The efficacy and safety of Xuefu Zhuyu Decoction combined with Image Mifepristone in the treatment of uterine leiomyoma: A systematic review
and meta-analysis
Shasha Shi a, Qiaobo Ye a, Chenghao Yu a,**, Fu Peng b,*
a Department of Basic Medicine, College of Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China
b Department of West China School of Pharmacy, College of Sichuan University, Chengdu, 610041, Sichuan, China
A R T I C L E I N F O
Keywords:
Xuefu zhuyu decoction Uterine leiomyoma Randomized controlled trial Meta-analysis
A B S T R A C T
Ethnopharmacological relevance: Uterine leiomyoma (UL) is a common severe gynecological issue. In China, Xuefu Zhuyu Decoction (XFZYD), combined with Mifepristone, is widely used in the treatment of UL. However, their combined effectiveness and safety for this purpose have not yet been explored.
Aim of the study: This systematic review aims to evaluate the effectiveness and safety of XFZYD combined with Mifepristone as a method of treatment for UL.
Materials and methods: We searched the following 7 databases: 3 English medical databases (PubMed, EMBASE, Cochrane Library), and 4 Chinese medical databases (Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and the Wanfang data- base). The primary outcome was the effect of XFZYD combined with Mifepristone on the effective rate, uterine leiomyoma volume (ULV), and uterine volume (UV) of uterine leiomyoma. Bias risk was assessed using the Cochrane risk of bias tool. The software RevMan5 was used to evaluate the quality of the included studies and process the data.
Results: The 11 studies included in this systematic review were all undertaken in China, with a total of 902 participants. The meta-analysis of XFZYD combined with Mifepristone compared with Mifepristone alone
showed that the effective rate (RR 1.20, 95% confidence interval (CI): 1.14–1.27, P < 0.00001), ULV (SMD -1.60, 95% CI: 2.11 to —1.08, P < 0.00001), and UV (SMD -1.65, 95% CI: 1.85 to —1.44, P < 0.00001) in the primary outcomes, and estradiol (E2) (MD -51.81, 95% CI: 69.68 to —33.94, P < 0.00001), luteinizing hormone (LH) (MD -3.09, 95% CI: 3.58 to —2.60, P < 0.00001), follicle stimulating hormone (FSH) (MD -1.09, 95% CI: 1.86 to
—0.31, P = 0.006), progesterone (P) (MD -3.55, 95% CI: 4.54 to —2.55, P < 0.00001), and adverse events (RR 0.55, 95% CI: 0.34–0.89), P = 0.01) in the secondary outcomes were significantly reduced, and the data were statistically significant. The subgroups of ULV, E2, and FSH showed that the treatment time might not have been the heterogeneous source of ULV and FSH, but was the heterogeneous source of E2. Sensitivity analysis was carried out on the 3 outcome indicators, and the results were relatively stable after excluding one reference for each indicator.
Conclusion: There is some encouraging evidence that the combination of XFZYD and Mifepristone can benefit
patients by treating UL. However, because of research shortcomings such as lacking allocation concealment and blindness, this study’s results should be treated with caution. In order to verify the advantages of this method, it is necessary to carry out further large-scale randomized controlled trials.
1. Introduction
Uterine leiomyoma (UL), also known as fibroma or leiomyoma, is a
gynecologic tumor in women (Borahay et al., 2017) with an estimated incidence of 20–77% (Baird et al., 2003). It is closely related to age, weight, and waist circumference, and it can be controlled by surgery or
* Corresponding author.
** Corresponding author.
E-mail addresses: [email protected] (C. Yu), [email protected] (F. Peng).
https://doi.org/10.1016/j.jep.2021.114551
Received 21 February 2021; Received in revised form 29 April 2021; Accepted 19 August 2021
Available online 21 August 2021
0378-8741/© 2021 Elsevier B.V. All rights reserved.
drug therapy (Sharami et al., 2019; Niles and Blaser, 2019). Although the surgery is minimally invasive (Marín-Buck et al., 2019), it causes immeasurable pain to female patients which is expensive (Fernandez et al., 2017). Therefore, the non-surgical treatment of UL is particularly important. At present, conventional drugs used for treating UL include Gonadotropin releasing hormone (GnRH) agonists, aromatase in- hibitors, and dopamine receptor agonists (Ciebiera et al., 2017).
