Efficacy and safety of traditional Chinese medicine in the treatment of menopause-like syndrome for breast cancer survivors: a systematic review and meta-analysis

Background In recent years, breast cancer (BC) incidence and mortality have been the highest in females. Menopause-like syndrome (MLS), arising from hypoestrogenism caused by endocrine therapy, significantly affects the quality of life for females. Traditional Chinese Medicine (TCM) has advantages in ameliorating MLS, but the efficacy of TCM in patients with BC has not been systematically evaluated. Methods A comprehensive search was performed on PubMed, Web of Science, Embase, Ovid, Cochrane Library, China National Knowledge Infrastructure, Wanfang database, Chinese Scientific Journals Database, and Clinical Trial Registry from inception to September 4, 2023. The Cochrane Risk of Bias assessment tool was used for the quality evaluation of the randomized controlled trials (RCTs). Review Manager 5.4 software was used for statistical analysis, and the Grading of Recommendations Assessment, Development, and Evaluation was used for quality evaluation of the synthesized evidence. Results This review included 42 studies involving 3112 female patients with BC. The results showed that the TCM group was better at decreasing the Kupperman Menopausal Index (KMI) scores (standardized MD, SMD = − 1.84, 95% confidence interval, CI [− 2.21–-1.46], Z = 9.63, P < 0.00001). Regarding the main symptoms of MLS, the TCM groups could significantly decrease the scores of hot flashes and night sweats (SMD = − 0.68, 95% CI [− 1.1–-0.27], Z = 3.24, P = 0.001), paraesthesia (SMD = − 0.48, 95% CI [− 0.74–-0.21], Z = 3.53, P = 0.0004), osteoarthralgia (SMD = − 0.41, 95% CI [− 0.6–0.21], Z = 4.09, P < 0.0001), anxiety (MD = − 0.85, 95% CI [− 1.13, − 0.58], Z = 6.08, P < 0.00001) and insomnia (MD = − 0.61, 95% CI [− 0.8, − 0.43], Z = 6.51, P < 0.00001). TCM can effectively improve the symptoms of MLS in patients with BC. Moreover, TCM could improve the objective response rate (ORR) by 50% (RR = 1.5, 95% CI [1.37–1.64], Z = 9.01, P < 0.00001). Follicle-stimulating hormone (FSH) and oestradiol (E2) had no significant difference compared with the control group (p = 0.81 and p = 0.87), and luteinizing hormone (LH) in the TCM group decreased significantly (MD = − 0.99, 95% CI [− 1.38, − 0.5], Z = 5.01, P < 0.00001). This means that the use of TCM does not negatively affect endocrine therapy and may even have a synergistic effect. The incidence of adverse events (AEs) was lower in the TCM groups than in the control groups. Conclusions The meta-analysis stated that TCM could better improve the MLS of patients, alleviate related symptoms, and did not increase adverse drug reactions in BC survivors. This review brings more attention to MLS, and the present findings shed light on the potential applications of TCM in the treatment of MLS in BC survivors. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-023-11789-z.


