterus and the cervix (total hysterectomy). The latter is more common but outcomes have not been systematically compared. OBJECTIVES: To assess and compare outcomes with subtotal hysterectomy versus total abdominal hysterectomy for benign gynaecological conditions. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group's specialised register of controlled trials (December 2005), Central (December 2005), Medline (1966 to December 2005), EmBase (1980 to December 2005), Biological Abstracts (1980 to December 2005), the National Research Register and relevant citation lists. SELECTION CRITERIA: Only randomised controlled trials of women undergoing either total or subtotal hysterectomy for benign gynaecological conditions were included. DATA COLLECTION AND ANALYSIS: Three trials that included 733 participants were included. Independent selection of trials and data extraction were undertaken by 2 reviewers and results compared. MAIN RESULTS: There was no evidence of a difference in the rates of incontinence, constipation or measures of sexual function. In one unblinded trial, a significantly greater proportion of women indicated that they had frequent episodes of urinary incontinence after subtotal hysterectomy when compared with total hysterectomy (OR=2.1, 1.02 to 4.3), but these results were not confirmed by the other two trials that measured both stress and urge incontinence and urinary frequency. . Length of surgery and amount of blood lost during surgery were significantly reduced during subtotal hysterectomy when compared with total hysterectomy, but there was no evidence of a difference in the odds of transfusion. Febrile morbidity was less likely (OR=0.43, 0.25 to 0.75) and ongoing cyclical vaginal bleeding one year after surgery was more likely (OR=11.3, 4.1 to 31.2) after subtotal when compared with total hysterectomy. There was no evidence of a difference in the rates of other complications, recovery from surgery or readmission rates. AUTHORS' CONCLUSIONS: This review has not confirmed the perception that subtotal hysterectomy offers improved outcomes for sexual, urinary or bowel function when compared with total abdominal hysterectomy. Surgery is shorter and intraoperative blood loss and fever are reduced but women are more likely to experience ongoing cyclical bleeding up to a year after surgery with subtotal hysterectomy compared to total hysterectomy.

A randomised trial comparing the levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding.

OBJECTIVE: To compare the levonorgestrel intrauterine system (LNG-IUS) (Mirena); Schering Co., Turku, Finland) and thermal balloon ablation (Thermachoice; Gynecare Inc., Menlo Park, CA, USA) for the treatment of heavy menstrual bleeding. DESIGN: An open, pragmatic, prospective randomised trial. SETTING: A menstrual disorders clinic at National Women's Hospital, Auckland, New Zealand. POPULATION: Seventy-nine women with heavy menstrual bleeding randomised to the LNG-IUS (40 women) or the thermal balloon ablation (39 women). METHODS: Women were randomised to treatment with the LNG-IUS or thermal balloon ablation and followed up by a postal and telephone questionnaire. MAIN OUTCOME MEASURES: Menstrual loss measured by a pictorial bleeding assessment chart (PBAC) at 3, 6, 12 and 24 months. Patient satisfaction, quality of life and menstrual symptoms were assessed by questionnaire administered at 3, 6, 12 and 24 months. Treatment side effects and treatment failures were also recorded. RESULTS: Both the treatments resulted in a significant reduction in PBAC scores. At 12 and 24 months, median PBAC scores were significantly lower in women treated with the LNG-IUS compared with women treated by thermal balloon ablation (11.5 versus 60.0 at 12 months [P= 0.002]; 12.0 versus 56.5 [P= 0.002] at 24 months). At 24 months, nine (35%) women still using the LNG-IUS had amenorrhoea compared with one (5%) woman successfully treated by thermal balloon ablation (P = 0.025). There were no significant differences in patient satisfaction between two treatments during follow up. Treatment failed in 11 (28%) women using the LNG-IUS and in 10 (26%) women treated with thermal balloon ablation. Overall, women in both groups showed an increased quality of life as a result of the treatment, with Short Form-36 scores increasing from 63.7 at randomisation to 76.1 at 24 months. CONCLUSIONS: At 12 and 24 months of follow up, women with heavy menstrual bleeding treated with the LNG-IUS have significantly lower PBAC scores than women treated with thermal balloon ablation. Both the treatments resulted in a significant increase in overall quality of life, but there were no significant differences between either treatment in quality of life, patient satisfaction or the number of women requesting an alternative treatment during 24 months of follow up.

