Abstract
Objectives:
To carry out a quantitative assessment of the therapeutic effect of Chinese herbal medicine (CHM), with Rehmannia glutinosa as the main ingredient, in treating perimenopausal syndrome (PMS) in breast cancer patients.
Methods:
Randomized controlled trials (RCTs) comparing CHM with Rehmannia glutinosa as the principal ingredient and Western medicine in treating PMS among breast cancer patients were retrieved from multiple databases. These databases included PubMed, Cochrane library, Embase, China National Knowledge Infrastructure, Wanfang Data, China Science and Technology Journal Database, and China Biology Medicine Database. The primary outcome was the change in the Kupperman index by the end of the follow-up period. Secondary outcomes were changes in Karnofsky performance status (KPS), the functional assessment of cancer therapy - breast (FACT-B), the percentages of T-cells, levels of gonadal hormones, and tumor markers in peripheral blood at the end of follow-up, and adverse events.
Results:
The meta-analysis included 17 RCTs involving 1,139 patients showing that CHM with Rehmannia glutinosa as the monarch drug significantly improved the Kupperman index (MD= -12.79, p<0.01), KPS score and increased the percentage of CD4 cells, reduced the percentage of CD8 cells, and improved the CD4/CD8 ratio in peripheral blood, compared to Western medicine. There were no significant differences in FACT-B scores. Levels of gonadal hormones in peripheral blood did not exhibit significant variations, and no severe adverse reactions were detected.
Conclusion:
These data suggest that CHM with Rehmannia glutinosa as the monarch drug may be applied in the treatment of PMS in patients with breast cancer. These results should be considered in the context of the methodological flaws and high heterogeneity of the included RCTs.
PROSPERO No. ID: CRD42022384810
Keywords: Chinese herbal medicine, Rehmannia glutinosa, breast cancer, perimenopausal syndrome, systematic review
Breast cancer, a type of malignancy, frequently originates in the epithelial cells of either the ducts or the lobules within the glandular tissue of the breast. Globally, breast cancer ranks first among cancers for incidence and mortality among women.1 According to GLOBOCAN, in 2020, breast cancer topped the list of newly-diagnosed cancers, with an age-standardized incidence rate of 39.10/100,000 women.2 Over recent years, the prevalence of breast cancer has been steadily surging. From 1990-2017, the global incidence rate of breast cancer ascended at an annual pace of 1.44%, whereas the mortality rate escalated by 0.23% per annum.3 Therapeutic interventions for breast cancer entail surgical procedures, radiation therapy, chemotherapeutic regimens, endocrine modulation therapy, and targeted therapeutic strategies.4 Most treatments lead to perimenopausal syndrome (PMS), characterized by hot flashes, nocturnal sweating, sleep disturbances, and fluctuations in mood. Perimenopausal syndrome can reduce quality of life and treatment compliance in individuals with breast cancer.
In recent years, Chinese herbal medicine (CHM) containing Rehmannia glutinosa as the monarch drug (a medication that serves a significant therapeutic function in a formulation) is utilised by a large number of individuals for PMS in patients with breast cancer.5-21 Rehmannia glutinosa, in the Scrophulariaceae family, has been recognized for centuries as a notable traditional medicine in East Asia.22 Researches show that Rehmannia glutinosa and its bioactive components have a wide range of pharmacological effects on the hematopoietic, immune, endocrine, cardiovascular, and nervous systems.23 However, the small sample size and heterogeneity among these studies has led to controversy over clinical efficacy and safety. The objective of this systematic literature review and meta-analysis was to quantitatively evaluate the effectiveness of CHM with Rehmannia glutinosa as the monarch drug for managing PMS in breast cancer patients. Findings will inform clinical decision making for this patient population.
Methods
This meta-analysis is reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.
Search methods
A search was carried out across the PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal, and China Biology Medicine databases, from their inception up to June 2024. The search terms used included Rehmannia glutinosa, Dihuang, menopause, hot flashes, breast, and cancer. The detailed search strategy is provided in Appendix 1. Searches were restricted to full-text articles published in English or Chinese. Clinical trial registers, databases such as the Chinese clinical trial registry and clinical trials were explored for ongoing or unpublished research studies.