Traditional Chinese medicine (TCM) has been used in the treatment of diseases for thousands of years and has gained the overwhelming trust from patients for its positive therapeutic effects. Xuefu Zhuyu Decoction (XFZYD) is composed of the peach kernel (Persicae Semen, Tao Ren), Saffron (Crocus sativus L, Hong Hua), angelica (Angelica sinensis (Oliv.)We also conducted searches in the international clinical trial registry (http://ClinicalTrials.gov/) and the Chinese clinical trial registry (htt p://www.chictr.org.cn/index.aspx).
2.3. Inclusion and exclusion criteria
The inclusion criteria of our review specified that: (I) all participants in the included studies were diagnosed with UL, without age and race restrictions; (II) the treatment method of the intervention group was XFZYD combined with Mifepristone, while the treatment method of the control group was Mifepristone alone; (III) all included studies were RCTs; (Ⅳ) The dosage of Chinese herbs in XFZYT is line with the stan-Diels, Dang Gui), radix rehmanniae (Rehmannia glutinosa (Gaetn.)dard described in the China Pharmacopoeia (2020 edition). On the basis Libosch. ex Fisch. et Mey, Sheng Di), chuanxiong rhizome (Ligusticum chuanxiong hort, Chuan Xiong), red peony root (Paeonia veitchii Lynch, Chi Shao), achyranthes root (Achyranthes bidentata Bl, Niu Xi), balloon flower (Platycodon grandiflorus, Jie Geng), Chinese thorowax (Bupleurum chinense DC, Chai Hu), bitter orange (Citrus aurantium L, Zhi Qiao), and glycyrrhiza (Glycyrrhiza uralensis Fisch, Gan Cao) (Wang Qingren, 2018). It has been shown that it can be used to treat a variety of gynecologic diseases, such as chronic pelvic inflammation (Jin et al., 2015), irregular menstruation (Zhang, 2009), and ovarian cysts (Li and MAO, 2003) caused by blood stasis. Studies on the pharmacological mechanism of XFZYD have shown that it can treat UL by regulating hormone levels in the treatment of UL (Zhou et al., 2019). Some clinical studies published in China have shown that XFZYD is often used in combination with Mifepristonein the treatment of UL with satisfactory therapeutic effects (Wang and cheng, 2002), but there is no systematic evidence to support these findings. Therefore, this systematic review and meta-analysis is the first comprehensive evaluation of the efficacy and safety of XFZYD combined with Mifepristone in the treat- ment of UL, providing a basis for clinical application.
2. Methods
This systematic review and meta-analysis was performed according to the Cochrane Handbook for Systematic Reviews of Interventions and is presented following the PRISMA (Preferred Reporting Items for Sys- tematic Reviews and Meta-analyses) (Kyoko et al., 2011) and PRISMA-CHM 2020(PRISMA Extension for Chinese Herbal Medicines 2020) guidelines.
2.1. Protocol and registration
This systematic evaluation was registered (PROSPERO registration: CRD42020164917, available online at http://www.crd.york.ac. uk/PROSPERO/myprospero.php).
2.2. Search strategy
We searched for randomized controlled trials (RCTs) reported through February 2020; the electronic databases included: the Cochrane Library, PubMed, Embase, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and the Wanfang database. As a herbal formula of traditional Chinese medicine, XFZYD is mainly used in China, so the 4 electronic databases of China were searched to obtain a comprehensive study.
The keywords for retrieving respectively or jointly relevant pub- lished studies from 7 electronic databases included: “Xuefu Zhuyu Decoction” “Xuefu Zhuyu” “uterine leiomyoma” “uterine fibroids” and so on. This retrieval strategy was determined after multiple searches. PubMed retrieval strategies were shown in Table S1. The aim was to locate RCTs of XFZYD in combination with Mifepristone for the treat- ment of UL, filter documents, and extract data according to inclusion and exclusion criteria. of XFZYT, the modified XFZYT was added no more than other three herb medicines according to the patient’s condition changes; (Ⅴ)Studies were from articles published in Chinese or English. Exclusion criteria ruled out any studies that: (I) displayed a lack of literature on related outcome indicators; (II) had been selected for duplicate published studies; (III) was impossible to extract the related data from the published results, and unable to obtain the primary data after contacting the author; (Ⅳ) the treatment group adopted other traditional Chinese medicine therapies, such as acupuncture and moxi- bustion, or other traditional Chinese medicine, (V) the control group was not treated with Mifepristone alone.
