Chinese herbal medicine for endometriosis

Abstract

Background

Endometriosis is characterized by the presence of tissue that is morphologically and biologically similar to normal endometrium in locations outside the uterus. Surgical and hormonal treatment of endometriosis have unpleasant side effects and high rates of relapse. In China, treatment of endometriosis using Chinese herbal medicine (CHM) is routine and considerable research into the role of CHM in alleviating pain, promoting fertility, and preventing relapse has taken place.

This review is an update of a previous review published in the Cochrane Database of Systematic Reviews 2009, issue No 3.

Objectives

To review the effectiveness and safety of CHM in alleviating endometriosis‐related pain and infertility.

Search methods

We searched the Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) and the following English language electronic databases (from their inception to 31/10/2011): MEDLINE, EMBASE, AMED, CINAHL, and NLH.

We also searched Chinese language electronic databases: Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Sci & Tech Journals (VIP), Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), and Chinese Medical Current Contents (CMCC).

Selection criteria

Randomised controlled trials (RCTs) involving CHM versus placebo, biomedical treatment, another CHM intervention; or CHM plus biomedical treatment versus biomedical treatment were selected. Only trials with confirmed randomisation procedures and laparoscopic diagnosis of endometriosis were included.

Data collection and analysis

Risk of bias assessment, and data extraction and analysis were performed independently by three review authors. Data were combined for meta‐analysis using relative risk (RR) for dichotomous data. A fixed‐effect statistical model was used, where appropriate. Data not suitable for meta‐analysis were presented as descriptive data.

Main results

Two Chinese RCTs involving 158 women were included in this review. Although both these trials described adequate methodology they were of limited quality. Neither trial compared CHM with placebo treatment.

There was no evidence of a significant difference in rates of symptomatic relief between CHM and gestrinone administered subsequent to laparoscopic surgery (RR 1.04, 95% CI 0.91 to 1.18). There was no significant difference between the CHM and gestrinone groups with regard to the total pregnancy rate (69.6% versus 59.1%; RR 1.18, 95% CI 0.87 to 1.59, one RCT).

CHM administered orally and then in conjunction with a herbal enema resulted in a greater proportion of women obtaining symptomatic relief than with danazol (RR 5.06, 95% CI 1.28 to 20.05; RR 5.63, 95% CI 1.47 to 21.54, respectively). Oral plus enema administration of CHM resulted in a greater reduction in average dysmenorrhoea pain scores than did danazol (mean difference (MD) ‐2.90, 95% CI ‐4.55 to ‐1.25).  For lumbosacral pain, rectal discomfort, or vaginal nodules tenderness, there was no significant difference between CHM and danazol.

Overall, 100% of women in both studies showed some improvement in their symptoms. Women taking CHM had fewer side effects than those taking either gestrinone or danazol.

Authors' conclusions

Post‐surgical administration of CHM may have comparable benefits to gestrinone. Oral CHM may have a better overall treatment effect than danazol and it may be more effective in relieving dysmenorrhoea when used in conjunction with a CHM enema. CHM appears to have fewer side effects than either gestrinone or danazol. However, more rigorous research is required to accurately assess the potential role of CHM in treating endometriosis.

Plain language summary

Chinese herbs for endometriosis

Endometriosis is a common gynaecological condition causing menstrual and pelvic pain. Treatment involves surgery and hormonal drugs, with potentially unpleasant side effects and high rates of reoccurrence of endometriosis. The two small studies in this review suggest that Chinese herbal medicine (CHM) may be as effective as gestrinone and may be more effective than danazol in relieving endometriosis‐related pain, with fewer side effects than experienced with conventional treatment. However, the two trials included in this review were small and of limited quality so these findings must be interpreted cautiously. Better quality randomised controlled trials are needed to investigate a possible role for CHM in the treatment of endometriosis.

Summary of findings

Summary of findings for the main comparison. CHM compared to gestrinone and danazol.

Study	Risk of bias	Number of participants	Comparisons	RR (95% CI)
Wu SZ 2006a	B‐moderate	100	CHM (oral + enema) versus gestrinone	RR 1.02 (95% CI 0.93 to 1.12)
Wu SZ 2006b	B‐moderate	58	CHM oral versus CHM oral+enema versus danazol	For 'symptomatic relief' CHM oral versus danazol RR 5.06 (95% CI 1.28 to 20.05) CHM oral+enema versus danazol RR 5.63 (95% CI 1.47 to 21.54)

Background

Description of the condition

Endometriosis is a disease characterized by the presence of tissue that is morphologically and biologically similar to normal endometrium in ectopic locations outside the uterine cavity. Hormonally stimulated cyclical bleeding from the endometriotic deposit appears to contribute to the induction of a local inflammatory reaction and fibrous adhesion; and, in the case of deep implants in the ovary, leads to the formation of an endometrioma or chocolate cyst.

Endometriosis classically presents with severe dysmenorrhoea, pelvic pain, dyspareunia, menstrual irregularities, and infertility. Systemic symptoms may also occur, such as fatigue, increased incidence of allergies, and autoimmune disease (Ballweg 2004). Definitive diagnosis is usually made through laparoscopic investigation although recent research suggests that non‐invasive symptom evaluation may have a greater positive prediction value (Ling 1999; Winkel 2003).

The precise prevalence of endometriosis is unclear but there is a broad consensus that between 5% to 15% of the female population will have signs and symptoms of the disease during their reproductive years (aged 15 to 50 years) (Eskenazi 1997; Stenchever 2001; Zondervan 2001).

Endometriosis is increasingly regarded as a complex, multi‐factorial condition of uncertain aetiology where immunological (Ballweg 2004; Lebovic 2001; Sheng 1998), hormonal (Noble 1997), genetic (Bischoff 2004; Malinak 1980), environmental (Ballweg 2004; Ohtake 2003), and possibly even psychological (Low 1993; Strauss 1992) factors combine together to create a context for rogue endometrial cells to develop into a full‐blown disease.

Description of the intervention

The conventional treatment of endometriosis can be broadly divided into medical or surgical management. Medical treatment ranges from symptomatic control with non‐steroidal anti‐inflammatory drugs (NSAIDs) and analgesics through to treatments that aim to suppress the normal ovarian production of estrogen by either hormonally simulating pregnancy (continuous oral contraceptives (COC) and progestins) or menopause (danazol and gonadotrophin‐releasing hormone agonists (GnRH‐a). Surgical intervention can be either 'conservative', involving the removal of endometrial lesions or the severing of the nerve pathways responsible for the transmission of pelvic and uterine pain, or 'definitive', involving the removal of the uterus and ovaries.

Danazol, progestins, GnRH‐a, and the COC have comparable short‐term rates of success in alleviating the symptoms of endometriosis and in partially reducing the size of endometriosis‐related lesions (GISG 1996; Moore 2004; Parazzini 2000; Prentice 2004; Selak 2007; Vercellini 1993). Unfortunately the benefits are poorly sustained over time with studies frequently reporting a high level of returning symptoms at six months post‐treatment (Vercellini 1993). Even studies with more positive findings commonly demonstrate a return of symptoms in over a third of the women two to three years after stopping treatment (Biberoglu 1981; Dmowski 1998).

The short‐term benefits of conventional medical treatment have to be balanced against the unpleasant and sometimes dangerous side effects resulting from these therapies. COC has been associated with increased thromboembolic risks (Anderson 2004). It is unsuitable for certain patient groups, such as women over the age of 35 years who smoke or who have a history of cardiovascular disease, and is obviously inappropriate for women trying to conceive. Danazol is associated with androgenic changes such as acne and weight gain, and menopausal symptoms such as flushing and fatigue. Concerns raised have highlighted its potential role in raising low‐density lipoprotein (LDL) cholesterol levels (Hughes 2004) and in possibly contributing to ovarian cancer (Cottreau 2003). GnRH‐a tend to produce a more hypo‐estrogenic state than danazol with more severe menopausal side effects such as hot flushes, insomnia, reduced libido, and vaginal dryness (Prentice 2004). Low estrogen levels can also cause serious osteoporosis and the long‐term risks of add‐back regimes using small amounts of progesterone and estrogen have not been adequately assessed as yet. Patients using progestin therapy reported a higher incidence of acne, fluid retention, bloating, and spotting. In addition, progestins are known to unfavourably reduce the level of high‐density lipoproteins in the blood, which could potentially increase the risk of cardiovascular side effects such as thrombosis (Vasilakis 1999).

The surgical management of endometriosis is also far from satisfactory. Two RCTs (Abbott 2004; Sutton 1994) and several observational studies (Abbott 2003; Fedele 2004; Wheeler 1983) demonstrate significant symptomatic relief after conservative laparoscopic surgery but in many cases these benefits were relatively short lived, with up to 44% of women experiencing a return of symptoms after one year (Lapp 2000). Surgery is also associated with the potential for serious side effects, with one study reporting that 2% to 3% of cases had post‐operative bowel perforations with peritonitis (Koninckx 1996); an anonymous survey of 1951 gynaecologists revealed a significant number of unreported complications suggesting that the incidence of complications is higher than is commonly stated (Feste 1999).

