Meta-Analysis of Chinese Traditional Medicine Bushen Huoxue Prescription for Endometriosis Treatment

Objectives To evaluate the efficacy and safety of Bushen Huoxue prescription (BSHXP) for endometriosis. Methods A meta-analysis was performed, and studies were searched from the seven databases from the date of database establishment to April 30, 2017. Randomized controlled trials (RCTs) that explored the efficacy and safety of BSHXP for patients with endometriosis were included. Two assessors independently reviewed each trial. The Cochrane Risk of Bias assessment tool was used for quality assessment. Results In the 13 included studies, the total effectiveness rates of BSHXP were higher than those of Western medicine (RR, 1.55; 95% CI, 1.03–2.32; P = 0.04), but the dysmenorrhea alleviation rates of the two treatments did not significantly differ (RR, 1.28; 95% CI, 0.70–2.34; P = 0.42). The pregnancy rates of BSHXP were also higher than those of hormone therapy (RR, 1.99; 95% CI, 1.17–3.39; P = 0.01). However, whether BSHXP is more effective than Western medicine in diminishing endometriotic cyst remains unknown. Conclusions Our study provides evidence that BSHXP is effective and safe for endometriosis, but this evidence is inconclusive because of the low methodological quality of the included RCTs. Our findings suggest that BSHXP is an alternative drug for endometriosis, but it should be further examined in future clinical research.


Introduction
Endometriosis is a gynecological disease characterized by the presence and growth of ectopic endometrial tissue and often associated with inflammation, chronic pain, and infertility [1]. Compared with normal females, affected women are at a twofold to threefold increased risk of developing ovarian cancer, although endometriosis is a seemingly benign disease [2]. The prevalence of endometriosis approximately ranges from 2% to 10% of reproductive aged women and to 50% of infertile women [3,4]. Endometriosis can significantly influence the quality of life, ability to work, and fertility of reproductive aged women [5]. However, endometriosis is poorly understood, and the incidence of endometriosis likely increases [6]. The definitive treatment for endometriosis remains a difficult problem [7]. Current treatment strategies 2 Evidence-Based Complementary and Alternative Medicine  been developed. Among various therapies for endometriosis, traditional Chinese medicine (TCM) has been preferred by women with endometriosis [14]. According to TCM theory, kidney deficiency and blood stasis are a common syndrome of endometriosis, which is usually characterized by various conditions, such as dysmenorrhea, back pain, blood clots in menstruation, cold hands and feet, and fatigue [15]. Endometriosis is effectively treated with Bushen Huoxue prescription (BSHXP). In vivo tests have shown that BSHXP can inhibit the invasion of endometrial stromal cells and the expression of MMP-9 [16]. Animal experiments have demonstrated that BSHXP can promote the ability of apoptotic cells in endometriosis to hasten the atrophy and regression of endometriotic tissues [17].
However, data supporting the validity of this treatment are insufficient. This systematic review aimed to evaluate the efficacy and safety of BSHXP as a treatment for endometriosis by integrating different outcomes from clinical studies.

Types of Participants.
Only female patients who satisfied at least one of the current diagnostic standards of endometriosis and kidney deficiency and blood stasis syndrome were included. No limitations on ethnicity or nationality were set. Patients with adenomyosis were excluded.

Types of Interventions.
RCTs that observed and compared the effects of BSHXP and Western medicine were identified. Patients in the treatment group were given a kidney-tonifying and blood-activating formula. Patients in the control group were treated with Western medicine. Patients were excluded when the trials included other cointerventions, including another herbal formula. We did not set limitations on dosages and routes of the administration of the traditional Chinese herbs.

Types of Outcome Measures.
The primary outcomes in this study were the total effectiveness rate, dysmenorrhea alleviation rate, and pregnancy rate. The secondary outcomes were changes in the size of endometriotic cyst and adverse events. The total effectiveness rate was assessed according to the evaluation criteria of the Guidelines of Clinical Research of New Drugs of Traditional Chinese Medicine (Table 1). Shan and W. Cheng). The references of the identified studies and ongoing registered clinical trials were also manually searched to retrieve unpublished articles. No restriction on language or publication status was set. The search terms for the literature search were as follows: ("endometriosis" OR "dysmenorrhea" OR "dyspareunia" OR "pelvic pain") AND ("tonifying kidney and activating blood" OR "bu shen" OR "wen shen" OR "zi shen" OR "huo xue" OR "qu yu" OR "xiao zheng") AND ("clinical trial" OR "randomized controlled trial" OR "randomised controlled trial").