Inclusion criteria included: I) study design: randomized controlled trials (RCTs); II) study subjects: individuals with a pathological diagnosis of breast cancer and those diagnosed with PMS by a clinician or through any established diagnostic criteria; III) intervention: treatment for PMS with CHM containing Rehmannia glutinosa as the monarch drug or CHM containing Rehmannia glutinosa as the monarch drug combined with Western medicine, and controls that received Western medicine. Chinese herbal medicine containing Rehmannia glutinosa as the monarch drug was characterized as prescriptions containing various herbs, or Chinese patent medicines, in which Rehmannia glutinosa had the largest weight ratio or ranked first among the CHM prescriptions, with no restrictions on dose, preparation, or mode of administration. Western medicine included drugs commonly used to treat PMS in clinical practice, such as oryzanol, remifemin, and vitamin B1, with no restrictions on treatment course (treatment course had to be the same in the intervention and control group); and IV) outcomes: the primary outcome was change in the Kupperman index at the end of follow-up. Secondary outcomes included changes in Karnofsky performance status (KPS), the functional assessment of cancer therapy - breast (FACT-B), percentages of T-cells (CD4, CD8, and CD4/CD8), levels of gonadal hormones (estradiol [E2], luteinizing hormone [LH], and follicle stimulating hormone [FSH]), and tumor markers (CEA, CA125, and CA153) in peripheral blood at the end of follow-up. Safety outcomes were findings on routine blood tests, liver and kidney function, and the occurrence rate of adverse events or side effects. Exclusion criteria included: I) trials that did not explicitly recognize Rehmannia glutinosa as the monarch drug; or 2) trials with incomplete data or duplicates.
Study selection and data extraction
References were managed using Endnote X9 (Clarivate Analytics). Two authors (DK and FH) independently screened titles and abstracts, assessed full text articles to identify trials that met the inclusion criteria, and extracted data, including general information (title, first author, and publication date); trial characteristics (sample size and sources of bias); subject characteristics (age, race, gender, and duration of disease); intervention details (medication, dosage, formulation, treatment duration, prescription, and follow-up); and outcomes (efficacy and safety). Discrepancies were resolved through discussion with a third author (LM).
Risk of bias assessment of included studies
Two authors (JX and DK) independently evaluated the methodological quality of the included trials using the Cochrane risk of bias-2 (RoB-2) tool.24 Evaluation criteria encompassed bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcomes, and bias in selection of the reported results. Risk of bias for each category was classified as high, low, or some concerns. Findings from the risk of bias assessment were presented using a risk of bias chart. Discrepancies were resolved through discussion with a third author (ZS).
Data synthesis and statistical analysis
Statistical analysis was carried out using Review Manager 5.4 and Stata SE 17. The effect measure was mean difference (MD) with corresponding 95% confidence interval (CI). To ensure all measurements were expressed using a single unit, E2 levels were converted from pg/mL to pmol/L using the formula: pg/ml*3.67=pmol/l.
Heterogeneity between trials was investigated with the χ test and the I2 index. A random-effects model was used in this meta-analysis because there was evidence of high heterogeneity between studies. Heterogeneity sources were identified through subgroup analysis, in which results for the primary outcome were stratified according to preparation of Rehmannia glutinosa (crude Rehmannia glutinosa, Shengdihuang, [CRG] or processed Rehmannia glutinous, Shudihuang, [PRG]), menopausal status, use of endocrine therapy, or treatment duration. Sensitivity analysis was carried out by excluding one study at a time to evaluate the robustness of the results. Publication bias was assessed for outcomes reported by ≥10 trials. A p-value of <0.05 was considered significant.
Results
The initial search yielded 1,883 articles, and screening resulted in 1,787 articles. After exclusion of 659 duplicates and 1128 articles that did not meet the inclusion criteria, 96 full text articles were examined. After exclusion of 79 articles because of study design, incomplete data or duplicate data, 17 RCTs were included in the meta-analysis (Figure 1).
Figure 1.
- Inclusion screening flow chart.
The included RCTs are presented in Table 1. All RCTs were published in Chinese and carried out between 2008-2024. The sample size of the RCTs varied between 42-132 patients that were aged 20-80 years. Treatment ranged from 2 weeks to 3 months.
Table 1.