In summary, current treatments all have high rates of reoccurrence and their short‐term benefits have to be balanced with concerns over immediate and longer‐term side effects.

CHM typically involves the use of herbal formulae of between 10 and 20 separate herbal ingredients selected from a Materia Medica of several hundred commonly herbs that are prepared either as a boiled decoction, as dried herbal extracts, or taken as pills. Usually CHM is administered orally but methods may include the use of enemas and intramuscular injections. Diagnostic and therapeutic treatment principles are framed according to the traditional Chinese understanding of pathological processes which can appear arcane, but may provide clinically useful phenotypes that could be used to inform clinical practice.

How the intervention might work

Chinese herbal medicine (CHM) is a system of medicine with an unbroken written tradition stretching back over two thousand years. Although endometriosis as a distinct entity did not exist in the classical tradition, the symptoms of dysmenorrhoea, dysuria, dyschezia, menorrhagia, and so on, were systematically differentiated and apparently well treated (Wu 1997). A common pattern underlying these conditions is the presence of what is known as stagnation of the blood and Qi (vital energy) causing localised obstructions and leading to pain. This is interestingly similar to the modern biomedical understanding of the central role that endometrial lesions play in the symptomatology of the disease.

We have recently seen increasing integration of western medicine and CHM in China, and in the past 10 years the use of laparoscopic diagnosis has allowed some evaluation of the specific benefits of CHM in the treatment of endometriosis through a number of clinical trials. For example, one Chinese language review identified 13 randomised clinical trials on CHM treatment of endometriosis from Chinese literature published between 1994 and 2000 (Xu et al 2004). In these trials 1076 women were involved and Chinese herbal medicines were applied either alone or in combination with biomedical drugs. The suggested mechanism of Chinese medicine for endometriosis may involve regulation of endocrine and immune systems, improvement of blood circulation, and anti‐inflammatory activity (Huang 2006; Xu et al 2004).

Modern research has shown that Chinese herbs categorised as 'blood moving' can promote microcirculation, improve the speed and volume of pelvic blood flow and reduce blood viscosity as measured by eg ESR, reduce inflammation, and prevent fibrosis (Neeb 2007, Zhu 1998) . Blood moving herbs have also demonstrated an effect on regulating altered humoral (IgG, IgA, IgM etc) and cellular immune parameters (NK cells / macrophages/ PGF2 etc. (Neeb 2007; Wu 2003; Zhu 1998). An altered immunological milieu is a recognised feature of endometriosis (Lebovic 2001).

In addition herbs described as 'Kidney yang tonics' have been reported as having similar immune‐regulating functions (Zhu 1998).

Both 'blood moving' and 'kidney tonifying' herbs have been shown to be able to affect the hypothalamic‐pituitary‐ovarian axis and thereby regulate FSH/LH oestrogen and progesterone levels (Liu 1998a; Zhu 1998).

The ability of CHM to affect these physiological changes suggests that this approach may have a biologically plausible mode of action.

Whilst herbs might contain phyto‐steroids these are considerably less potent than synthetic steroids. There are no reports of any androgenic or cholesterol raising adverse effects from herbs used in the treatment of endometriosis.

Why it is important to do this review

At present no other English language systematic review has been conducted to evaluate the results of these studies. Given that the conventional treatment of endometriosis has limited long term benefits and is associated with a relatively high level of adverse effects it is important that novel approaches, that can be used either independently or as adjuvant treatments to conventional care, are identified and carefully evaluated. There is considerable anecdotal evidence supporting the use of CHM as a potential treatment for endometriosis and we have reviewed the available Chinese and English language literature on the subject in an attempt to establish whether CHM has a valid role in the treatment of this common and disabling condition.

Objectives

To review the effectiveness and safety of CHM in alleviating endometriosis‐related pain and infertility.

Methods

Criteria for considering studies for this review

Types of studies

Published and unpublished randomised controlled trials (RCTs) were eligible for inclusion. We excluded non‐randomised studies (for example studies with evidence of inadequate methods of sequence generation such as alternate days, patient numbers) as they are associated with a high risk of bias. If any crossover trials were found, it was planned to include only data from the first phase, as the crossover is not a valid design in this context.

Types of participants

Trials including women of reproductive age with a laparoscopically confirmed diagnosis of endometriosis were eligible for inclusion.

Types of interventions

Trials comparing the following interventions were eligible for inclusion:

CHM versus placebo;

CHM versus conventional biomedical treatment;

CHM plus conventional biomedical treatment versus conventional biomedical treatment alone;

One CHM strategy versus a different CHM strategy.

Types of outcome measures

Primary outcomes

• Relief of endometriosis‐related pain (both in the long term and short term)

Secondary outcomes

• Improvement in fertility rates (live birth or pregnancy)

• Reduction in the size and extent of endometrial cysts

• Improvement in quality of life scores

• Improvement of endometriosis‐related symptoms apart from pain (e.g. fatigue)

• Adverse effects resulting from the CHM intervention

• Rates of reoccurrence

It was our intention to investigate long‐term outcomes (and several of the studies we had to reject reported on recurrence rates) but using the trials that were eligible for inclusion we were not able to fulfil this objective in terms of symptomatic relief. Wu SZ 2006a did have a 24 month follow up but this was to assess pregnancy outcomes.

Search methods for identification of studies

We searched for all published and unpublished RCTs of CHM for endometriosis, without language restriction and in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co‐ordinator:

Electronic searches

We searched the following on the 31/10/11: 
 (1) Menstrual Disorders and Subfertility Group Trials Register; 
 (2) Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) using the keywords: endometriosis, Chinese herbal medicine; 
 (3) MEDLINE, EMBASE, AMED, CINAHL, and NLH English language electronic databases (from inception to the present); for a detailed search string see Appendix 1;

(4) Chinese language electronic databases Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Sci & Tech Journals (VIP), Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), and Chinese Medical Current Contents (CMCC) using the following terms: Zigong Neimo Yiwei Zheng (endometriosis), Chuantong Yiyao (traditional medicine), Zhong Yao (Chinese medicine), Cao Yao (herbal medicine), Tiqu Yao (plant extract), Buchong Yiyao (complementary medicine).

Searching other resources

JPL searched the Chinese language databases to identify trials that could be considered for inclusion in this review. AF did the same in the English language databases. We handsearched reference lists of articles retrieved by the search.

Data collection and analysis

Selection of studies

AF and SC (in the UK) and JPL (in China) independently reviewed the studies retrieved by the search and identified those eligible for inclusion. Owing to some confusion over the term 'randomised' in Chinese research papers, the authors of all papers considered suitable for inclusion were telephoned by JPL to confirm that proper randomisation procedures had been applied. GL and PL acted in an advisory capacity during this process. Any differences of opinion were resolved through discussion.

Data extraction and management

Two review authors independently extracted data from eligible studies, resolving any disagreements by discussion. Data extracted included study characteristics and outcome data.

Assessment of risk of bias in included studies

AF and SC (in the UK) and JPL (in China) independently reviewed the studies retrieved by the search and rated them 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 reporting); and other sources of bias. Disagreements were resolved by discussion or by a third review author. GL and PL acted in an advisory capacity during this process.

See Figure 1; Figure 2

1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Trials were assessed to determine how successfully selection, performance, detection, attrition, reporting and other biases were minimized.

To minimize bias related to random sequence generation and allocation concealment (selection bias)

• A clear and acceptable method of randomisation

• Quality of allocation concealment

To minimize bias related to blinding (performance and detection bias)

• Were the participants blinded?

• Were the outcome assessors blinded to the assignment status?

To minimize bias related to incomplete outcome data (attrition bias)

• A record of the number of randomised participants excluded or lost to follow up

• A record of treatment compliance

• An intention‐to‐treat analysis

To minimize selective reporting (reporting bias)

• Were the outcome measures used clearly defined and clearly and consistently reported?

To minimize other bias

• Comparable treatment and control groups at entry

• Confirmation that the care programmes, apart from the trial options, were identical

For each domain of bias, we assigned one of the following three judgements: low risk of bias, unclear risk of bias, or high 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 risk ratios (RRs) and 95% confidence intervals (CIs).

For continuous data (for example quality of life), if all studies reported exactly the same outcomes we planned to calculate mean difference (MDs) between treatment groups; or, if similar outcomes were reported on different scales, to calculate the standardised mean difference (SMD). However, no continuous data were reported by the included studies.

Unit of analysis issues

Analysis was per woman randomised.

Dealing with missing data

The data were analysed on an intention‐to‐treat basis as far as possible and attempts were made to obtain missing data from the original trialists. Where data were unobtainable, it was planned that only the available data would be analysed.

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. If pooling was undertaken we planned to assess statistical heterogeneity by the measure of the I² statistic. An I² measurement greater than 50% would be taken to indicate substantial heterogeneity (Higgins 2003; Higgins 2008). If we detected substantial heterogeneity, we planned to explore possible explanations in sensitivity analyses and to take any statistical heterogeneity into account when interpreting the results, especially if there was any variation in the direction of effect.