2.4. Outcome measures
The primary outcomes included the effective rate, uterine leio- myoma volume (ULV, cm3), and uterine volume (UV, cm3). The sec-
ondary outcomes included the total incidence of adverse events (%), the incidence of estradiol (E2, pmol/L), luteinizing hormone (LH, IU/L), follicle stimulating hormone (FSH, IU/L), and progesterone (P, nmol/L).
2.5. Study selection and data extraction
The 2 reviewers (Shasha Shi, Qiaobo Ye) read the title and abstract of the article independently, and then read the full text after screening to determine whether the final article should be included. Any differences were resolved by consensus or negotiation with a third party (Fu Peng). The integration process was shown as a PRISMA flow diagram (Fig. 1). The data was extracted and managed by 2 reviewers. The data collection form was designed in advance, and each reviewer independently extracted and collected data from the articles involved, including gen- eral trial characteristics (title, author, year); baseline data (sample size, age, sex, disease course); intervention measures (Chinese patent medi- cine dose, control intervention medication, intervention time); results (primary outcome indicators, secondary outcome indicators, adverse events).
2.6. Quality assessment
2 reviewers assessed the quality of the included study using the risk of bias tool recommended by the Cochrane collaboration. According to the Cochrane Handbook (Higgins et al., 2013), the risk of bias assess- ment was divided into 6 items: random sequence generation; concealed allocation; blind implementation of participants and personnel; blind method of outcome assessment; incomplete result data; selective reporting, and other sources of bias. Each project had three categories:
“high risk,” “low risk,” and “unclear.” Other deviations included profit
deviations and sample calculations. In the case of inconsistency, 2 re- viewers themselves or with a third party (Fu Peng) negotiated to resolve the difference.
2.7. Statistical analysis
This systematic review used Review Manager RevMan Study flow chart (PRISMA flow diagram). (developed by the UK’s International Cochrane Collaboration) software to analyze the data and I2 statistics to evaluate the statistical heteroge- neity of the research results. If I2 < 50%, it was considered that there was no heterogeneity, and a fixed-effect model was adopted. If I2 > 50%, it was considered that there was significant heterogeneity; the source of heterogeneity was then explored through subgroup analysis or sensi- tivity analysis. If there was no apparent clinical or methodological heterogeneity, it was considered as statistical heterogeneity, and the random-effect model was used for analysis. Descriptive analysis was used if there was significant clinical heterogeneity between 2 groups and subgroup analysis was not available. Risk ratio (RR) was used for binary results, and weighted mean differences (WMDs) were used for contin- uous results. WMD was selected when the measurement methods and units of the same intervention were identical. Standard Mean Difference (SMD) was selected when different measurement methods, different units or large differences in mean were used for the same intervention. For all the estimates, we calculated the 95% CI.
2.8. Subgroup and sensitivity analyses
Subgroup analysis focused on the effect of different intervention characteristics on the cure rate, such as the difference of treatment duration, dosage, and so on. A sensitivity analysis was performed to verify the stability of the results. After each document was excluded, the new results were analyzed again and compared with the original consolidated results to see if the study had affected the stability of the results.
2.9. Assessment of reporting bias
For the significant outcome indicators, a funnel plot was used qualitatively detect publication bias when the number of the included study was 10. Egger’s and Begg’s tests were used to assess potential publication bias quantitatively.
3. Results
3.1. Literature search
After searching, a total of 150 studies were included, among which 109 articles were repeated and deleted. After reading the title and ab- stract of 41 studies, 29 studies were found not to meet the requirements and were therefore excluded. The reasons for exclusion were listed as follows: (I) 3 studies were non-RCTs; (II) 2 studies were animal experi- ments; (III) 12 studies were not XFZYD combined with Mifepristone; (Ⅳ) the disease of 3 studies was not UL; (Ⅴ) 2 studies were theoreticaldiscussion; (Ⅶ) 7 studies were medical records.With reference to the inclusion and exclusion criteria. the full text of 12 studies was read to determine inclusion in the systematic review. In the process of full-text reading, 1 study (Yang, 2016) was excluded for lack of sufficient data. Eventually, 11 studies (Chen, 2014; He, 2012; Hu, 2019; Li et al., 2017; Huang, 2018; Liu, 2017; Peng, 2014, 2017; Tianet al., 2013; Wang and Liu, 2019; Yang, 2018) which had been per- formed in China were eligible for this systematic review, and the PRISMA flow diagram was shown in Fig. 1.