Data Extraction. Two reviewers (Dong-xia Zhai and
Dan-ying Zhang) extracted basic information independently by using a standardized data extraction form. Disagreements were resolved by discussion or consensus with a third reviewer (Chao-qin Yu). Some important data, including first author's name, publication year, sample size, treatment interventions and control groups, BSHXP composition, treatment duration, outcome measures, and adverse effects, were extracted from primary trials. If a study was incomprehensive Evidence-Based Complementary and Alternative Medicine 3 or uncertain, we then contacted the corresponding author by telephone, email, and fax to obtain the correct data.

Assessment of Risk of Bias.
The risk of bias of the eligible trials was assessed by two independent authors using the Cochrane Risk of Bias tool [19]. Disagreements were resolved by obtaining consensus with a third reviewer (Chao-qin Yu). The risk of bias was evaluated on the basis of these domains: (1) selection bias (adequate sequence generation and concealment of allocation); (2) performance bias (blinding of the investigator and blinding of the assessor); (3) detection bias (blinding of the assessor); (4) attrition bias (incomplete outcome data addressed); (5) reporting bias (free of selective reporting); and (6) other sources of bias (other potential threats to validity).

Data
Analyses. BSHXP and Western medicine were compared in this review. Outcome measures after treatment were presented as risk ratio (RR) with 95% CI for dichotomous outcomes. Cochrane's values and 2 tests were determined to examine the level of heterogeneity between trials. A random-effects model was used to evaluate the effects of BSHXP on endometriosis if 2 > 50% or < 0.1. Otherwise, a fixed-effects model was utilized.
< 0.05 was considered statistically significant. Data were subjected to meta-analysis by using Review Manager 5.3 (Cochrane Community, London, United Kingdom, 2014).

Study Selection.
A total of 146 studies were collected through document retrieval. Of these studies, 12 duplicate publications were removed. After their titles and abstracts were scanned, 77 articles were also excluded because they were clinical experience reports, case studies, and animal research. The 28 remaining full-text articles were further analyzed, but 15 trials were also eliminated because of the following: 2 non-RCT studies, 3 articles with duplicate publication of data, 4 articles with mixed interventions, and 6 articles with a control group containing herbal therapies. Finally, 13 eligible studies involving 936 patients with endometriosis were included in our meta-analysis ( Figure 1). Table 2. This meta-analysis included 13 trials. Of these trials, 12 were published in Chinese and 1 was presented in English. Of the 936 patients with endometriosis enrolled in these trials, 492 were assigned to the treatment group and 444 were designated in the control group. The sample sizes of these trials ranged from 48 to 120. The baseline in all of the trials did not significantly differ.

Total Effectiveness
Rates. In 10 studies, 633 patients with endometriosis were included. The experimental and control groups received BSHXP and Western medicine, respectively. Heterogeneity tests involved a fixed-effects model to describe the data of the total effectiveness ( 2 = 8.18; = 0.52; 2 = 0%). Our meta-analysis confirmed that the total effective rate of the BSHXP group was higher than that of the control group (RR, 1.55; 95% CI, 1.03-2.32; = 0.04, Figure 3(a)).

Dysmenorrhea Alleviation
Rates. In 7 studies, the effects of BSHXP and Western medicine on dysmenorrhea were compared and evaluated. Of the 314 patients with  endometriosis included in these studies, 167 were included in the BSHXP group and 147 were assigned in the Western medicine group. The pooled results from these trials did not significantly differ in terms of the dysmenorrhea alleviation rates between the two groups (RR, 1.28; 95% CI, 0.70-2.34; = 0.42, Figure 3(b)).

Pregnancy Rates.
In 3 trials, pregnancy rates were reported. A total of 114 patients were included in the BSHXP group and 103 patients were assigned to the control group. Our meta-analysis showed that the pregnancy rates of the BSHXP group were higher than those of the Western medicine group (RR, 1.99; 95% CI, 1.17-3.39; = 0.01, Figure 3(c)).

Change in Size of Endometriotic Cysts.
In 6 studies, changes in the size of ectopic cysts were described. Three studies [24,27,29] compared the maximum cross-sectional areas of the cysts; two studies [20,30] compared the maximum diameter line; one study [32] compared the reduction rates. Data could not be analyzed statistically because of inconsistent measurement standards. Thus, we only described the results of the original study.
In 2 studies [24,29], the sizes of the cyst before and after treatment between BSHXP-and Western medicine-treated groups did not significantly differ ( > 0.05). Also the sizes of the cysts between the two groups did not also significantly vary after treatment ( > 0.05). In 4 studies [20,27,30,32], the size of the cysts significantly differed ( < 0.05) before and after treatment between BSHXP-and Western medicinetreated groups. Nevertheless, the sizes of the cysts in these two groups did not significantly differ after treatment ( > 0.05).
Thus, our findings failed to support that TCM was more effective than Western medicine in reducing the size of endometriotic cysts.