Introduction
Breast cancer (BC) describes a range of malignancies occurring in the mammary glands and is the most prevalent cancer worldwide [1].According to the latest statistics, there were 2,261,419 new cases of BC and 684,996 BC-related deaths in 2020, accounting for the first and sixth highest number of diagnosed cancer cases and deaths, respectively, worldwide [2].The National Institutes of Health (NIH) estimated that the number of new BC cases in 2024 would be 287,850, accounting for 15% of all new cancer cases.Meanwhile, 43,250 new deaths will occur in 2024, accounting for 7.1% of all cancer deaths [3].To prolong the life of patients and improve survivors' quality of life, it is increasingly important to improve and enrich BC treatment [4].Among BC treatments, endocrine therapy refers to the systematic use of aromatase inhibitor (AI) or oestrogen receptor (ER) modulators to reduce female hormone levels, inhibit ovarian function, and control tumour growth in female BC survivors who are ER-positive [5].Notably, the ovarian damage caused by endocrine therapy could significantly reduce the secretion of oestrogen, which could significantly influence the function of the female endocrine system [6].Due to endocrine therapy, female hormones suddenly and unnaturally drops, resulting in symptoms similar to menopause, such as hot flashes and night sweats, paraesthesia, osteoarthralgia, anxiety, insomnia, etc., which is called menopause-like syndrome (MLS), seriously affecting the patients' quality of life [7].Female hormones are an important indicator in the process of endocrine therapy, and inhibiting the increase in female hormones is of great significance in controlling the development of BC [8].How to relieve MLS and improve the quality of life of patients without increasing female sex hormones is very important.
Traditional Chinese Medicine (TCM) is an important source of antitumour drugs.Approximately 50% of the currently used antitumour drugs are directly or indirectly derived from TCM, including various compounds, such as alkaloids, polysaccharides, polyphenols, diterpenes, and unsaturated fatty acids [9,10].TCM can reduce the development of tumour resistance and inhibit malignant metastasis of tumour cells [11].Moreover, in addition to their effects on cancer cells, some TCMs exhibit other biological activities in noncancer cells, such as antioxidant, anti-inflammatory, and immunomodulatory activities, thereby enhancing patient immunity, increasing therapeutic efficacy, and reducing toxicity [12,13].
Several clinical trials have explored the efficacy of TCM in MLS in BC survivors.A trial found that ribociclib plus endocrine therapy improves the progression-free survival (PFS) period and has controllable safety in premenopausal, hormone receptor (HR)-positive and human epidermal growth factor receptor-2 (HER 2)-negative BC patients compared with the control group [14].Another multicentre, open-label, randomized, controlled, phase 3 trial suggested that the combination of TCM and endocrine therapy may be a potential treatment option for ER-positive and HER 2-negative primary BC patients at high risk [15].However, no systematic review has been found in evaluating this topic based on recent evidence.Therefore, this review aimed to systematically assess the efficacy and safety of TCM in the treatment of menopause-like syndrome (MLS) in BC survivors using recently available evidence.

Registration
We registered this systematic review and meta-analysis with PROSPERO (CRD42022316111).This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16].The PRISMA checklist is available in Supplementary file 1.Since this study was based on data extracted from published trials, ethical approval was not needed.

Eligibility criteria Patients
Patients with a definite pathological diagnosis of BC with oestrogen receptor (ER)-positive patients and without any other malignancies was included in this study.Patients with MLS who have received or are currently undergoing endocrine therapy.There was no restriction in terms of cancer stages and menstrual cycles.

Intervention
Chinese herbal medicine was a requirement for patients in the experimental groups.There were no restrictions on Chinese herbal medicine forms, therapeutic dose, or frequency of administration.TCM and other interventions can exist in tandem.

Comparison
Placebo or blank controls were included.

Outcomes
The primary outcomes included the MLS status, which was evaluated by menopause assessment scales (Kupperman Menopausal Index [KMI] [17].Secondary outcomes were female hormones, including E 2 , FSH and LH.Objective Response Rate (ORR) as evaluated by the Response Evaluation Criteria in Solid Tumours [18].The safety outcome indicators were adverse events (AEs).

Study design
Randomized controlled trials (RCTs) with or without blinded methods were included in this study.

Exclusion criteria
(1) Data extracted from the articles were insufficient, or the full text could not be obtained; (2) duplicate publications in different databases; (3) outcome indicators did not meet the requirements of this study.

Search strategy
A comprehensive search included searching for PubMed, Web of Science, Embase, Ovid, Cochrane Library, China National Knowledge Infrastructure, Wanfang database, Chinese Scientific Journals Database, and Clinical Trial Registry from the inception of each until September 4, 2023.The MeSH terms and free terms were used to conduct the search.The search steps are supplied in Supplementary file 2.

Study selection
All search results were imported into EndNote X9 (Clarivate, London, United Kingdom).Two independent researchers conducted title, abstract, and full-text screening of the included trials.All disagreements were resolved by discussion or by the intervention of a third researcher when needed.The SD of the change from baseline for the experimental intervention was input using the following formula [19]: The mean value of the change from baseline for the experimental intervention was input using [20]: all data were rounded to two decimal places.