3.2. Study characteristics
The primary characteristics of the included studies were shown in Table 1. There were 902 participants in this study, including 453 in intervention groups and 449 in control groups, both of which were undertaken in China. The researchers included in the study were from the inpatient department or outpatient department of their respective institutions. All included were diagnosed with UL, according to inter- nationally recognized diagnostic standards. The treatment strategy of the intervention groups was XFZYD combined with Mifepristone, while the treatment strategy of the control groups was Mifepristone alone. The duration of treatment was divided into 2 months, 3 months, and 6 months. Among the significant outcome indicators, 11 studies (Chen, 2014; He, 2012; Hu, 2019; Li et al., 2017; Huang, 2018; Liu, 2017; Peng,2014, 2017; Tian et al., 2013; Wang and Liu, 2019; Yang, 2018) reportedthe effective rate, 7 studies (Chen, 2014; Hu, 2019; Li et al., 2017;Huang, 2018; Peng, 2014; Tian et al., 2013; Yang, 2018) reported the
ULV, and 6 studies (Chen, 2014; Hu, 2019; Li et al., 2017; Peng, 2014; Tian et al., 2013; Yang, 2018) reported the UV.
Among the secondary outcome indicators, 7 studies (Chen, 2014; Li et al., 2017; Liu, 2017; Peng, 2014, 2017; Tian et al., 2013; Yang, 2018) reported E2 and LH, 6 studies (Chen, 2014; Li et al., 2017; Liu, 2017; Peng, 2014, 2017; Tian et al., 2013) reported FSH, 5 studies (Chen,
2014; Liu, 2017; Peng, 2014, 2017; Tian et al., 2013) reported P, 1 study (Hu, 2019) reported TCM symptom score, 9 studies (Hu, 2019; Li et al., 2017; Huang, 2018; Liu, 2017; Peng, 2014, 2017; Tian et al., 2013;Wang and Liu, 2019; Yang, 2018) reported adverse reactions, and 1 study (Li et al.,2017) reported menstrual cycle and menstrual volume (Table 1).Table 1Characteristics of included trials.
3.3. Risk of bias assessment of the included studies
All studies mentioned grouping by random method, and 5 studies (Hu, 2019; Li et al., 2017; Peng, 2014, 2017; Yang, 2018) mentioned that a random sequence was generated through random number table. No research mentioned the distribution concealment of random methods, implementation of blind methods, withdrawal, or missing patient information. The quality of the included literature was evaluated according to the quality evaluation scale Risk of Bias Table recommended by the Cochrane Handbook. Most of the research evaluation items were uncertainty risks, and the overall literature quality had moderate bias risks. The specific results were mapped by RevMan 5.3 software (Fig. 2).
3.4. The methodological quality of the included studies
The 11 included studies were assessed using the Cochrane Collabo- ration tool. 2 independent reviewers evaluated the quality of each study. The third reviewer resolved differences.
3.5. Publication bias
A funnel chart was used to evaluate the publication bias of 10 articles or more. Therefore, only the validity of the primary outcome met the conditions, as showed in Fig. 3. The results of the analysis showed that there was moderate symmetry between different studies, which indi- cated that the potential of publication was relatively low (Fig. 3). Both
Egger’s regression and Begg’s tests were conducted. No evident publi- cation bias was found in the eligible studies through this analysis (P = 0.0662 for Egger’s test, and P = 0.0617 for Begg’s test).
3.6. Primary outcomes
3.6.1. Effective rate
A total of 11 studies (Chen, 2014; He, 2012; Hu, 2019; Li et al., 2017;
Huang, 2018; Liu, 2017; Peng, 2014, 2017; Tian et al., 2013; Wang and Liu, 2019; Yang, 2018) were evaluated for clinical efficacy. The het- erogeneity test results showed that P 0.67 and I2 0%, indicating that
the included studies were homogeneous. The analysis results showed statistical significance for the effective rate level using the fixed-effect model (N = 902, RR 1.20, 95% CI: 1.14–1.27, P < 0.00001).