Only two trials (testing CHM against different conventional biomedical interventions) were eligible for this review so no assessment of statistical heterogeneity was undertaken (Higgins 2003).

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, the authors aimed to minimize their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there were 10 or more studies in an analysis, it was planned to use a funnel plot to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).

Data synthesis

If the studies were sufficiently similar, we planned to combine the data using fixed‐effect models in the following comparisons:  

• CHM versus placebo;

• CHM versus conventional biomedical treatment;

• CHM plus conventional biomedical treatment versus conventional biomedical treatment alone;

• CHM strategy versus another CHM strategy.

Only two trials (testing CHM against different conventional medical interventions) were eligible for this review so no meta‐analysis was undertaken (Higgins 2003).

Subgroup analysis and investigation of heterogeneity

If data were available, we planned to undertake subgroup analysis according to the type of intervention (for example type of biomedical treatment, type of CHM).

Sensitivity analysis

If there were sufficient studies, we planned to conduct sensitivity analyses for the primary outcome to determine whether the review conclusions would have differed if

eligibility were restricted to studies without high risk of bias.

Results

Description of studies

Results of the search

One hundred and ten trials were initially identified in the 2009 review. A further 39 were identified for the updated review in November 2010, and an updated search identified an additional 47 clinical trials in October 2011 using the search strategy described above. All of these trials took place in China and were reported in Chinese. However, no new trials were eligible to be included based on the previous inclusion criteria (see table 'Characteristics of excluded studies').

Included studies

Only two trials (Wu SZ 2006a; Wu SZ 2006b) were able to be included in this review. The trials took place in a hospital outpatient department in China and were reported in Chinese. They were presented in four publications: one trial was reported in three publications each describing different outcome measures (Wu SZ 2006b). The review authors were able to confirm adequate randomisation and they acquired more information about methods and data via telephone discussion.

Participants

In total, 158 women were included in the two trials. The average age was 30 years (SD 4.5 years) with an age range of 23 to 45 years.

Diagnostic criteria 

Laparoscopic diagnosis and American Fertility Society (AFS) staging

Vaginal or rectal B‐ultrasound

All participants were diagnosed according to traditional Chinese medicine as having Qi and blood stagnation with an underlying kidney deficiency.

Herbal intervention 

In one trial (Wu SZ 2006b), women were randomised into three groups: CHM endometriosis pills (Nei Yi Wan) (n = 16), CHM endometriosis pills (Nei Yi Wan) plus CHM enema (n = 24), or danazol (n = 18). In another trial, women were randomised into two groups: Nei Yi Wan plus herbal enema (n = 48) or gestrinone (n = 52) (Wu SZ 2006a).

Herb formulation

Details of which herbs were used are included in the table Characteristics of included studies.

Comparisons and control groups

Chinese herbs were used in the active groups. Danazol or gestrinone were used in the control groups.

Outcomes measured

The included trials used the same Chinese validated outcomes (CAITWN 1991) and divided responses to treatment into four categories: 'symptomatic relief' described a complete resolution of all symptoms and signs and included pregnancy, when desired, within three years of stopping treatment; 'significant improvement' described when most symptoms resolved and pelvic masses were reduced in size; 'improvement' described symptomatic improvement and no worsening of symptoms within three months of stopping the treatment but only minor or no change in pelvic masses; and finally 'no effect' was where symptoms either remained unchanged or worsened during the intervention.

Fertility rates were reported in one trial (Wu SZ 2006a).

The two trials reported the incidence of adverse effects as an outcome.

Data were also presented describing changes in the biochemical markers CA 125, a cancer antigen, and EmAb. Whilst these may reflect the measurable effects of an intervention and contribute to the biological plausibility of CHM, they are not considered in this review. Neither would they be considered as 'objective disease markers' in western gynaecological practice.

Excluded studies

In the first analysis, 85 trials were excluded from the review for the following reasons: 43 trials did not have equal numbers in the experimental and control groups and did not present a clear account of the randomisation procedures leading to this discrepancy; 13 trials combined CHM with several other non‐herbal therapeutic interventions (such as acupuncture) as part of the experimental intervention; 10 trials used non‐authorised or experimental treatments such as mifepristone or tamoxifen as the control intervention; six trials did not report results using validated diagnostic criteria or outcomes measures; five trials had insufficient or unclear data to enable a reasonable assessment of the trial; four trials did not consider the primary or secondary outcomes defined for this review; three trials were not RCTs; and one was a duplicate report.

This left 25 randomised trials for consideration. However, insistence on a laparoscopic diagnosis and a new Cochrane requirement to contact all authors of Chinese RCTs to check for adequate randomisation procedures resulted in a second analysis where 12 trials were excluded because they did not have a laparoscopically confirmed diagnosis. Of the remaining 13 trials, 11 were excluded because: for three the authors could not be contacted; two authors refused to respond to questions relating to randomisation; three trials allocated participants according to patient preference; and three trials were quasi‐randomised, according to the time of their first visit.

An updated search completed in October 2010 identified another 39 trials for consideration. Only five of these trials reported details of laparoscopic confirmation or randomisation. After phone call confirmations it was apparent that three of these papers did not employ adequate randomisation and for the remaining two trials the authors could not be contacted. As a result there has been no amendment to the previous findings of this review. An further updated search in October 2011 identified 47 trials, and only four trials appeared eligible for inclusion. After checking against inclusion criteria, they were all excluded and the reasons were presented in the table 'Characteristics of excluded studies'.

Risk of bias in included studies

See Figure 1; Figure 2

The included trials (Wu SZ 2006a; Wu SZ 2006b) described adequate ('A') randomisation and allocation concealment methods using a random numbers generated randomisation sequence which was transferred to sealed envelopes. The trials also reported single blinding for participants, and assessor blinding. Both trials were given an overall 'B' status with a moderate risk of bias.

Allocation

Both studies were rated as at low risk of this bias because they used acceptable methods of randomisation and allocation concealment.

Blinding

Both studies were rated as at high risk of these biases because of the use of an active herbal enema without any inert control.

Incomplete outcome data

Both studies were rated as at low risk of this bias because few or no participants were excluded from the analysis.

Selective reporting

Both studies were rated as at low risk of this bias because they reported the expected outcomes.

Other potential sources of bias

Both studies were rated as at low risk of other potential sources of bias.

Effects of interventions

See: Table 1

Chinese herbal medicine versus gestrinone

Overall, 100% of women in both the CHM and the gestrinone groups showed some improvement in their symptoms. However, in some participants this may have been a relatively minor improvement in symptoms whilst in others it related to more substantial resolution of pelvic masses, disappearance of symptoms, and a successful pregnancy.

There was no significant difference between the CHM Nei Yi Wan (oral plus enema) and gestrinone for the symptomatic relief rate (95.65% versus 93.87%; RR 1.02, 95% CI 0.93 to 1.12) (Wu SZ 2006a). The intention‐to‐treat analysis also showed no significant difference between the groups for the symptomatic relief rate (RR 1.04, 95% CI 0.91 to 1.18). The study followed the patients for one to 24 months for pregnancy. The number of participants with confirmed pregnancy was 4 (at 3 months), 17 (at 4 to 6 months), 8 (at 7 to12 months), 2 (at 13 to 24 months), and 1 (at over 24 months) in the CHM group; while it was 0, 12, 12, 3, and 2 in the gestrinone group, respectively. There was no significant difference between the two groups with regard to the total pregnancy rate (69.6% versus 59.1%; RR 1.18, 95% CI 0.87 to 1.59) (Wu SZ 2006a).

Chinese herbal medicine versus danazol

In total, 100% of women in the CHM and danazol groups showed some improvement in their symptoms.

The CHM Nei Yi Wan and Nei Yi Wan plus enema groups reported a greater proportion of women obtaining symptomatic relief than for danazol (56.3% versus 11.1%; RR 5.06, 95% CI 1.28 to 20.05; and 62.5% versus 11.1%; RR 5.63, 95% CI 1.47 to 21.54, respectively) (Wu SZ 2006b).

Oral plus enema administration of the CHM Nei Yi formulation showed a greater reduction in average dysmenorrhoea pain scores than with danazol (MD ‐2.90, 95% CI ‐4.55 to ‐1.25; P < 0.01). There were no significant differences between either CHM Nei Yi pills and danazol (MD ‐1.01, 95% CI ‐3.11 to 1.09) or CHM oral plus enema and danazol (MD ‐1.89, 95% CI ‐3.89 to 0.11).

Combined administration of CHM Nei Yi, orally and by enema, showed a greater improvement measured as the disappearance or shrinkage of adnexal masses than did treatment with danazol (RR 1.70, 95% CI 1.04 to 2.78). For lumbosacral pain, rectal discomfort, or vaginal nodules tenderness there was no significant difference either between CHM Nei Yi pills and danazol or between CHM oral plus enema and danazol (Comparisons 2.3 to 2.6).