Endometrial destruction techniques for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is a significant health problem in premenopausal women; it can reduce their quality of life and cause anaemia. First-line therapy has traditionally been medical therapy but this is frequently ineffective. On the other hand, hysterectomy is obviously 100% effective in stopping bleeding but is more costly and can cause severe complications. Endometrial ablation is less invasive and preserves the uterus, although long-term studies have found that the costs of ablative surgery approach the cost of hysterectomy due to the requirement for repeat procedures. A large number of techniques have been developed to 'ablate' (remove) the lining of the endometrium. The gold standard techniques (laser, transcervical resection of the endometrium and rollerball) require visualisation of the uterus with a hysteroscope and, although safe, require skilled surgeons. A number of newer techniques have recently been developed, most of which are less time consuming. However, hysteroscopy may still be required as part of the ablative techniques and some of them must be considered to be still under development, requiring refinement and investigation. OBJECTIVES: To compare the efficacy, safety and acceptability of methods used to destroy the endometrium to reduce HMB in premenopausal women. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials (April 2004). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2004), MEDLINE (1966 to July 2004), EMBASE (1980 to July 2004), Current Contents (1993 to week 38, 2001), Biological Abstracts (1980 to June 2001), PsycLIT (1967 to August 2001), CINAHL (1982 to July 2004) and the metaregister of controlled trials and ISRCTN register (December 2004). We also searched reference lists of articles and contacted pharmaceutical companies and experts in the field. SELECTION CRITERIA: Randomised controlled trials comparing different endometrial ablation techniques in women with a complaint of heavy menstrual bleeding without uterine pathology. The outcomes included reduction of heavy menstrual bleeding, improvement in quality of life, operative outcomes, satisfaction with the outcome, complications and need for further surgery or hysterectomy. DATA COLLECTION AND ANALYSIS: The two review authors independently selected trials for inclusion, assessed trials for quality and extracted data. Attempts were made to contact authors for clarification of data in some trials. Adverse events were only assessed if they were separately measured in the included trials. MAIN RESULTS: In the comparison of the newer non-hysteroscopic techniques (second generation) with the gold standard hysteroscopic ablative techniques (first generation) overall, surgery was an average of 15 minutes shorter (weighted mean difference (WMD) 14.9, 95% CI 10.1 to 19.7), local anaesthesia was more likely to be employed (odds ratio (OR) 8.3, 95% CI 3.9 to 17.5) and equipment failure was more likely (OR 4.2, 95% CI 1.3 to 13.8) with second-generation ablation. Women undergoing newer ablative procedures were less likely to have fluid overload, uterine perforation, cervical lacerations and hematometra than women undergoing the more traditional type of ablation and resection techniques (OR 0.13, 95% CI 0.04 to 0.5; OR 0.21, 95% CI 0.07 to 0.7; OR 0.12, 95% CI 0.05 to 0.3 and OR 0.25, 95% CI 0.09 to 0.7, respectively). However, women were more likely to have nausea and vomiting and uterine cramping (OR 2.3, 95% CI 1.5 to 3.4 and OR 1.8, 95% CI 1.1 to 2.9, respectively). Some differences were also found in amenorrhoea rates and satisfaction rates, but there did not appear to be a trend over time so these results may be due to chance. AUTHORS' CONCLUSIONS: Endometrial ablation techniques continue to play an important role in the management of HMB. The rapid development of a number of new methods of endometrial destruction has made systematic comparisons between methods and with the 'gold standard' of transcervical resection of the endometrium (TCRE) difficult. Most of the newer techniques are technically easier than hysteroscopy-based methods to perform. However, uterine perforation, which is the major complication of endometrial ablation, cannot be excluded without hysteroscopy. Overall, the existing evidence suggests that success rates and complication profiles of newer techniques of ablation compare favourably with TCRE, although technical difficulties with new equipment need to be ironed out.

Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in women and it accounts for 12% of all gynaecology referrals in the UK. Heavy menstrual bleeding is clinically defined as greater than or equal to 80 ml of blood loss per menstrual cycle. However, women may complain of excessive bleeding when their blood loss is less than 80 ml. Hysterectomy is often used to treat women with this complaint but medical therapy may be a successful alternative. The intrauterine coil device was originally developed as a contraceptive but the addition of uterine relaxing hormones, progestogens, to these devices resulted in a large reduction in menstrual blood loss. Case studies of two types of progesterone or progestogen-releasing systems, Progestasert and Mirena, reported reductions of up to 90% and that dysmenorrhoea may be improved. Insertion, however, may be regarded as invasive by some women, which affects its acceptability as a treatment. Frequent intermenstrual bleeding and spotting is also likely during the first few months. OBJECTIVES: To determine the effectiveness and acceptability of progesterone or progestogen-releasing intrauterine devices in achieving a reduction in heavy menstrual bleeding. SEARCH STRATEGY: All studies which might describe randomised controlled trials of progesterone or progestagen-releasing intrauterine devices for the treatment of heavy menstrual bleeding were obtained by electronic searches of The Cochrane Library, MEDLINE (1966 to 2005) and EMBASE (1980 to 2005). Companies producing progestogen-releasing intrauterine devices and experts in the field were contacted for information on published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials in women of reproductive age treated with progesterone or progestogen-releasing intrauterine devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding within primary care, family planning or specialist clinic settings were eligible for inclusion. Women with postmenopausal bleeding, intermenstrual or irregular bleeding, or pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Potential trials were independently assessed by three review authors and nine trials met the criteria for inclusion in the review. The reviewers extracted the data independently and data were pooled where appropriate. Odds ratios (OR) were estimated from the data for dichotomous outcomes and weighted mean differences (WMD) for continuous outcomes. The primary outcome was reduction in menstrual blood loss but incidence of side effects, changes in quality of life, satisfaction and acceptability measures were also assessed. MAIN RESULTS: Progesterone or progestogen-releasing intrauterine systems have not been compared to placebo or no treatment. Progestasert has been compared to a number of different medical therapies in one small study but no conclusions can be made about its effectiveness. The levonorgestrel-releasing intrauterine device (LNG IUS) has been compared to oral cyclical norethisterone (NET) administered on days 5 to 26 of the menstrual cycle in one trial and was significantly more effective although there was a large reduction in loss from baseline in both groups. Some short term side effects were more common in the LNG IUS group but a significantly greater proportion of women in this group were satisfied and willing to continue with their treatment. In one trial of women awaiting hysterectomy, where the LNG IUS was compared with a control group taking their existing medical therapy, a higher proportion of the women in the intrauterine device group cancelled their planned surgery after six months of treatment. The LNG IUS has been compared to an endometrial ablation: either transcervical resection of the endometrium (TCRE) (two trials) or balloon ablation (three trials). There was a significantly greater mean reduction in menstrual bleeding in one trial in those undergoing balloon ablation (WMD -45.2 units, 95% CI -56.9 to -33.5), a lower score on the pictorial blood loss chart (PBAC) (WMD 33.2 units, 95% CI 27.2 to 39.2) and higher rates of successful treatment in 3 trials including both balloon and TCRE (OR 0.28, 95% CI 0.14 to 0.58) but the rates of satisfaction with treatment was were similar. There was no conclusive evidence of changes in quality of life between groups but women with the LNG IUS had a greater incidence of progestogenic side effects within one year. The LNG IUS has been compared to hysterectomy in one trial. There was no evidence of a change in quality of life scores but the LNG IUS treatment had lower costs than with hysterectomy, both at one and five-years follow up. AUTHORS' CONCLUSIONS: The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than cyclical norethisterone (for 21 days) as a treatment for heavy menstrual bleeding. Women with an LNG IUS are more satisfied and willing to continue with treatment but experience more side effects, such as intermenstrual bleeding and breast tenderness. The LNG IUS results in a smaller mean reduction in menstrual blood loss (as assessed by the PBAC chart) than endometrial ablation but there is no evidence of a difference in the rate of satisfaction with treatment. Women with an LNG IUS experience more progestogenic side effects compared to women having TCRE for treatment of their heavy menstrual bleeding but there is no evidence of a difference in their perceived quality of life. The LNG IUS treatment costs less than hysterectomy but there is no evidence of a difference in quality of life measures between these groups. There are no data available from randomised controlled trials comparing progesterone-releasing intrauterine systems to either placebo or other commonly used medical therapies for heavy menstrual bleeding.

High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer.