3.6.2. Uterine leiomyoma volume
Funnel plot.0.00001) was statistically significant (Fig. 6).To further analyze the stability of the results, we made sensitivity analyses and excluded each item from all the included studies. ExcludingA total of 7 studies (Chen, 2014; Hu, 2019; Huang, 2018; Li et al., 2017; Peng, 2014; Tian et al., 2013; Yang, 2018) reported ULV data, ofwhich 1 study (Huang, 2018) was incomplete, so 6 articles (Chen, 2014;Hu, 2019; Li et al., 2017; Peng, 2014; Tian et al., 2013; Yang, 2018) finally evaluated this index. There was obvious heterogeneity between 3.6.3. Uterine volume 3.7. Secondary outcomes A meta-analysis of subgroup analysis of uterine leiomyoma volume. In order to further analyze the stability of the results, we performed a sensitivity analysis and excluded each item from all included studies. Except for other studies, there was little difference in the results of meta- analysis, indicating that the combined data analysis was stable. Mean- 3.7.2. Luteinizing hormone A total of 7 studies (Chen, 2014; Li et al., 2017; Liu, 2017; Peng, 3.7.3. Follicle stimulating hormone 3.7.4. Progesterone 3.8. Adverse events Adverse events were recorded in 9 studies (Hu, 2019; Li et al., 2017; Huang, 2018; Liu, 2017; Peng, 2014, 2017; Tian et al., 2013; Wang and 3.9. Sensitivity analysis A one by one elimination method was adopted to conduct sensitivity analysis of the above indexes. The effects and P-value changes were observed after the exclusion of the included studies in turn. The results showed that after excluding any included literature, there was no sig- nificant change in the effect size of prognostic indicators, which confirmed the stability and reliability of the meta-analysis. 4. Discussion A total of 11 RCTs were systematically analyzed to evaluate the ef- ficacy of XFZYD combined with Mifepristone in the treatment of UL. The 11 studies, conducted in China, involved 902 participants. The results showed that XFZYD combined with Mifepristone was superior to Mife- pristone alone in effective rate and reduction of UV, ULV, E2, LH, FSH, and P, and the data was statistically significant. The analysis of ULV, E2, and FSH showed that there was significant heterogeneity in the study. We performed a subgroup analysis of these 3 outcomes according to treatment duration, which suggested that grouping factors may have been the source of heterogeneity for E2. We then used a sensitivity analysis to evaluate the stability of the results. The results showed that Li QY 2017 might have been the source of ULV heterogeneity, Tian ZS 2013 may have been the source of E2 heterogeneity, and Liu YQ 2017 may have been the source of FSH heterogeneity. After the exclusion of these studies, the results showed that the 95% CI was slightly changed and overlapped a lot, indicating that the results of the meta-analysis were relatively stable. Funnel chart bias indicated that the effective rate of XFZYD combined with Mifepristone in the treatment of UL had low publication bias, and the meta-analysis results were stable. The included studies showed that the adverse events of XFZYD combined with Mifepristone were less than those of Mifepristone alone. These data were statistically significant. The results of this meta-analysis showed that XFZYD combined with mifepristone is more effective than mifepristone alone in the treatment of UL. The TCM compound XFZYD is one of the decoctions commonly used in the clinical treatment of UL. The prescription has the therapeutic effect of promoting blood circulation and alleviating pain, which have been widely recognized in China (Tang et al., 2017). The pharmaco- logical mechanism of XFZYD was different from that of the compounds currently studied. According to TCM theory, the pharmacological actionof TCM compounds is determined by the synergistic interaction of various components, rather than a single component (Li et al., 2001). The total effective rate is the index of TCM to evaluate the overall therapeutic effect. The size of uterine fibroids can directly reflect the therapeutic effect, and the change of hormone can reflect whether the disease control is stable. This study comprehensively explored the effi- cacy of XFZYD combined with Mifepristone in the treatment of UL through the above