Adverse effects

No significant adverse effects were observed in the 46 participants who received CHM Nei Yi Wan plus CHM Nei Yi enema (Wu SZ 2006a). Thirteen out of 49 participants who received gestrinone developed acne, 19 developed increased glutamic alanine transaminase (GPT) levels (which returned to normal after termination of the treatment), and 31 had oligomenorrhoea (Wu SZ 2006a). In the second trial (Wu SZ 2006b), four patients had a dry mouth, and one patient had acne of the 16 patients who took CHM Nei Yi Wan; two patients had dry mouth, 11 had rectal tenesmus in the initial two weeks, and one had a weight gain of 3 kg in the 24 patients who received CHM oral plus enema. In contrast, in the danazol group 13/18 developed acne, 3/18 had a weight gain of 3 kg, 2/18 a weight gain of 2 kg, 1/18 a weight gain of 1.5 kg, 2/18 increased GPT levels, and 4/18 oligomenorrhoea.

Discussion

Summary of main results

There were only very limited data available from two small trials comparing the same CHM interventions with two conventional treatments for endometriosis, danazol and gestrinone. The comparison of CHM with gestrinone showed no evidence of a difference between the two groups in the rates of symptomatic relief and pregnancy. However, there were fewer side effects in the CHM group than in the gestrinone and danazol groups. It should be noted that the shrinkage of adnexal masses reported in these trials was determined by ultrasound investigation and not via laparoscopy.

Overall completeness and applicability of evidence

There was an unexplained discrepancy in the rates of symptomatic relief between the two trials. Wu SZ 2006a reported a symptomatic relief rate for CHM of 95.65% and 93.87% for gestrinone; whilst Wu SZ 2006b reported symptomatic relief rates for oral CHM, oral plus enema CHM, and danazol of 56.3%, 62.5%, and 11.1%, respectively. Both trials used the same standardised assessment measures (CAITWN 1991), however discussion with the authors revealed that in Wu SZ 2006a laparoscopic investigation and confirmation of endometriosis was combined with active surgical treatment for both groups whilst in Wu SZ 2006b laparoscopy was solely for diagnostic purposes. This explains the substantial difference in rates of symptomatic relief between the two groups but introduces a new variable into the analysis. In effect we have one trial (Wu SZ 2006a) comparing laparoscopic treatment with either gestrinone or CHM as a post‐surgical adjuvant treatment and a second trial (Wu SZ 2006b) comparing purely medical interventions. Both trials reflect treatment options that are relevant to the management of endometriosis.

The completeness of the available data is limited by the tendency of Chinese reports to be restricted to two to three pages in length. These reports do not have the same depth of information required by Western journals. With regard to fertility, the papers do describe how many women are married and how many are sexually active but there are no relevant data on fertility (duration, clinical investigations etc). Other symptoms such as dyspareunia may be included in the overall analysis of symptoms but are not described as a separate outcome.

Fundamental to the understanding of endometriosis in Chinese medicine is the notion of stagnation of Qi, or vital energy, as a pre‐requisite for the subjective experience of pain; and of blood, which tends to localise and intensify the experience of pain and can lead to the formation of distinctive, substantial lesions. Differential diagnosis is further refined into a number of single or complex syndromes on the basis of information derived from traditional methods of clinical assessment such as tongue and pulse diagnosis, investigation of aetiological factors, the subjective presentation of the symptoms of endometriosis (for example a description of the nature and location of the pain), and an evaluation of the general health of the patient as evidenced from sleep patterns, digestive status, and subjective sense of temperature for example. This complex and involved process is considered essential to the successful treatment of the disease.

For a comprehensive introduction to Chinese medicine see Maciocia (Maciocia 1998).

Quality of the evidence

There are no clear data on participant blinding during the trials. Although Wu SZ 2006a and Wu SZ 2006b claimed to be single blind trials, it is difficult to know how this was maintained in the group receiving the herbal enema. There was no evaluation of the success of blinding during the trials. This increased the risk of bias in the trials.

Many of the trials that were excluded due to poor methodology described the ability of CHM to act as an immunological and hormonal modulator, and to break down the fibrous adhesions that characterize endometriosis. These data are interesting and suggest biologically plausible mechanisms that could underpin the effectiveness of CHM. However, a detailed analysis of this work is beyond the remit of this review.

Agreements and disagreements with other studies or reviews

Compared with danazol, both the CHM groups produced a greater rate of symptomatic relief. However the confidence intervals for these outcomes were very large, which brings into question the reliability of the findings. The combined oral plus enema approach also led to women in the CHM group having a greater reduction of average dysmenorrhoea scores and more shrinkage of adnexal masses than for those taking danazol. There was no difference between the oral CHM group and the danazol group for any of these outcomes. There was no evidence of a difference between CHM and danazol in the relief of lumbosacral pain or rectal irritation. Women taking danazol exhibited considerably more adverse effects than did women taking CHM.

Authors' conclusions

Implications for practice.

The included trials suggest that following laparoscopic surgery, combined oral and enema administration of CHM has a comparable beneficial effect to gestrinone but with fewer adverse effects. Oral and enema administration of CHM may be more effective than danazol in providing extended relief of endometriosis symptoms and in shrinking adnexal masses, with fewer adverse effects. However, these are two very small trials and it may not be possible to generalize the results.

Further research, with larger numbers of participants, is required to substantiate these results and to explore the role of CHM as a stand‐alone medical option or as a post‐surgical adjuvant in the treatment of endometriosis.

Implications for research.

Despite the large number of clinical trials exploring the role of CHM in the treatment of endometriosis methodological shortcomings have led to the exclusion of all but two trials. There are a number of reasons for these exclusions including no laparoscopic confirmation of endometriosis, unequal group sizes, and a lack of validated outcomes. The most worrying shortcoming in the trial reports is a misunderstanding of what is required for a randomised controlled trial. The use of quasi‐randomisation or allocation according to patient preference does not constitute adequate randomisation and allows an unacceptably high risk of bias in a trial. There is an urgent need for Chinese researchers to adopt rigorous standards of randomisation and allocation concealment and to present the data in a transparent fashion. The nature of CHM and herbal products make blinding problematic and CHM clinical trials may have to be more pragmatic. In addition, it was not clear from the trial reports that laparoscopy involved active treatment in one case whilst in the other it was used only for diagnostic purposes. This is poor quality reporting that has the potential to confuse and undermine CHM research.

It is important that transparent, pragmatic but rigorous clinical research methodologies are developed that accommodate the complex, individualised, and changing nature of CHM interventions. Future research should provide more detailed accounts of symptomatic changes to include, for example, dyspareunia and daily pelvic pain rather than amalgamating these symptoms into an overall measure of change. In addition, future research should incorporate quality of life outcome measures and qualitative research to provide a more detailed account of the effect of the CHM intervention on the lives of women suffering from this disease. Finally, it is also essential that any research investigating CHM for endometriosis incorporates an extended follow‐up period to identify any long‐term benefits and to make an accurate record of rates of recurrence after CHM treatment. This will be an important point of comparison between CHM and conventional medicine.

In the period between the original review in 2009 and the revised review in 2012 it appears that the methodological quality of clinical trials of CHM for endometriosis has not improved. This apparent lack of development is unfortunate as it continues to undermine the ability of CHM trials to contribute to rigorous systematic reviews.

Feedback

Comments from Professor Colquhoun, 16 June 2012

Summary

While I don't dispute the conclusions, this review seems to be written in a very partisan way. 
 1. The section on "how the intervention might work" is written much as one would expect from true believers in Traditional Chinese Medicine (TCM). Pre‐scientific ideas should not be part of a Cochrane review. 
 2. Sentences like the following also exemplify this problem: "Fundamental to the understanding of endometriosis in Chinese medicine is the notion of stagnation of Qi, or vital energy, as a pre‐requisite for the subjective experience of pain; and of blood, which tends to localise and intensify the experience of pain and can lead to the formation of distinctive, substantial lesions". The idea of "Qi" is pre‐scientific myth, and need not be mentioned in the assessment of clinical trials. 
 3. The abstract, under main results, says "Two Chinese RCTs involving 158 women were included in this review. Both these trials described adequate methodology. Neither trial compared CHM with placebo treatment." That immediately suggests that there is little stuff that's worth reviewing. Yet the plain language summary says 
 "This review suggests that Chinese herbal medicine (CHM) may be useful in relieving endometriosis‐related pain with fewer side effects than experienced with conventional treatment." This seems absurdly upbeat, given what was actually discovered. 
 4. The authors of this review seem to be true believers in TCM. The first author, at least, makes his living from it. No doubt anyone who does a trial hopes that the new treatment will turn out well, but most do not have an ideological belief that one treatment is better than another. That is certainly not true in alternative medicine. 
 It seems to me to be quite inappropriate for Cochrane reviews of alternative medicine to be written by people who make their living from practising it. Such people, by definition, believe in concepts that are outside science. This is not the first Cochrane review to suffer from this problem. In the interests of maintaining your excellent reputation, I suggest that you give this matter serious consideration.

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

1.The basis of Traditional Chinese Medicine (TCM) is to provide a set of clinical syndromes that describe the detailed presentations for a particular condition. These small, but to the Chinese clinically relevant differences, directly affect the herbal prescription provided to the patient. The syndromes represent a detailed phenotypic description of the presenting problem.