- Characteristics of 17 articles.
| Studies ID | Sample sizes | Mean age (years) | Interventions | Treatment duration | PRG/CRG | Menopausal status | Endocrine therapy | Outcomes | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Trials | Controls | Trials | Controls | Trials | Controls | ||||||
| Yu et al5 | 37 | 38 | 34-52 | 36-53 | Liuwei Dihuang pill, 30 pills bid + Jiawei Xiaoyao pill, 6g bid + TAM 10mg, bid | TAM 10mg bid | 2 months | PRG | Premenopausal | Yes | Kupperman, KPS |
| Ren6 | 32 | 32 | 48 (30-60) | 47 (30-60) | CHM 200ml bid + endocrine therapy | Premenopausal (TAM 10mg bid or 20mg qd, toremifene 60mg qd); postmenopausal (letrozole 2.5mg qd or anastrozole 1mg qd or exemestane 25 mg qd) | 3 months | PRG | Both premenopausal and postmenopausal | Yes | Kupperman, FACT-B, E2, FSH, LH |
| Sun et al7 | 31 | 30 | 36.23±5.72 | 37.31±4.89 | CHM 200ml bid +TAM 10mg bid | TAM 10mg bid | 2 months | PRG | Premenopausal | Yes | Kupperman, E2 |
| Zhang et al8 | 64 | 48 | 46.1±9.1 | 45.8±8.6 | Xiaoyao pill 8 pills tid + Liuwei Dihuang pill 8 pills tid | Oryzanol 20mg tid | 20 days | PRG | Unclear | Part of them | kupperman |
| Tian9 | 41 | 41 | 30-64 | 31-65 | Oryzanol 20mg tid + CHM bid | Oryzanol 20mg tid | one month | PRG | Unclear | Yes | Kupperman, E2, FSH, LH |
| Sheng10 | 23 | 20 | 45-70 | 45-70 | Oryzanol 20mg tid + VitB1 20mg tid + CHM tid | Oryzanol 20mg tid + VitB1 20mg tid | 3 weeks | PRG | Postmenopausal | Yes | Kupperman, E2, LH |
| Sui11 | 29 | 30 | 45-80 | 45-80 | Anastrozole 1mg qd or letrozole 2.5mg qd or exemestane 25mg qd + CHM bid | Anastrozole 1mg qd or letrozole 2.5mg qd or exemestane 25mg qd | 2 months | PRG | Postmenopausal | Yes | Kupperman, KPS, FACT-B, CEA, CA125, CA153 |
| Zhou et al18 | 25 | 25 | 44-58 | 43-57 | Remifemin 0.28g bid + CHM bid | Remifemin 0.28g bid | 3 months | CRG | Premenopausal | Unclear | E2, FSH, LH |
| Sun12 | 30 | 30 | 20-45 | 20-45 | CHM 200ml bid | Oryzanol 20mg tid | 3 months | CRG | Premenopausal | Part of them | Kupperman, E2, FSH |
| Wu13 | 36 | 36 | 31-52 | 31-52 | Endocrine therapy + CHM 200ml bid + Tianwang Buxin Dan one pill bid | Endocrine therapy | 2 months | CRG | Unclear | Yes | Kupperman, KPS, E2, FSH |
| Wu et al19 | 39 | 39 | 43-63 | 42-64 | TAM 10mg bid + oryzanol 20mg tid + VitB1 10mg bid + CHM bid | TAM 10mg bid + oryzanol 20mg tid + VitB1 10mg bid | 3 months | CRG | Unclear | Yes | E2, FSH, LH, CA125, CA153 |
| Zhu et al14 | 61 | 60 | 59.43±6.4 | 59.7±6.61 | Letrozole 2.5mg qd + CHM bid | Letrozole 2.5mg qd | 2 months | CRG | Postmenopausal | Yes | Kupperman, FACT-B, CD4, CD8, CD4/CD8 |
| Xie15 | 30 | 30 | 30-55 | 30-55 | TAM 10mg bid + CHM bid | TAM 10mg bid | 3 months | CRG | Premenopausal | Yes | Kupperman, KPS, E2, FSH, CD4, CD8, CD4/CD8,CEA, CA125, CA153 |
| Guo et al20 | 30 | 30 | 36-72 | 36-72 | CHM bid | Oryzanol 20mg tid | one month | CRG | Both premenopausal and postmenopausal | Unclear | E2, FSH |
| Xiao et al16 | 25 | 25 | 60.8±8.7 | 62.1±9.4 | Letrozole 2.5mg qd + CHM bid | Letrozole 2.5mg qd + oryzanol 10mg tid | 2 months | PRG +CRG | Postmenopausal | Yes | Kupperman, CA153 |
| Liu17 | 22 | 20 | 67.33±5.33 | 68.08±4.77 | Letrozole 2.5mg qd + CHM bid | Letrozole 2.5mg qd | 3 months | PRG +CRG | Postmenopausal | Yes | kupperman, E2, CEA, CA125,CA153 |