indicators, and the final research results were encouraging. The results of this study are beneficial to both patients and decision-makers of clinical practice. It will help improve the quality of life of UL patients and provide patients with new options for non-drug treatment. It also provides evidence-based medicine basis for the treat- ment of UL with this combination of TCM and western medicine, which will promote the application and popularization of this program. The results of this meta-analysis showed that the efficacy of XFZYD combined with Mifepristone in the treatment of UL was superior to that of Mifepristone alone. However, our systematic review and meta- analysis had some limitations. These limitations included no descrip- tion of TCM syndrome diagnosis in the studies, and no evaluation of TCM syndrome improvement after treatment. Most of the included studies had small sample sizes, lack of description of the blinding method, unclear description of the conditions leading to loss of partic- ipants, and poor methodological quality. In this study, the longest intervention time of XFZYD combined with Mifepristone was 6 months, which was insufficient to evaluate the effect of XFZYD combined with Mifepristone in the entire course of disease and complications. Follow- up after treatment was not reported in the included studies. There was heterogeneity among the studies, which may have influenced the assessment of therapeutic efficacy in meta-analysis. In addition, the studies included in this meta-analysis were all con- ducted in China, so it is unclear whether the success of XFZYD combined with Mifepristone in treating UL can be transferred to women in other nationalities. In some studies, the adverse events of XFZYD combined with Mifepristone in the treatment of UL have not been well reported, and its safety need be conservatively evaluated. The above mentioned factors may have led to biased results. The relevant pharmaceutical companies were not contacted as part of this systematic review, so it is not clear whether pharmaceutical companies have conducted unpub- lished relevant studies. 5. Conclusions The meta-analysis of this systemic review showed that XFZYD com- bined with Mifepristone was effective in the treatment of UL. However, the study had some limitations that need to be addressed in the future. Larger RCT sample sizes, higher methodological quality and longer-term clinical trials involving more countries will help to further verify the efficacy and safety of XFZYD combined with Mifepristone in the treat- ment of UL. Ethical Aggregate data were extracted from published studies; no patients were involved in the conduct of this study; thus, ethical approval and informed consent were not required. Authors’ contributions Declaration of competing interest Acknowledgments Abbreviations UL uterine leiomyoma XFZYD Xuefu Zhuyu Decoction Appendix A. Supplementary data References Niles, K.M., Blaser, S., Shannon, P., et al., 2019. Fetal arthrogryposis multiplex Tian, Zhisong, amp, Ren, Huayi, 2013. Clinical efficacy analysis of xuefu zhuyu
different tests (P < 0.0001 and I2 84%). Therefore, a random effect model was adopted; the analysis results showed statistical significance in the ULV level (N 488, SMD -1.60, 95% CI: 2.11 to 1.08, P <0.00001) (Fig. 5).We used treatment duration of 3 and 6 months as the criteria for subgroup analysis to comprehensively evaluate the overall risk of ULVaffected by treatment duration. There was apparent heterogeneity be- tween different tests in the 3 months group (P < 0.00001 and I2 89%) and 6 months group (P 0.12 and I2 59%). The test results of sub- group analysis (P 0.83, I2 0%) indicated that this grouping factormight not be a source of heterogeneity in a meta-analysis. The difference of ULV level (N = 488, SMD -1.60, 95% CI; —2.11 to —1.08, P
A total of 6 studies (Chen, 2014; Hu, 2019; Li et al., 2017; Peng,2014; Tian et al., 2013; Yang, 2018) have been evaluated for UV. The homogeneity was good (P 0.55, I2 0%). Using the fixed-effect model, the results of the meta-analysis showed statistical significance in the UV level (N 488, SMD -1.65, 95% CI; 1.85 to 1.44,P < 0.00001) (Fig. 7). A meta-analysis of clinical efficacy rate. A meta-analysis of uterine leiomyoma volume.