Data extraction
Data extracted from the RCTs included names of authors, year of publication, number of patients, method of randomization, mean age, type of disease, duration of treatment and outcomes.The original authors were contacted by email when necessary to obtain any missing data or to inquire about errors or ambiguous information.

Quality assessment
Version 2 of the Cochrane Risk of Bias Tool (RoB 2) of the included RCTs was evaluated as low risk, some concerns, and unclear risk based on the evaluation of the following domains: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases [14].

Statistical analysis
The meta-analysis was conducted using Review Manager version 5.4 (Cochrane Collaboration, 2020).Random-effects and fixed-effects models were selected for the meta-analysis.When I2 > 50, the random-effects model was chosen.Otherwise, the fix-effects model was selected.Sensitivity or subgroup analyses were conducted to determine the cause of heterogeneity if it existed.The risk ratio (RR) was used to evaluate dichotomous outcomes, while the mean difference (MD) or standardized MD (SMD) was used to assess continuous variables.The MD was selected when these variables were all obtained using the same rating instrument, and the SMD was selected when different scales were used to measure the same outcome [21].The effect estimates with their 95% CIs are reported herein.The I 2 inconsistency index was used to quantify heterogeneity.Funnel plots were used to verify bias when there were more than 10 studies.The results of the sensitivity analysis are also reported herein.

Quality of the synthesized evidence
Quality assessment of the synthesized evidence was performed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.Evidence quality could be downgraded by five factors: RoB, heterogeneity, indirectness, imprecision, and publication bias.The quality of evidence was rated as high, moderate, low, or very low.

Literature search
According to the search strategy, a total of 1577 articles were retrieved.After reading the title and abstract, 759 articles were excluded.After screening these articles according to the search strategy and exclusion criteria, 385 articles were eliminated as follows: there were no RCTs, 295 did not meet the inclusion criteria, and 96 studies lacked outcome measures.) were further analysed (Fig. 1).Table 1 reports the characteristics of the included studies.The composition and dosage of TCM included in the article are shown in Supplementary file 3.

Quality evaluation of the literature
The quality of the included studies was assessed using the Cochrane Collaboration RoB 2.0 tool (Fig. 2).Regarding random sequence generation, 25 RCTs were evaluated as having "some concerns" because these studies only mentioned the randomized grouping but did not mention the specific allocation methods used.Four RCTs used other randomized methods, which could lead to random bias.One RCT may have had a bias of 'Deviations from intended interventions' .One RCT may have had a bias of 'Measurement of the outcome' .The risk of selection and reporting bias were low in all the studies.