| Li et al21 | 25 | 25 | 53.76±8.86 | 54.96±8.55 | Endocrine therapy + CHM bid | Endocrine therapy + alprazolam | 2 weeks | CRG | Unclear | Yes | PSQI, kupperman, KPS, E2, FSH, LH |
Xiao et al16 reported the outcome indicators at 4 weeks and 8 weeks, and finally included the outcome indicators at 8 weeks for meta-analysis. TAM: tamoxifen, PRG: processed Rehmannia glutinosa (Shudihuang), CRG: crude Rehmannia glutinosa (Shengdihuang), CHM: Chinese herbal medicine, KPS: Karnofsky performance status, FACT-B: functional assessment of cancer therapy - breast, E2: estradiol, LH: luteinizing hormone, FSH: follicle stimulating hormone
Risk of bias assessment
There were some concerns on the randomization process in 12 trials, deviations from the intended interventions in 15 trials and missing outcome data in 4 trials. All RCTs exhibited a low risk of bias regarding measurement of the outcomes and selective reporting (Figure 2).
Figure 2.
- Risk of bias summary.
Meta-analysis of the Kupperman index
The Kupperman index was reported in 14 RCTs (n=951).5-18 The meta-analysis revealed a notable enhancement in the Kupperman index in patients with breast cancer and PMS treated with CHM with Rehmannia glutinosa as the monarch drug compared to Western medicine (MD= -12.79, 95% CI: [-15.76 to -9.82]; p<0.01; I2=91.7%, Figure 3). There was evidence of high heterogeneity between studies, but the treatment effect was maintained in subgroup analyses (Table 2), and the sensitivity analysis showed that the heterogeneity could not be attributed to any one RCT (Figure 4).
Figure 3.
- Forest plot of the influence of Chinese herbal medicine with Rehmannia glutinosa as the monarch drug in the Kupperman index.
Table 2.
- Subgroup analysis of Kupperman index between the Chinese herbal medicines group and the control group.
| Subgroups | Studies | Sample sizes | Heterogeneity test I2(%) | Effect size | ||||
|---|---|---|---|---|---|---|---|---|
| Trials | Controls | MD | 95% CI | P-values | ||||
| Monarch drug | ||||||||
| CRG | 5 | 182 | 181 | 97.7 | -15.05 | -22.94 | -7.17 | <0.01 |
| PRG | 7 | 257 | 239 | 22.21 | -9.88 | -11.34 | -8.41 | <0.01 |
| CRG+PRG | 2 | 47 | 45 | 0.00 | -13.90 | -17.18 | -10.62 | <0.01 |
| Menopausal status | ||||||||
| Postmenopausal | 5 | 160 | 155 | 72.57 | -14.34 | -17.95 | -10. 74 | <0.01 |
| Premenopausal | 4 | 128 | 128 | 91.98 | -12.28 | -17.43 | -7.13 | <0.01 |
| Both | 1 | 32 | 32 | -6.14 | -8.03 | -4.25 | <0.01 | |
| Unclear | 4 | 166 | 150 | 95.81 | -13.36 | -21.77 | -4.94 | <0.01 |
| Endocrine therapy | ||||||||
| All | 12 | 392 | 387 | 92.64 | -13.11 | -16.48 | -9.74 | <0.01 |
| Part | 2 | 94 | 78 | 85.42 | -10.91 | -17.30 | -4.51 | <0.01 |
| Treatment duration | ||||||||
| ≥3 months | 5 | 137 | 132 | 92.18 | -12.06 | -16.71 | -7.41 | <0.01 |
| <3 months | 9 | 349 | 333 | 91.61 | -13.20 | -17.23 | -9.17 | <0.01 |
PRG: processed Rehmannia glutinosa (Shudihuang), CRG: crude Rehmannia glutinosa (Shengdihuang)
Figure 4.
- Forest plot of sensitivity analysis.
Meta-analysis of secondary outcomes
Karnofsky performance status was reported in 6 RCTs (n=358).5,12,14,16,18 The meta-analysis demonstrated a significant improvement in KPS in patients with breast cancer and PMS treated with CHM with Rehmannia glutinosa as the monarch drug compared to patients treated with Western medicine (MD=7.61; 95% CI: [3.79-11.44]; p<0.01; I2=80.9%, Table 3).