2. The quoted sentence about Qi is taken out of context and the author of the letter therefore implies that we have a belief system that is at odds with good science. This is incorrect. Our description is about how TCM should be evaluated regarding endometriosis. It does not directly impact on the very rigorous Cochrane systematic review process and assessment of the trials but it does provide some background information for the reader. Our group agreed that these phenotypic descriptions may possibly prove to have some clinical value and we would be remiss to leave them out at this stage. The history of science suggests that there is a danger in adhering too firmly to existing understanding/paradigms and too easily reject observations that do not fit with that understanding. Surely a great strength of science is to explore and quantify observations that may seem unlikely and investigate them thoroughly‐ in this particular case to search and critique the empirical evidence of effectiveness – and not to dismiss them because they offend our current understanding of what is plausible and real? In response to the Prof Colquoun's concerns we have edited the Background section of the review and provided some additional material about what constitutes a CHM intervention and introduced some of the modes of action that might be involved as biologically plausible mechanisms for CHM.

3. Cochrane reviews undergo an extremely rigorous peer‐reviewed process. Only 2 out of 196 trials made it through this process. The two trials reported provided important comparisons with existing treatments, so for patients and clinicians are well worth reviewing and reporting. Our summary is a cautious and accurate assessment of the evidence that we considered. We also make it very clear that further work is needed to substantiate these findings. We are aware that a significant number of Cochrane reviews come to similar conclusions for both conventional and complementary medicine and are available on the Cochrane website. We have edited the Plain Language Summary of the review to specify which conventional treatments were reviewed.

4. There is no evidence (other than hearsay from the author of the letter) for the statement that the authors are ‘true believers’. Clinicians working in areas of uncertainty in both conventional and complementary medicine need to determine and critique the evidence base for their practice. It is vital that clinicians with expertise in their clinical areas are involved in research, including systematic reviews. This applies to all or most Cochrane reviews both on Complementary and Alternative Medicines (CAM) and in more traditional clinical areas, and is the basis of academic medicine. Academic GPs who make a living from being GPs are essential contributors to Cochrane reviews of therapies for primary care as indeed would be the case for all medical specialities. It would be harmful for the research process if general physicians, GPs and pharmacologists could not work in the areas where they receive funding for their clinical or research work. The research process in this review was rigorous and transparent and like all good science can be replicated by others in the scientific community using the same methods.

It is perhaps worth noting that a better term to avoid unnecessary polarisation of views and practice in this area is Complementary and Alternative medicine.

Contributors

Professor David Colquhoun, University College London

Andrew Flower, University of Southhampton

Jian Ping Liu, Beijing University of Chinese Medicine

George Lewith,University of Southampton

Paul Little, University of Southampton

Qing Li, Beijing University of Chinese Medicine

What's new

Date	Event	Description
10 July 2012	Feedback has been incorporated	Background amended to include more detail. Minor edits to abstract and plain language summary. No change to conclusions.

History

Protocol first published: Issue 2, 2007
 Review first published: Issue 3, 2009

Date	Event	Description
19 March 2012	New search has been performed	An updated search of the same electronic databases has been conducted. No additional studies were able to be included in the review.
19 March 2012	New citation required but conclusions have not changed	No new studies could be added to the review.
7 April 2008	Amended	Converted to new review format.
9 February 2007	New citation required and major changes	Substantive amendment

Appendices

Appendix 1. Search strategies

AMED (Allied and Complementary Medicine)

1 Controlled study/ or Randomized Controlled Trial/ 
 2 Placebo/ 
 3 Random$.tw. 
 4 latin square.tw. 
 5 crossover.tw. 
 6 cross‐over.tw. 
 7 placebo$.tw. 
 8 ((doubl$ or singl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw. 
 9 (comparativ$ adj5 trial$).tw. 
 10 (clinical adj5 trial$).tw. 
 11 animal/ not (human/ and animal/) 
 12 alternative medicine/ or traditional medicine/ or chinese medicine/ 
 13 Complementary Therapie$.ti,ab,hw,tn,mf. 
 14 Plant Extract/ 
 15 phytodrug$.ti,ab,hw,tn,mf. 
 16 phytopharmaceutic$.ti,ab,hw,tn,mf. 
 17 (traditional adj medicine).ti,ab,hw,tn,mf. 
 18 alternative medicine.ti,ab,hw,tn,mf. 
 19 Complementary Therap$.ti,ab,hw,tn,mf. 
 20 plant extract$.ti,ab,hw,tn,mf. 
 21 herb$.ti,ab,sh. 
 22 or/1‐10 
 23 22 not 11 
 24 or/12‐21 
 25 Endometriosis/ or endometriosis.mp. 
 26 24 and 25 
 27 23 and 26 
 28 from 27 keep 1‐2

EBM Reviews ‐ Cochrane Central Register of Controlled Trials 
 
 1 randomized controlled trial.pt. 
 2 controlled clinical trial.pt. 
 3 Randomized Controlled Trials/ 
 4 Random allocation/ 
 5 double‐blind method/ 
 6 single‐blind method/ 
 7 Random$.tw. 
 8 clinical trial.pt. 
 9 exp clinical trials/ 
 10 (clin$ adj25 trial$).ti,ab,sh. 
 11 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).ti,ab,sh. 
 12 Placebos/ 
 13 placebo$.ti,ab,sh. 
 14 random$.ti,ab,sh. 
 15 Research design/ 
 16 or/8‐15 
 17 animal/ not (human/ and animal/) 
 18 7 or 16 
 19 18 not 17 
 20 medicine, traditional/ or medicine, chinese traditional/ 
 21 Complementary Therapies/ 
 22 plant extracts/ or drugs, chinese herbal/ 
 23 Plants, Medicinal/ 
 24 Drugs, Non‐Prescription/ 
 25 herb$.ti,ab,sh. 
 26 Chinese medicine.ti,ab,sh. 
 27 Phytotherapy/ 
 28 phytopharmaceutic$.ti,ab,sh. 
 29 (herb$ adj5 therap$).ti,ab,sh. 
 30 (traditional adj medicine).ti,ab,sh. 
 31 alternative medicine.ti,ab,sh. 
 32 Complementary Therap$.ti,ab,sh. 
 33 plant extract$.ti,ab,sh. 
 34 or/20‐33 
 35 endometriosis.mp. or Endometriosis/ 
 36 34 and 35 
 37 19 and 36 
 38 from 37 keep 1‐4

CINAHL ‐ Cumulative Index to Nursing & Allied Health Literature

1 Controlled study/ or Randomized Controlled Trial/ 
 2 Double blind procedure/ 
 3 Single Blind Procedure/ 
 4 Crossover procedure/ 
 5 Drug comparison/ 
 6 Placebo/ 
 7 Random$.tw. 
 8 latin square.tw. 
 9 crossover.tw. 
 10 cross‐over.tw. 
 11 placebo$.tw. 
 12 ((doubl$ or singl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw. 
 13 (comparativ$ adj5 trial$).tw. 
 14 (clinical adj5 trial$).tw. 
 15 or/7‐14 
 16 animal/ not (human/ and animal/) 
 17 15 not 16 
 18 alternative medicine/ or traditional medicine/ or chinese medicine/ 
 19 Complementary Therapie$.ti,ab,hw,tn,mf. 
 20 Plant Extract/ 
 21 Chinese Drug/ 
 22 Chinese Herb/ 
 23 Medicinal Plant/ 
 24 Non Prescription Drug/ 
 25 Herb/ 
 26 phytodrug$.ti,ab,hw,tn,mf. 
 27 phytopharmaceutic$.ti,ab,hw,tn,mf. 
 28 (traditional adj medicine).ti,ab,hw,tn,mf. 
 29 alternative medicine.ti,ab,hw,tn,mf. 
 30 Complementary Therap$.ti,ab,hw,tn,mf. 
 31 plant extract$.ti,ab,hw,tn,mf. 
 32 or/18‐31 
 33 endometriosis.mp. or ENDOMETRIOSIS/ 
 34 32 and 33 
 35 17 and 34 
 36 from 35 keep 1

EMBASE

1 Controlled study/ or Randomized Controlled Trial/ 
 2 Double blind procedure/ 
 3 Single Blind Procedure/ 
 4 Crossover procedure/ 
 5 Drug comparison/ 
 6 Placebo/ 
 7 Random$.tw. 
 8 latin square.tw. 
 9 crossover.tw. 
 10 cross‐over.tw. 
 11 placebo$.tw. 
 12 ((doubl$ or singl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw. 
 13 (comparativ$ adj5 trial$).tw. 
 14 (clinical adj5 trial$).tw. 
 15 or/7‐14 
 16 animal/ not (human/ and animal/) 
 17 15 not 16 
 18 alternative medicine/ or traditional medicine/ or chinese medicine/ 
 19 Complementary Therapie$.ti,ab,hw,tn,mf. 
 20 Plant Extract/ 
 21 Chinese Drug/ 
 22 Chinese Herb/ 
 23 Medicinal Plant/ 
 24 Non Prescription Drug/ 
 25 Herb/ 
 26 phytodrug$.ti,ab,hw,tn,mf. 
 27 phytopharmaceutic$.ti,ab,hw,tn,mf. 
 28 (traditional adj medicine).ti,ab,hw,tn,mf. 
 29 alternative medicine.ti,ab,hw,tn,mf. 
 30 Complementary Therap$.ti,ab,hw,tn,mf. 
 31 plant extract$.ti,ab,hw,tn,mf. 
 32 or/18‐31 
 33 endometriosis.mp. or ENDOMETRIOSIS/ 
 34 32 and 33 
 35 17 and 34 
 36 from 35 keep 1‐8