Outcomes KMI
Twenty-eight RCTs used Kupperman (KMI) to evaluate MLS.The total KMI score in the experimental groups that received TCM was significantly lower than that in the control groups (standardized MD, SMD = − 1.84, 95% confidence interval, CI [− 2.21--1.46],Z = 9.63, P < 0.00001).Owing to the high clinical heterogeneity and low quality of the included literature, some heterogeneity occurred.(I 2 = 92%) (Fig. 3).Reviewing the included article data, it was found that 5 RCTs used KMI tables with different versions, which had an impact on the heterogeneity.After conducting sensitivity analysis, heterogeneity decreased to 74% (standardized MD, SMD = − 1.38, 95% confidence interval, CI [− 1.61--1.16],Z = 11.96,P < 0.00001).The sensitivity analysis image can be found in Supplementary file 5.
In addition, it was interesting to compare the efficacy and safety of TCM for the treatment of MLS in different stages of BC.Because the inclusion of RCTs did not provide a hierarchical design for different tumour stages, this article can only display the forest plot showing the total KMI score based on stages of BC, as shown in Fig. 4. The results showed that the TCM group was better at decreasing the KMI scores (standardized MD, SMD = − 1.85, 95% confidence interval, CI [− 2.29 --1.4],Z = 8.13, P < 0.00001).In addition, 2 RCTs used KMI tables with different versions, which had an impact on heterogeneity (standardized MD, SMD = − 1.5, 95% confidence interval, CI [− 1.8 --1.21],Z = 9.92, P < 0.00001).The sensitivity analysis image can be found in Supplementary file 4.
Due to the particularity of endocrine therapy for breast cancer, this article also analysed the KMI with the menstrual cycle as the subgroup analysis standard.As shown in Fig. 5, according to the grouping of menstrual cycles, each subgroup and overall data of the observation group showed better efficacy in treating MLS (standardized MD, SMD = − 1.55, 95% confidence interval, CI [− 1.82 --1.27],Z = 10.96,P < 0.00001).The sensitivity analysis image can be found in Supplementary file 5.
In addition, the symptom scores of each item in the KMI score table also have statistical significance.Flashes of hot flashes and night sweats, which were some of the most significant symptoms of menopause, were analysed in 6 studies.Compared with the Z = 3.24, P = 0.001).However, the heterogeneity was slightly higher (I 2 = 75%).The results are shown in Fig. 6.Paraesthesia in KMI was reported by 6 RCTs (Fig. 7).The result suggests that the experimental group had an obvious effect on paraesthesia in KMI compared with the control group (SMD = − 0.48, 95% CI [− 0.74--0.21],Z = 3.53, P = 0.0004).In addition, 7 RCTs reported osteoarthralgia among the KMI score table and showed that patients who received TCM  P < 0.00001) (Fig. 10).From the data analysis, the TCM group plays an important role in alleviating the MLS of patients with BC after endocrine therapy.

Female hormone
Female hormones mainly include E 2 , FSH and LH.First, 21 RCTs, which included 1484 patients, mentioned E 2 (Fig. 12).The results indicated that there was no statistical significance between the TCM groups and the control groups (p = 0.87).In addition, there were a total of 20 RCTs including 1404 patients related to FSH, and the forest plot of FSH also did not show a significant improvement between the two groups (p = 0.81) (Fig. 13).Fifteen RCTs comprising 1081 patients showed that those who received TCM tended to have a greater reduction in LH than those who received endocrine therapy or placebo in Fig. 14 (MD = − 0.99, 95% CI [− 1.38, − 0.5], Z = 5.01, P < 0.00001).The changes in female hormones suggest that TCM intervention will not affect the treatment of BC with endocrine drugs.

AEs
Six RCTs mentioned AEs, including menstrual disorder, arthralgia, hot flashes, elevated blood pressure, oedema and gastrointestinal discomfort.The RCTs showed that the incidence of AEs such as arthralgia and oedema in the intervention group was lower than that in the control group.No statistically significant differences were found in the occurrence rates of menstrual disorders, hot flashes, elevated blood pressure, or gastrointestinal discomfort.This indicates that TCM was safe in the treatment of Menopause-like Syndrome of BC.

Analysis of publication Bias
According to the funnel plot, KMI, FSH and LH were analysed.The funnel plot of the primary outcome (KMI) showed no complete symmetry and indicated the existence of publication bias.Publication bias may be associated with negative results not being published.The data

Assessment of the quality of evidence
Based on the GRADE criteria, the quality of evidence assessment was performed (Table 2).Most of the total KMI, MLS symptoms of each item in KMI, ORR, female hormones and AEs were assessed as low-quality evidence owing to clinical heterogeneity and low participant numbers in most studies.The quality of evidence assessment is available in Supplementary file 5.