Table 3.
- Meta-analysis of Karnofsky performance status, functional assessment of cancer therapy - breast, T-cell subset, gonadal hormone concentrations, and tumor markers.
| Outcomes | Studies | Sample sizes | Heterogeneity test | Effect size | |||||
|---|---|---|---|---|---|---|---|---|---|
| Trials | Controls | I2(%) | P-values | MD | 95%CI | P-values | |||
| KPS | 6 | 179 | 179 | 80.9 | <0.01 | 7.61 | 3.79 | 11.44 | <0.01 |
| FACT-B | |||||||||
| PWB | 2 | 90 | 90 | 98.1 | <0.01 | 6.11 | -0.38 | 12.61 | 0.07 |
| SWB | 3 | 122 | 122 | 97.0 | <0.01 | 3.00 | -0.64 | 6.65 | 0.11 |
| EWB | 3 | 122 | 122 | 98.8 | <0.01 | 3.63 | -1.47 | 8.73 | 0.16 |
| FWB | 3 | 122 | 122 | 97.1 | <0.01 | 3.80 | -0.06 | 7.56 | 0.05 |
| AC | 3 | 122 | 122 | 98.8 | <0.01 | 4.25 | -2.22 | 10.72 | 0.19 |
| T-cell subset | |||||||||
| CD4 | 3 | 121 | 120 | 98.5 | <0.01 | 8.84 | 2.46 | 15.22 | <0.01 |
| CD8 | 3 | 121 | 120 | 84.7 | <0.01 | -2.15 | -4.00 | -0.30 | 0.02 |
| CD4/CD8 | 3 | 121 | 120 | 98.4 | <0.01 | 0.37 | 0.03 | 0.71 | 0.03 |
| Gonadal hormone concentrations | |||||||||
| E2 | 12 | 349 | 354 | 92.7 | <0.01 | 1.14 | -2.73 | 5.01 | 0.56 |
| LH | 5 | 184 | 183 | 15.1 | 0.32 | -0.90 | -2.02 | 0.22 | 0.11 |
| FSH | 10 | 308 | 304 | 13.7 | 0.24 | 0.58 | -0.41 | 1.57 | 0.25 |
| Tumer markers | |||||||||
| CA-125 | 4 | 120 | 119 | 0.0 | 0.72 | -0.16 | -0.93 | 0.61 | 0.68 |
| CA-153 | 5 | 145 | 144 | 0.0 | 0.99 | 0.22 | -1.22 | 1.66 | 0.77 |
| CEA | 3 | 81 | 80 | 0.0 | 0.99 | -0.28 | -0.84 | 0.28 | 0.33 |
PWB: physical well-being, SWB: social/family well-being, EWB: emotional well-being, FWB: functional well-being, AC: additional concerns, E2: estradiol, LH: luteinizing hormone, FSH: follicle stimulating hormone
The FACT-B was reported in 3 RCTs (n=244).6,12,15 The meta-analysis demonstrated no significant improvements in the physical well-being (MD=6.11; p=0.07), social/family well-being (MD=3.00; p=0.11), emotional well-being (MD=3.63; p=0.16), functional well-being (MD=3.80; p=0.05), and additional concerns (MD=4.25; p=0.19) domains of the FACT-B in patients with breast cancer and PMS treated with CHM with Rehmannia glutinosa as the monarch drug compared to Western medicine. (Table 3).
T-cell subset percentages in peripheral blood were reported in 3 RCTs (n=241).13,15,16 The meta-analysis demonstrated an increase in the percentage of CD4 cells (MD=8.84; p<0.01), a decrease in the percentage of CD8 cells (MD= -2.15; p=0.02), and an improvement in the CD4/CD8 ratio (MD=0.37; p=0.03) in patients with breast cancer and PMS treated with CHM with Rehmannia glutinosa as the monarch drug compared to Western medicine (Table 3).
The E2 levels in peripheral blood were reported in 12 RCTs (n=703).6,7,9-11,13,14,16-21 The LH levels in peripheral blood were reported in 5 RCTs (n=324).6,9,17,19,20 The FSH levels in peripheral blood were reported in 10 RCTs (n=612).6,9,11,13,14,16,17,19-21 The meta-analysis demonstrated no significant difference in E2 levels (MD=1.14; p=0.56), LH levels (MD= -0.90; p=0.11), or FSH levels (MD=0.58; p=0.25) in patients with breast cancer and PMS treated with CHM with Rehmannia glutinosa as the monarch drug compared to Western medicine (Table 3).