3.7.1. Estradiol
MD -51.81, 95% CI; 69.68 to 33.94, P < 0.00001) (Fig. 8).We used 2, 3, and 6 months of treatment duration as the criteria for subgroup analysis to comprehensively evaluate the overall risk of A total of 7 studies (Chen, 2014; Li et al., 2017; Liu, 2017; Peng,2014, 2017; Tian et al., 2013; Yang,2018) reported E2 data. There was obvious heterogeneity between different tests (P 0.02, I262%). Therefore, a random effect model was adopted, and the results of the meta-analysis showed statistical significance in the E2 level (N = 516, treatment duration affecting E2. There was mild heterogeneity in the 3 months group (P 0.15 and I2 41%). The test results of subgroup analysis (P 0.03 and I2 72%) indicated that this grouping factor might be a source of heterogeneity in a meta-analysis. The difference of E2 level (N = 516, MD -51.81, 95% CI; —69.68 to —33.94, P < 0.00001) A meta-analysis of primary outcomes comparison between XFZYD plus Mifepristone therapy group and Mifepristone alone therapy group.
while, the heterogeneity changed significantly after the exclusion of Tian et al., ‘s 2013 study (25) (I2 43%, N 452, MD -59.28, 95% 74.57 to 44.00, P < 0.00001). This finding suggested that this study may have been the source of heterogeneity in E2 data.
heterogeneity test results showed that P 0.14, I2 37%, indicating that the included studies were homogeneous. Using the fixed effect model, the result of the meta-analysis showed statistical significance at the LH level (N 516, MD -3.09, 95% CI: 3.58 to 2.60, P < 0.00001)
(Fig. 10).
A total of 6 studies (Chen, 2014; Li et al., 2017; Liu, 20172014, 2017; Tian et al., 2013) reported FSH data. There was apparent heterogeneity between different tests (P 0.04, I2 58%). Therefore, a random effect model was adopted, and the results of the analysis showed Subgroup analysis of the incidence of estradiol.to 0.31, P 0.006) (Fig. 11). We used 2, 3, and 6 months of treatment duration as the criteria for a source of heterogeneity in a meta-analysis. The difference of FSH level (N 434, MD -1.09, 95% CI: 1.86 to 0.31), P 0.006) was statistically
significant (Fig. 12). To further analyze the stability of the results, we performed a sensitivity analysis and excluded each item from all the included studies. Excluding other studies, meta-analysis indicating that the combined data analysis was stable. After excluding Liu et al. 2017, the heteroge- neity changed significantly (I2 17%, N 374, MD -0.97, 95% CI: 1.43 to 0.51), P < 0.0001). This suggested that this study may have been the source of heterogeneity in FSH data.
A total of 5 studies (Chen, 2014; Liu, 2017; Peng, 2014, 2017; Tian et al., 2013) were evaluated for P. The heterogeneity test results showed that P 0.52, and I2 0%, which indicated that the included studieswere homogeneous. Using the fixed-effect model, the results of the meta-analysis showed statistical significance at P level (N = 334, MD-3.55, 95% CI: 4.54 to —2.55), P < 0.00001) (Fig. 13).
Liu, 2019; Yang, 2018), of which 1 study (Tian et al., 2013) displayed inconsistent data; thus, it was excluded. We assessed the safety of XFZYD in combination with Mifepristone by the overall incidence of adverse events. In the meta-analysis, the results of adverse events were shown in
As the incidence of UL increases, the cost of treatment plays a vital role in the world’s health and economic burden (Harrington et al., 2020). Therefore, it is very important to develop effective drugs or methods for the treatment of UL. At present, TCM and complementary alternative therapies for the treatment for UL have attracted more and more attention. In China, TCM has a long history of use as an adjuvant therapy for UL and has been recognized by clinicians. The multi-component of TCM compound determined its multi-effect, mul- ti-target and multi-pathway in the treatment of UL (Li et al., 2020).
(I) Conception and design: Chenghao Yu. (II) Administrative support: Shasha Shi. (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: Shasha Shi, Qiaobo Ye. (V) Data analysis and interpretation: Shasha Shi, Qiaobo Ye. (VI) Manuscript writing: Shasha Shi, Fu Peng. (VII) Final approval of manuscript: Shasha Shi, Qiaobo Ye, Chenghao Yu, Fu Peng.
The authors announced that they have no competing interests.
Funding:This work was supported by the Sichuan Provincial Department of Science and Technology Experimental Formulae Sichuan Youth Science and Technology Innovation Research Team
(2020JDTD0022) and Chengdu University of Traditional Chinese Med- icine “Xinglin Scholar” Discipline Talent Research Promotion Plan (XSGG2019006). Recipient: Chenghao Yu.
TCM Traditional Chinese medicine RCTs randomized controlled trials
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