BACKGROUND: Overall survival rates are disappointing for women with early poor prognosis breast cancer. Autologous transplantation of bone marrow or peripheral stem cells (in which the patient is both donor and recipient) has been considered a promising technique because it allows much higher doses of chemotherapy to be used. OBJECTIVES: To compare the effectiveness of high dose chemotherapy and autograft versus conventional chemotherapy for women with early poor prognosis breast cancer. Outcomes were survival rates, toxicity and quality of life. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group specialised register, The Cochrane Controlled Trials Register (Cochrane Library Issue 3, 2004), MEDLINE (1966 to November 2004), EMBASE (1980 to November 2004), PsycINFO (1984 to November 2004), Cinahl (1982 to November 2004), web sites of co-operative research groups and ASCO (American Society of Clinical Oncologists) and reference lists of articles found. SELECTION CRITERIA: Randomised controlled trials comparing high dose chemotherapy and autograft versus conventional chemotherapy for women with early poor prognosis breast cancer. DATA COLLECTION AND ANALYSIS: Fifteen trials were considered. Thirteen were included and two were excluded. Three independent reviewers extracted data. MAIN RESULTS: Analysis included 2535 women randomised to receive high dose chemotherapy with autograft and 2529 randomised to receive conventional chemotherapy. There were 65 treatment-related deaths on the high dose arm and four on the conventional dose arm (RR 8.58 (95% CI 4.13, 17.80). Many studies have not completed follow-up and have reported only preliminary results. There was a statistically significant benefit in event-free survival for women in the high dose group at three years (RR 1.12 (95% CI 1.06, 1.19)) and at four years (RR 1.30 (95% CI 1.16, 1.45)). At five and six years there was no statistically significant difference between the groups in event-free survival. With respect to overall survival, there was no statistically significant difference between the groups at any stage of follow up. Morbidity was more common and more severe in the high dose group. However there was no statistically significant difference between the groups with respect to the incidence of second cancers at five to seven years' follow up. Women in the high dose group reported significantly worse quality of life scores immediately after treatment, but few statistically significant differences were found between the groups by one year. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the routine use of high dose chemotherapy with autograft for women with early poor prognosis breast cancer.

High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer.

BACKGROUND: There is a hypothesis that high dose chemotherapy with autologous bone marrow or peripheral stem cell transplantation (autograft) may improve survival for women with metastatic breast cancer. OBJECTIVES: To compare the effectiveness of high dose chemotherapy and autologous bone marrow or stem cell transplantation with conventional chemotherapy for women with metastatic breast cancer. SEARCH STRATEGY: We used the Cochrane Breast Cancer Group search strategy, adding these terms: bone marrow transplantation, stem cell transplantation, autologous stem cell support. The following databases were searched: MEDLINE (until November 2004), EMBASE (until November 2004), ASCO (American Society of Clinical Oncology) (1995-2004) and the COCHRANE LIBRARY (Issue 4 2004). We searched the Cochrane Breast Cancer Group database and cooperative research groups' websites for unpublished trials. SELECTION CRITERIA: Randomised controlled trials comparing the effectiveness of high dose chemotherapy and autograft with conventional chemotherapy for women with metastatic breast cancer. Studies included one or more of the following outcomes: treatment related mortality, overall or progression-free survival at 1, 2, 3, 5 or 7 years, morbidity, quality of life measures, time to tumour progression, overall survival time. DATA COLLECTION AND ANALYSIS: Six randomised controlled trials met the inclusion criteria. Two independent reviewers extracted data. MAIN RESULTS: In total 438 eligible women were randomised to receive high dose chemotherapy with autograft and 412 were randomised to receive conventional treatment. There were fifteen treatment-related deaths among the high dose group and two in the control (conventional dose) group (RR 4.07 (95% CI 1.39, 11.88)). There was no statistically significant difference in overall survival between the high dose and control groups at one year, three years or five years. At one and five years of follow up, there was a statistically significant difference in event-free survival, favouring the high dose group (one year: RR 1.76 (95% CI 1.40, 2.21); five years: RR 2.84 (95% CI 1.07, 7.50). Toxicity was more severe in the high dose group. Only one of the trials has followed up all women for five years and further data are awaited. AUTHORS' CONCLUSIONS: Although there is statistically significant evidence that high dose chemotherapy and autograft improves event free survival compared to conventional chemotherapy, there is no statistically significant evidence of benefit in overall survival for women with metastatic breast cancer. High dose chemotherapy with bone marrow or stem cell transplantation should not be given to women with metastatic breast cancer outside of clinical trials.

Long term hormone therapy for perimenopausal and postmenopausal women.

BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (oestrogens with or without progestogens) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term oestrogen-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking oestrogen-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women.