The CA-125 levels in peripheral blood were reported in 4 RCTs (n=239).12,16,18,20 The CA-153 levels in peripheral blood were reported in 5 RCTs (n=289).12,16-18,20 The CEA levels in peripheral blood were reported in 3 RCTs (n=161).12,16,18 The meta-analysis demonstrated no significant difference in CA-125 levels (MD= -0.16; p=0.68), CA-153 levels (MD=0.22; p=0.77), or CEA levels (MD= -0.28; p=0.33) in patients with breast cancer and PMS treated with CHM with Rehmannia glutinosa as the monarch drug compared to Western medicine (Table 3).
Adverse events
A total of 13 RCTs described that adverse reactions (namely, gastrointestinal reactions, liver dysfunction, and so on) were not observed.5-7,10-18,21 A total of 4 RCTs did not describe adverse reactions.8,9,19,20
Publication bias
Publication bias was assessed for the 14 RCTs reporting the Kupperman index. The funnel plot and Egger regression method (p=0.77) implied there was no publication bias (Figure 5).
Figure 5.
- Publication bias funnel plot.
Discussion
This systematic literature review and meta-analysis quantitatively evaluated the effectiveness of CHM with Rehmannia glutinosa as the monarch drug for the treatment of PMS in patients with breast cancer. The meta-analysis included 17 RCTs involving 1,139 patients with breast cancer and PMS. Findings showed that CHM with Rehmannia glutinosa as the monarch drug significantly improved the severity of PMS symptoms (Kupperman index), functional performance (KPS score), and quality of life (FACT-B score) in individuals with breast cancer and PMS compared to Western medicine. The CHM with Rehmannia glutinosa as the monarch drug also increased the percentage of CD4 cells, reduced the percentage of CD8 cells, and improved the CD4/CD8 ratio in peripheral blood, improving the body’s immune function. There were no significant differences in gonadal hormone levels or tumor markers in peripheral blood and no serious adverse reactions were observed. These results align with prior systematic reviews and meta-analyses examining the efficacy of CHM in managing PMS among breast cancer patients.25,26 This systematic literature review and meta-analysis investigated the effectiveness of CHM with Rehmannia glutinosa as the monarch drug in this patient population.
The findings of this meta-analysis indicate that the use of CHM with Rehmannia glutinosa as the monarch drug may benefit patients with breast cancer and PMS and is generally safe. Other herbs frequently used with Rehmannia glutinosa included Poria cocos (Fuling) (n=12 RCTs), Cornus officinalis Siebold & Zucc. (shanzhuyu) (n=11 RCTs), and Bupleurum alpinum Nyman (Chaihu) (n=10 RCTs). The present meta-analysis implies that Rehmannia glutinosa as the monarch drug and these other herbs represent a core herbal prescription that warrants investigation in clinical trials for patients with breast cancer and PMS.
Modern scientific techniques and methodologies are required to clarify the potential therapeutic mechanisms of CHM with Rehmannia glutinosa as the monarch drug may in patients with breast cancer and PMS. Catalpol is an active ingredient in Rehmannia glutinosa.27 Catalpol can induce apoptosis in breast cancer in vitro and in vivo and inhibit apoptosis and oxidative stress in glucose-deprived H9c2 cells by enhancing cell mitophagy and modulating the estrogen receptor, thereby protecting cardiomyocytes from myocardial ischemia.28,29 Dried root of Rehmannia glutinosa can prevent bone loss caused by ovariectomy without affecting hormones like estrogen.30 The present study showed that CHM with Rehmannia glutinosa as the monarch drug significantly improved the severity of PMS symptoms compared to Western medicine in patients with breast cancer; however, E2 levels in peripheral blood were not significantly different. The pharmacological mechanism of Rehmannia glutinosa in patients with breast cancer and PMS warrants further investigation. Tamoxifen, an endocrine therapy used to treat breast cancer, has the dual effect of stimulating and antagonizing estrogen in different tissues. Estrogen antagonism occurs in breast tissue and estrogen-like effects occur in uterine, heart, and bone tissue; therefore, estrogen levels in peripheral blood are unlikely to generate meaningful information on the mechanism of action of Rehmannia glutinosa. Future research may explore the effect of CHM with Rehmannia glutinosa as the monarch drug on the myocardium, bone tissue, and uterus (endometrium, uterine fibroids, and adenomyosis) in patients with breast cancer and PMS.