Summary of Evidence.
A total of 936 patients with endometriosis were collected from the 13 RCTs in the review. The baseline of each study was consistent, and no statistical heterogeneity was observed. Our meta-analysis obtained the following results: (1) BSHXP did not significantly differ from Western medicine in terms of improving endometriosisrelated symptoms and syndromes. (2) Similar to Western medicine, BSHXP emerged as an effective alternative therapy to alleviate endometriosis-associated pain. (3) BSHXP could significantly enhance the clinical pregnancy rate, but this conclusion should be further verified in future studies. (4) Studies have yet to provide evidence supporting that BSHXP is more effective than Western medicine in terms of reducing the size of endometriotic cysts. (5) The adverse effects of BSHXP were less reported than those of Western medicine, although six trials described serious events. Considering the number of the analyzed RCTs and the high risk of bias, we experienced difficulty in obtaining our conclusions.

Promising Alternative Therapy for Endometriosis.
Longterm therapy is required for patients diagnosed with endometriosis. Current medical treatments may elicit side effects, such as inhibiting ovulation and menstruation and reducing estradiol to postmenopausal levels, because a definitive treatment for endometriosis has yet to be established [33,34]. However, the natural history of this disease remains poorly understood [34]. As a chronic condition, endometriosis threatens the health of patients and entails high cost of care [35,36]. Medical treatment should completely cure endometriosis rather than provide temporary relief from its symptoms [37]. In terms of endometriosis-associated infertility, new therapies have been developed to control pain symptoms without inhibiting ovulation [38]. New drugs replacing hormonal medicine for endometriosis will be available in the future, and these therapies should provide a normal and safe option for infertility [39]. In this regard, Chinese herbal medicines as complementary medicines are of great interest. Traditional Chinese medicine has been used to treat endometriosis. Tonifying kidney and activating blood stasis therapy may be a promising approach to treat endometriosis.
Considering syndrome differentiation and treatment system, doctors believe that endometriosis is mostly caused by kidney deficiency and blood stasis. Tonifying kidney and activating blood stasis prescriptions are designed. According to TCM theory, kidneys store essence and dominate reproduction. Chinese nourishing kidney herbs can regulate the hypothalamus-pituitary-ovary axis in dual directions and improve the functions of ovaries [40]. Liuwei Dihuang decoction, a well-known kidney-tonifying recipe, can enhance the rates of high-quality oocytes and embryos by regulating the microenvironment for oocytes of patients with endometriosis [41]. Ectopic cysts induce periodical bleeding defined in Chinese medicine as abnormal blood flow causing blood stasis. Activating blood herbs can promote blood circulation and alleviate blood stasis. Its treatment mechanism may be related to the regulation of immune conditions and the promotion of cell apoptosis in ectopic endometrium in vivo [42][43][44]. However, valid evidence, including meta-analysis results, has yet to be obtained for further recommendation. To our knowledge, this meta-analysis is the first research written in English to examine the effectiveness of BSHXP for endometriosis treatment.

Limitations
The methodologic quality of this review was generally poor. Although all of the studies were randomized, only two trials involved sequence generation [21,23]. No trials reported allocation concealment. If patients and implementers were aware of the interventions, this meta-analysis would directly result in performance and detection biases. Seven trials reported adverse events, and these adverse events were described briefly. Therefore, the conclusion about the safety of BSHXP could not be obtained definitely.
This meta-analysis was also limited by various evaluating criteria among different studies. For example, three trials compared the maximum cross-sectional areas in terms of the size of cysts, two trials compared the maximum diameter, and one trial indicated the reduction ratio. Thus, we were unable to analyze these data uniformly. We suggest that researchers should use internationally unified diagnostic and scoring criteria in the future.
The combination of laparoscopy and histological verification is considered as a standard diagnostic technique for endometriosis. Only three trials demonstrated that all of the patients were diagnosed with laparoscopy. In other trials, some included in this review used a clinical diagnostic standard and others employed laparoscopic diagnosis. However, we were unable to divide laparoscopic-and clinicaldiagnosed cases into two subgroups for sensitivity analysis because counting all of the cases of laparoscopic diagnosis in one study is impossible.
Evidence-Based Complementary and Alternative Medicine 9

Conclusion
Our study provided evidence that BSHXP is effective and safe for endometriosis, but this evidence is inconclusive because of the low methodological quality of the included RCTs. Our findings suggest that BSHXP is an alternative drug for endometriosis, but it should be further examined in future clinical research.