MEDLINE

1 randomized controlled trial.pt. 
 2 controlled clinical trial.pt. 
 3 Randomized Controlled Trials/ 
 4 Random allocation/ 
 5 double‐blind method/ 
 6 single‐blind method/ 
 7 or/1‐6 
 8 clinical trial.pt. 
 9 exp clinical trials/ 
 10 (clin$ adj25 trial$).ti,ab,sh. 
 11 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).ti,ab,sh. 
 12 Placebos/ 
 13 placebo$.ti,ab,sh. 
 14 random$.ti,ab,sh. 
 15 Research design/ 
 16 or/8‐15 
 17 animal/ not (human/ and animal/) 
 18 7 or 16 
 19 18 not 17 
 20 medicine, traditional/ or medicine, chinese traditional/ 
 21 Complementary Therapies/ 
 22 plant extracts/ or drugs, chinese herbal/ 
 23 Plants, Medicinal/ 
 24 Drugs, Non‐Prescription/ 
 25 herb$.ti,ab,sh. 
 26 Chinese medicine.ti,ab,sh. 
 27 Phytotherapy/ 
 28 phytopharmaceutic$.ti,ab,sh. 
 29 (herb$ adj5 therap$).ti,ab,sh. 
 30 (traditional adj medicine).ti,ab,sh. 
 31 alternative medicine.ti,ab,sh. 
 32 Complementary Therap$.ti,ab,sh. 
 33 plant extract$.ti,ab,sh. 
 34 or/20‐33 
 35 endometriosis.mp. or Endometriosis/ 
 36 34 and 35 
 37 19 and 36 
 38 from 37 keep 1‐11

Appendix 2. Commonly used Chinese herbs in the treatment of endometriosis.

Commonly used herbs in the treatment of endometriosis

 Herbs to move Blood

• E Zhu (Curcumae Rhizoma)

• San Leng (Sparganii Rhizoma)

• Dang Gui (Wei) (Angelica sinensis)

• Chi Shao (Paeoniae Radix rubra)

• Tao Ren (Persicae Semen)

• Dan Shen (Salviae miltiorrhizae Radix)

• Yan Hu Suo (Corydalis Rhizoma)

• Chuan Xiong (Chuanxiong Rhizoma)

• Wu Ling Zhi (Trogopterori Faeces)

• Hong Hua (Carthami Flos)

• Da Huang (Rhei Radix et Rhizoma)

• Mu Dan Pi (Moutan Cortex)

• Pu Huang (Pollen Typhae)

• Shui Zhi (Hirudo seu Whitmaniae)

• Yi Mu Cao (Leonuri Herba)

• Tu Bie Chong (Eupolyphaga/Steleophaga)

• Mo Yao (Myrrha)

• Ru Xiang (Olibanum)

• Xue Jie (Draconis Sanguis)

• San Qi (Notoginseng Radix)

• Chuan Niu Xi (Cyathulae Radix)

Herbs to move Qi 

• Xiang Fu (Cyperi Rhizoma)

• Wu Yao (Linderae Radix)

• Chai Hu (Bupleuri Radix)

• Chuan Lian Zi (Semen Nelumbinis Nuciferae)

• Zhi Ke (Aurantii Fructus)

Herbs to nourish Blood 

• Dang Gui (Angelica Radix sinensis)

• Bai Shao (Paeoniae Radix alba)

• Gou Qi Zi (Lycii Fructus)

 Herbs to nourish Qi 

• Huang Qi (Astragali Radix)

• Dang Shen (Codonopsitis Radix)

• Bai Zhu (Atractylodes radix)

 Herbs to invigorate Yang 

• Du Zhong (Eucommiae Cortex)

• Ba Ji Tian (Morindae officinalis Radix)

• Xu Duan (Dipsaci Radix)

• Yin Yang Huo (Herba Epimedii)

• Tu Si Zi (Cuscutae Semen)

Herbs to dispel Cold

• Gan Jiang (Zingiberis Rhizoma

• Wu Zhu Yu (Evodiae Fructus)

• Rou Gui (Cinnamomi Cortex)

• Hui Xiang (Foeniculu Fructus)

Herbs to resolve Phlegm and soften hardness

• Zao Jiao Ci (Spina Gleditsiae Sinensis)

• Mu Li (Ostreae Concha)

• Xia Ku Cao (Prunellae Spica)

• Hai Zao (Herba Sargassii)

• Kun Bu (Eckloniae Thallus)

Herbs to clear Fire Poison

• Hong Teng (Sargentodoxae Caulis)

• Bai Jiang Cao (Patriniae Herba)

Data and analyses

Comparison 1. CHM versus gestrinone.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Symptomatic relief	1	95	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.93, 1.12]
2 Symptomatic relief rate (intention‐to‐treat)	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.91, 1.18]
3 Pregnant rate (accumulated from 3‐24 months of follow‐up)	1	95	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.87, 1.59]

1.1. Analysis.

Comparison 1 CHM versus gestrinone, Outcome 1 Symptomatic relief.

1.2. Analysis.

Comparison 1 CHM versus gestrinone, Outcome 2 Symptomatic relief rate (intention‐to‐treat).

1.3. Analysis.

Comparison 1 CHM versus gestrinone, Outcome 3 Pregnant rate (accumulated from 3‐24 months of follow‐up).

Comparison 2. CHM versus danazol.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Symptomatic relief	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 CHM Nei Yi pills vs Danazol	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	5.06 [1.28, 20.05]
1.2 CHM Nei Yi pills + CHM Nei Yi enema vs Danazol	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	5.63 [1.47, 21.54]
2 Dysmenorrhea score	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 CHM Nei Yi pills vs Danazol	1	34	Mean Difference (IV, Fixed, 95% CI)	‐1.01 [‐3.11, 1.09]
2.2 CHM Nei Yi pills + CHM Nei Yi enema vs Danazol	1	42	Mean Difference (IV, Fixed, 95% CI)	‐2.9 [‐4.55, ‐1.25]
3 Lumbosacral pain relief	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 CHM Nei Yi pills versus Danazol	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.86, 1.70]
3.2 CHM Nei Yi pills + CHM Nei Yi enema vs Danazol	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.82, 1.62]
4 Rectal Irritation relief	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1 CHM Nei Yi pills vs Danazol	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.90, 3.10]
4.2 CHM Nei Yi pills + CHM Nei Yi enema vs Danazol	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.78 [0.99, 3.20]
5 Tenderness of vaginal nodules in posterior fornix	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1 CHM Nei Yi pills vs Danazol	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.87, 1.97]
5.2 CHM Nei Yi pills + CHM Nei Yi enema vs Danazol	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.84, 1.90]
6 Adnexal masses disappearance or shrinkage	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.1 CHM Nei Yi pills vs Danazol	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.79, 2.50]
6.2 CHM Nei Yi pills + CHM Nei Yi enema vs Danazol	1	36	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [1.04, 2.78]

2.1. Analysis.

Comparison 2 CHM versus danazol, Outcome 1 Symptomatic relief.

2.2. Analysis.

Comparison 2 CHM versus danazol, Outcome 2 Dysmenorrhea score.

2.3. Analysis.

Comparison 2 CHM versus danazol, Outcome 3 Lumbosacral pain relief.

2.4. Analysis.

Comparison 2 CHM versus danazol, Outcome 4 Rectal Irritation relief.

2.5. Analysis.

Comparison 2 CHM versus danazol, Outcome 5 Tenderness of vaginal nodules in posterior fornix.

2.6. Analysis.

Comparison 2 CHM versus danazol, Outcome 6 Adnexal masses disappearance or shrinkage.

Comparison 3. CHM versus CHM.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Symptomatic relief	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 CHM Nei Yi pills + CHM Nei Yi enema vs Nei Yi pills	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.65, 1.89]
2 Dysmenorrhea score	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 CHM Nei Yi pills + CHM Nei Yi enema vs Nei Yi pills	1	40	Mean Difference (IV, Fixed, 95% CI)	‐1.89 [‐3.89, 0.11]
3 Lumbosacral pain relief	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 CHM Nei Yi pills + CHM Nei Yi enema vs Nei Yi pills	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.74, 1.23]
4 Rectal Irritation relief	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1 CHM Nei Yi pills + CHM Nei Yi enema vs Nei Yi pills	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.79, 1.44]
5 Tenderness of vaginal nodules in posterior fornix	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1 CHM Nei Yi pills + CHM Nei Yi enema vs Nei Yi pills	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.74, 1.25]
6 Adnexal masses disappearance or shrinkage	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.1 CHM Nei Yi pills + CHM Nei Yi enema vs Nei Yi pills	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.85, 1.72]

3.1. Analysis.

Comparison 3 CHM versus CHM, Outcome 1 Symptomatic relief.