Discussion
In this study, an extensive search was performed to evaluate the efficacy and safety of TCM in the treatment of MLS for BC.On the one hand, this article mainly explains that TCM can improve patients' quality of life and prolong survival time.On the other hand, the article also demonstrates that TCM does not change patients' hormone levels, which cannot cause recurrence and metastasis.The specific performance is the relief of hot flashes and night sweats, paraesthesia, osteoarthralgia, anxiety and insomnia.In addition, common AEs, such as arthralgia and oedema, were significantly decreased in the TCM groups compared with the control groups.No statistically significant differences were found in the occurrence rates of menstrual disorders, hot flashes, elevated blood pressure, or gastrointestinal discomfort.This means that there were no differential AEs in the MLS with TCM treatment group compared to the control group.BC has become a major health problem for women over the past two decades owing to its high incidence and mortality rates [22].The epidemiology of BC in women shows that high levels of sex hormones lead to early menarche and late menopause in women, which has been proven to be related to the increased risk of BC [23].A two-sample Mendelian randomization study found that increasing levels of bioavailable testosterone, dehydroepiandrosterone sulphate, testosterone, and oestradiol may increase the risk of ER + BC, consistent with the results of observational studies [24].The use of aromatase inhibitors (AIs), LHRH-α, oestrogen receptor antagonists, and other adjuvant endocrine therapies in clinical practice is the standard treatment method for ER+ BC patients.Although endocrine therapy is available to BC patients, it has many adverse effects, such as causing MLS, which worsens the quality of life of patients and prognosis [25].In addition, long-term use of endocrine therapy may lead to drug resistance.A study found that approximately 30% of BC patients will develop endocrine resistance after receiving tamoxifen treatment [26].The latest research has found that when patients develop resistance to endocrine therapy, their sex hormone levels begin to fluctuate and gradually increase, leading to tumour metastasis or recurrence [27].The acquired drug resistance of ER + BC is a complex and dynamic biological process.Thus, it is critical to assess and treat MLS in BC survivors.
In recent years, TCM and their synthetic derivatives have made significant contributions to drug therapy, especially for cancers [6,28].One previous study summarized and discussed the effects of TCM in tumour treatment [29].For instance, TCM can exert antitumour effects by inhibiting myeloid-derived suppressor cells, enhancing natural killer and cytolytic T cells [30], alleviating resistance to multiple chemotherapeutic drugs through their multitargeted therapeutic effects [31,32], sensitizing tumour cells to chemotherapy drug s [33] and lessening the side effects of the rest of the treatmen t [34].A clinical study found that TCM can safely and effectively improve MLS in BC patients.With the development of tumour treatment, TCM, which have been considered     [11,35,36].An increasing number of RCTs are using TCM to treat MLS in BC survivors.
Although the meta-analysis strictly followed the review procedures published, there are still some limitations that deserve to be explored for future improvement.First, although the RCTs included in this paper are sufficient, most of them are small sample tests, and the standards between the tests are not uniform, which may lead to high heterogeneity.Second, the heterogeneity of the data analysed by tumour staging and menstrual cycle subgroups in the article was relatively low, while the heterogeneity was higher when endocrine therapy drugs were used as the grouping standard.This may be due to the variety of endocrine therapy drugs and differences in drug use among manufacturers or individuals, resulting in inconsistent standards and high heterogeneity.Third, none of the trials showed allocation concealment or blinding procedures, which also reflects the problem of low quality of the article.It will be even better to collect high-quality evidence from papers.However, for the above three reasons, there is a lack of high-quality original research in this systematic review and meta-analysis.More RCTs with large-scale, multicentre, and uniform criteria are needed.However, compared with the previous literature, this review thoroughly summarizes the clinical findings of past RCTs related to TCM and systematically discusses the main beneficial effects of TCM in the treatment of MLS.These findings suggest that treatment with TCM may improve the QoL of patients with BC.

Conclusion
This review indicates the efficacy and Safety of TCM Medicine in the Treatment of MLS for BC Survivors.More prospectively designed, large-size, and standard clinical trials are needed to confirm the present findings.
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Table 1
Characteristics of reports extracted from the databases

Table 1 (
continued) Events (AEs).CG control group, EG experimental group, N not reported

Table 2
Quality of evidence assessment

Risk of bias Inconsistency Indirectness Imprecision Publication bias Overall certainty of evidence Study event rates (%)
CI confidence interval, MD mean difference, RR risk ratio, SMD standardised mean difference Explanations a Most information is from studies at unclear risk of bias b Clinical heterogeneity exists owing to the different treatment plan c Small sample size d Potential limitations are likely to lower confidence in the estimate of effect