3.2. Analysis.

Comparison 3 CHM versus CHM, Outcome 2 Dysmenorrhea score.

3.3. Analysis.

Comparison 3 CHM versus CHM, Outcome 3 Lumbosacral pain relief.

3.4. Analysis.

Comparison 3 CHM versus CHM, Outcome 4 Rectal Irritation relief.

3.5. Analysis.

Comparison 3 CHM versus CHM, Outcome 5 Tenderness of vaginal nodules in posterior fornix.

3.6. Analysis.

Comparison 3 CHM versus CHM, Outcome 6 Adnexal masses disappearance or shrinkage.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Wu SZ 2006a.

Methods	Trial design: parallel randomised controlled trial Blinding: single blinding Study duration: December 1999 to May 2005 Statistics: adequate (Chi2 test used for 'overall improvement') Funding source declared
Participants	100 cases of endometriosis complicated by infertility Experimental group: 48 Control group: 52 Drop‐out rate: 5% (2 from experimental group, 3 from control group) Laparoscopic diagnosis: yes Other diagnostic criteria: Chinese validated criteria Baseline comparison: adequate
Interventions	Nei Yi pills (10g twice daily) plus Nei Yi enema (70ml daily) versus gestrinone (0.25 mg twice a week) for 3 months Nei Yi pills consisted of: Dan Shen (Salviae multiorrhizae Radix), Xue Jie (Draconis Sanguis), San Leng (Sparganii Rhizoma), E Zhu (Curcumae Rhizoma), Tao Ren (Persicae Semen), San Qi (Notoginseng Radix), Dang Gui (Angelica sinensis), Gui Zhi (Cinnamomi Ramulus), Xiang Fu (Cyperi Rhizoma), Niu Xi (Achyranthis bidentate Radix) Nei Yi enema consisted of: Dan Shen (Salviae multiorrhizae Radix), Xue Jie (Draconis Sanguis), Chi Shao (Paeonia rubra Radix), Hu Zhang (Radix et Rhizoma Polygoni Cuspidati), San Leng (Sparganii Rhizoma), E Zhu (Curcumae Rhizoma), Tao Ren (Persicae Semen) Treatment duration: 3 months
Outcomes	A) Clinical outcomes: 1. symptomatic relief (defined as disappearance of symptoms, pelvic mass; pregnancy or birth within 3 years for those with infertility) 2. significant improvement (almost complete disappearance of symptoms or shrinkage of pelvic mass by ultrasound; or pregnancy) 3. improvement (relief of symptoms but not disappearance, no change or moderate shrinkage of pelvic mass) 4. no effect (no change of symptoms or become worse) 5. overall improvement (1+2+3) B) Adverse effects
Notes	Follow up from 1‐24 months
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation	Low risk	Randomisation achieved using random number sequence from table in statistical textbook
Allocation concealment	Low risk	Allocation concealment achieved by sorting numbers into envelopes
Blinding All outcomes	High risk	Although described as patient and assessor blinded (and confirmed with author) there is no description of an attempt to match the herbal enema with an inert control, so it is very unlikely patients were not aware of which group they were allocated to
Incomplete outcome data addressed All outcomes	Low risk	Two cases in treatment group and three cases in control group were lost during follow up. Adequate outcomes data presented
Free of selective reporting	Low risk	Identified outcomes adequately reported as compared with the description in methods
Free of other bias	Low risk	No source of other bias noted

Wu SZ 2006b.

Methods	Trial design: parallel randomised controlled trial Blinding: described as single blinding Study duration: December 1999 to October 2003 Statistics: adequate (Mann‐Whitney test and Annova test used for data analyses) Funding source declared
Participants	58 cases of endometriosis with clear inclusion and exclusion criteria Experimental group 1: 16 Experimental group 2: 24 Control group: 18 Drop‐out rate: 0 Laparoscopic diagnosis: yes Other diagnostic criteria: Chinese validated criteria Baseline comparison: adequate
Interventions	Experimental group 1: Nei Yi pills (10g twice daily) Experimental group 2: Nei Yi pills (10g twice daily) plus Nei Yi enema (70ml daily) Control group: danazol (400mg/day) Nei Yi pills consisted of: Dan Shen (Salviae multiorrhizae Radix), Xue Jie (Draconis Sanguis), San Leng (Sparganii Rhizoma), E Zhu (Curcumae Rhizoma), Tao Ren (Persicae Semen), San Qi (Notoginseng Radix), Dang Gui (Angelica sinensis), Gui Zhi (Cinnamomi Ramulus), Xiang Fu (Cyperi Rhizoma), Niu Xi (Achyranthis bidentate Radix) Nei Yi enema consisted of: Dan Shen (Salviae multiorrhizae Radix), Xue Jie (Draconis Sanguis), Chi Shao (Paeonia rubra Radix), Hu Zhang (Radix et Rhizoma Polygoni Cuspidati), San Leng (Sparganii Rhizoma), E Zhu (Curcumae Rhizoma), Tao Ren (Persicae Semen) Treatment duration: 3 months
Outcomes	A) Clinical outcomes: 1. symptomatic relief (defined as disappearance of symptoms, pelvic mass; pregnancy or birth within 3 years for those with infertility) 2. significant improvement (almost complete disappearance of symptoms, shrinkage of pelvic mass by ultrasound; or pregnancy) 3. improvement (relief of symptoms but not disappearance, no change or moderate shrinkage of pelvic mass) 4. no effect (no change of symptoms or become worse) 5. overall improvement (1+2+3) B) Adverse effects
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation	Low risk	Randomisation for allocation of three groups was generated through random number table
Allocation concealment	Low risk	Allocation sequence was concealed through numbered, sealed, opaque envelopes
Blinding All outcomes	High risk	Although described as patient and assessor blinded (and confirmed with author) there is no description of an attempt to match the herbal enema with an inert control, so it is very unlikely patients were not aware of which group they were allocated to
Incomplete outcome data addressed All outcomes	Low risk	No patient was lost during treatment or follow up
Free of selective reporting	Low risk	Identified outcomes adequately reported compared with the descriptions in the methods
Free of other bias	Low risk	No source of other bias noted

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Bian 2009	No laparoscopic confirmation
Cai 1999	Unequal group size with no account of randomisation process.
Chai H 1996	Unequal group size with no account of randomisation process.
Chai LS 2004	Unequal group size with no account of randomisation process.
Che 2006	Unequal group size with no account of randomisation process. Also non validated outcomes measures.
Chen 2003	Unequal group size with no account of randomisation process.
Chen 2006	Uses an experimental treatment (oral provera) as part of the active and control intervention.
Chen 2006a	Combines CHM with therapeuetic ultrasound.
Chen 2010	Didn't consider pain as a primary outcome
Chui YX	No clear data on diagnostic or outcomes criteria.
Cui 2010	No clear data on diagnostic criteria. Didn't consider pain as a primary outcome
Fan 2003	Combined TCM with experimental WM treatment (mifepristone).
Fan HX 2004	Group allocation according to patient preference
Fang 2003	Unequal group size with no account of randomisation process.
Fei 2004	Unequal group size with no account of randomisation process.
Fei 2009	No laparoscopic confirmation.Didn't consider pain as a primary outcome
Fong 2004	Insufficient and unclear data to enable a reasonable assessment of the trial.
Fong 2006a	Control group used experimental WM treatment (tamoxifen)
Fong DL 2006	Group allocation according to patient preference
Fu 2005	Acupuncture used together with CHM in active group.
Gao 2003	Unequal group size with no account of randomisation process.
Gu 2005	Not an randomised controlled trial.
Han 2001	Used experimental treatment (tamoxifen) as the control group.
Hao 2009	Combined TCM with experimental WM treatment(mifepristone)
He H 2004	Unequal group size with no account of randomisation process.
He JY 2005	Randomised according to patient preference
He RZ 2004	No laparoscopic confirmation
Hou 2010	No laparoscopic confirmation.Didn't consider pain as a primary outcome
Hu 2000	Unequal group size with no account of randomisation process.
Hu 2005	Unequal group size with no account of randomisation process.
Hu 2009	Control group used experimental WM treatment(mifepristone)
Huang 2000	Unequal group size with no account of randomisation process.
Huang 2000a	No validated outcomes criteria.
Huang 2009	Didn't consider pain as a primary outcome
Huang 2010	Group allocation according to the time of the patients' first visit
Jia 2004	Insufficient data to enable a reasonable assessment of the trial.
Kui JY 2001	Did not respond to questions relating to randomisation
Leng 2009	No laparoscopic confirmation. Didn't consider pain as a primary outcome
Li 1999	Unequal group size with no account of randomisation process.
Li 2003	Unequal group size with no account of randomisation process.
Li 2004	The trial did not use validated outcomes.
Li 2006	Unequal group size with no account of randomisation process.
Li 2007	Unequal group size with no account of randomisation process.
Li 2007a	Insufficient data on the primary outcome to enable a reasonable assessment.
Li 2009	Control group used electrochemical therapy
Li QX 2009	Didn't consider pain as a primary outcome
Li XL 2009	No laparoscopic confirmation
Lian 2009	Adequate and reliable details lacking regarding randomisation.
Liao 2004	Unequal group size with no account of randomisation process.
Liao 2010	No laparoscopic confirmation
Lin 2006	Unequal group size with no account of randomisation process.
Lin 2006a	Too many treatment variables‐including experimental treatment mifespristone.
Liu 1994	Too many treatment variables‐combined TCM plus hormonal treatment compared to a variety of hormonal control interventions.
Liu 1998	Unequal group size with no account of randomisation process.
Liu 1998a	Unequal group size with no account of randomisation process.
Liu 1998b	Too many treatment variables (CHM combined with Gossypol acetic acid and acupuncture).
Liu 2001	Unequal group size with no account of randomisation process.
Liu 2003	Use of acupuncture in the active treatment group.
Liu 2004	Unequal group size with no account of randomisation process. No validated outcomes measures.
Liu 2005	Did not consider pain as a primary outcome.
Liu 2009	No laparoscopic confirmation
Liu FY 2003	Did not respond to questions relating to randomisation
Liu GY 2003	Quasi‐randomised according to time of initial presentation
Lu 2003	Unequal group size with no account of randomisation process. Experimental treatment (tamoxifen) used as a control.
Lu 2005	Unequal group size with no account of the randomisation process and the use of an experimental treatment (mifepristone) as a control.
Lu 2007	Randomised trial in participants with endometriosis, but the diagnosis was not confirmed by laparoscopic procedure.
Lu 2007a	Adequate and reliable details lacking regarding randomisation.
Lu XP 1999	Unequal group size with no account of randomisation process.
Luo 2001	Used mifespristone‐experimental treatment for endometriosis as the control group
Luo 2006	Unequal group size with no account of randomisation process.
Ma 2009	No clear data on diagnostic or outcomes criteria
Mo 2010	Control group used experimental WM treatment(mifepristone)
Ou 2007	The trial did not use validated outcomes measures.
Pan XR 2003	No laparoscopic confirmation
Qi 2006	Unequal group size with no account of randomisation process.
Qi YH 2011	130 confirmed endometriosis patients were randomised into herbal treatment group (n=75) or no intervention control group (n=55) after laparoscopic surgery. After our telephone interview, we were told they used random number table to allocate patients. However, some patients (about 10) assigned to control group asked for herbal treatment and they were analysed in the herbal treatment group.
Qian 2000a	No validated outcomes criteria.
Qian J 2000	No laparoscopic confirmation
Qiu L 2005	Authors could not be contacted to confirm randomisation details
Qiu YJ 2004	No laparoscopic confirmation
Quan 2010	Group allocation according to the time of the patients' first visit
Ren YL 2005	Unequal group size with no account of randomisation process.
Ren YL2005	No laparoscopic confirmation
Shen XJ 2011	A clinical case series study without control group.
Shong 2005	Unequal group size with no account of randomisation process.
Si 2006	No validated outcomes criteria.
Su CZ 2002	No laparoscopic confirmation
Sun YZ 2003	No laparoscopic confirmation
Tang 2009	No laparoscopic confirmation
Tang 2010	Group allocation according to the time of the patients' first visit
Wang 1996	Unequal group size with no account of randomisation process.
Wang 1999	Too many treatment variables. CHM combined with penicillin, metronidazole + oral contraceptive compared with gestrinone.
Wang 2001	No validated outcomes measures. Control group used experimental treatment (tamoxifen).
Wang 2002	Used tamoxifen as a control for CHM. This is not a standard Western medical treatment for endometriosis.
Wang 2002a	No information on pain as a primary outcome.
Wang 2002b	Identical paper to Wang 1999.
Wang 2004	Unequal group size with no account of randomisation process.
Wang 2004a	Unequal group size with no account of randomisation process.
Wang 2005	Used experimental treatment (tamoxifen) as the control group.
Wang 2006a	Too many treatment variables. Also use Tamoxifen with CHM as active treatment with unequal group size and no account of randomisation.
Wang 2006b	Pain was not the primary outcome and the trial only provided data for pain reduction on 7/78 participants in the trial group and 12/78 in the control group.
Wang 2009	Didn't considet pain as a primary outcome
Wang 2010	Didn't consider pain as a primary outcome
Wang LX 2006	Authors could not be contacted to confirm details of randomisation.
Wang W 2009	Didn't consider pain as a primary outcome
Wang XR 2009	Didn't consider pain as a primary outcome
Wu 1999	Unequal group size with no account of randomisation process.
Wu 2000a	Confounding Comparison of Laparoscopy + CHM with CHM and with Danazol. Too many treatment variables.
Wu 2003a	No control group‐not a randomised controlled trial.
Wu 2004	Unequal group size with no account of randomisation process.
Wu 2006c	Part of a series of reports on the same trial. However this report considered the endometriosis markers EmAb and CA125 and did not provide any new clinical data relevant to this review.
Wu 2009	Authors could not be contacted to confirm randomisation details
Wu HY 2009	Didn't consider pain as a primary outcome
Wu SS 2000	No laparoscopic confirmation
Wu XJ 2009	Too many treatment variables
Xia 2010	No laparoscopic confirmation
Xiang 2001	Uses acupuncture as part of the active intervention.
Xiong 2004	Too many treatment variables (CHM combined with indomethacin or norethisterone or danazol).
Xu 2004	Unequal group size with no account of randomisation process.
Xu 2004a	Unequal group size with no account of randomisation process.
Xu 2004b	Unequal group size with no account of randomisation process.
Xu 2005	Unequal group size with no account of randomisation process.
Xu HX 2011	Trial was claimed to be randomised, but after we contacted with authors, we were confirmed that they did not implement real randomisation process to allocate patients.
Xuan JS 2005	Quasi randomised according to the time of patient presentation.
Xue 2009	Didn't consider pain as a primary outcome
Yan 2004	Insufficient data about outcomes criteria and unequal group size with no account of randomisation process.
Yang 2006	Quasi randomised according to the time of patient presentation.
Yang 2006a	Uses experimental treatment (tamoxifen) as a control. Also unclear outcomes measures and no report on pain reduction.
Yang 2006b	Unequal group size with no account of randomisation process and insufficient data for evaluation.
Yang HY 2001	No laparoscopic confirmation
Yang Y	Included acupuncture in the active treatment group.
Ye LQ 2004	No laparoscopic confirmation
Yu 1996	Too many treatment variables‐combined TCM plus hormonal treatment compared to a variety of hormonal control interventions. Also unequal group size with no account of randomisation process.
Yu 2003	Not a randomised controlled trial.
Yu 2010	Control group used experimental WM treatment(mifepristone)
Yuan 2003	Unequal group size with no account of randomisation process. Also too many treatment variables including CHM, surgery, danazol and tamoxifen.
Zhang 2004	Unequal group size with no account of randomisation process.
Zhang 2009	No validated outcomes criteria
Zhang 2010	Didn't respond to questions relating to randomisation
Zhang HQ2009	No laparoscopic confirmation
Zhao 2002	The trial did not use validated outcomes measures.
Zhao 2010	Randomised according to patient preference
Zhong 2009	Authors could not be contacted to confirm randomisation details
Zhou 2010	No clear data on diagnostic critetia
Zhu 2000a	Combined TCM with experimental WM treatment (mifepristone). Also unequal group size with no account of randomisation process.
Zhu 2001	Unequal group size with no account of randomisation process.
Zhu FH 2011	Trial was claimed to be randomised, but no information on randomisation methods. Our telephone contacts failed after trying several times.
Zhu HY 2002	No laparoscopic confirmation
Zhu L 2000	No laparoscopic confirmation
Zou 2010	No laparoscopic confirmation

Differences between protocol and review

In the protocol it was stated that quasi‐randomised trials would be included in the review. However these trials were excluded from the main review.

Contributions of authors

AF adapted the original title, developed the protocol, co‐authored the final review, and co‐ordinated the project. 
 AF and JPL co‐drafted the first versions of the protocol, and the final review. 
 AF and JPL conducted provisional Chinese and English language searches, and QL updated the searches and contacted authors to confirm trial eligibility for inclusion. 
 GL and PL reviewed and commented upon the initial drafts of the review.

SC and AF conducted the initial processes of trial selection and data extraction, reviewed and commented on by JPL. For the revised review LQ searched for and identified relevant studies. Any studies that may have been eligible for inclusion were discussed between LQ, JPL and AF.

Sources of support

Internal sources

• JP Liu and Q Li were supported by Beijing University of Chinese Medicine, China.

External sources

• Complementary Medicine Research Unit, UK.

Declarations of interest

None known

New search for studies and content updated (no change to conclusions), comment added to review