The RCTs included in this meta-analysis used multi-herb formulae, most frequently Rehmannia glutinosa combined with Poria cocos (Fuling) (n=12 RCTs), Cornus officinalis Siebold & Zucc. (shanzhuyu) (n=11 RCTs), and Bupleurum alpinum Nyman (Chaihu) (n=10 RCTs). These formulae appeared to be beneficial in patients with breast cancer and PMS but the active components and underlying mechanisms of action remain unclear. Pachymic acid (PA), the most active compound in Poria cocos (Fuling), can induce cytotoxicity in the human breast cancer cell line MDA-MB-231, but not the human normal breast cell line MCF-10A.31 Purified triterpenes dehydropachymic acid and polyporenic acid C (PPAC) extracted from Poria cocos(Fuling) can dose dependently downregulate the expression of CDC20 in the human pancreatic cancer cell line PANC 1 to block tumor progression.32 Secoiridoids from Cornus officinalis Siebold & Zucc. (shanzhuyu) can potentiate progesterone signaling to relieve PMS.33 Saikosaponin A (SSA), a primary triterpenoid saponin derived from Bupleurum alpinum Nyman (Chaihu), can suppress tumor growth in an orthotopic 4T1 breast cancer model by inhibition of tumor angiogenesis and reverse P-glycoprotein-mediated multidrug resistance in breast cancer therapy.34,35
Study’s limitations
First, the risk of bias assessment indicated the methodological quality of the 17 included RCTs was low; none of the RCTs calculated optimal sample size to ensure sufficient power for detecting statistical significance; and 4 RCTs did not report adverse reactions. Second, PMS was diagnosed according to TCM theory, but there are no concise and precise standards in TCM practice. Third, although Rehmannia glutinosa was the monarch drug, included RCTs used many different multi-herb formulae, and the duration of the intervention was short, ranging from 2 weeks to 3 months.
In conclusion, findings from this meta-analysis suggest that CHM with Rehmannia glutinosa as the monarch drug may be used to treat PMS in patients with breast cancer. These results should be considered in the context of the methodological flaws and high heterogeneity between included RCTs. Large scale RCTs with longer follow-up are required to verify these data.
Acknowledgment
The authors gratefully acknowledge Medjaden Inc. for the English language editing.
Appendix 1.
- Detail search strategy in PubMed.
Footnotes
References
- 1.Yang YH, Liu JW, Lu C, Wei JF. CAR-T cell therapy for breast cancer: from basic research to clinical application. Int J Biol Sci 2022; 18: 2609-2626. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Qiu HB, Cao SM, Xu RH. Time trends in cancer incidence, mortality and burden in China were analyzed based on global epidemiological data in 2020 and compared with data from the United States and the United Kingdom. Chin J Cancer 2022; 41: 165-177. [In Chinese]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Lima SM, Kehm RD, Terry MB. Global breast cancer incidence and mortality trends by region, age-groups, and fertility patterns. EClinicalMedicine 2021; 38: 100985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G. Breast cancer. Lancet 2021; 397: 1750-1769. [DOI] [PubMed] [Google Scholar]
- 5.Yu J, Wang XM, Yang GW, Tang WJ, Zhao WS. [Clinical study of Liuwei Dihuang Wan combined with Jiawei Xiaoyao Wan in the treatment of breast cancer complicated with perimenopausal syndrome]. Modern Chin Clin Med 2008: 17-19. [In Chinese]. [Google Scholar]
- 6.Ren G. [The research of Ru Jifang and Liuwei Dihuang decoction in treatment of menopausal syndromes and breast cancer]. GZUCM 2014. [In Chinese]. [Google Scholar]
- 7.Sun SL, Zhang HR. [Clinical study on prevention and treatment of tamoxifen side effects with Xiaoyao Powder]. J Basic Chin Med 2013; 19: 956-957. [In Chinese]. [Google Scholar]
- 8.Zhang F, Chen Y. [Clinical observation on the intervention of breast cancer menopausal syndrome by soothing liver and nourishing kidney]. Guiding Journal of Traditional Chinese Medicine and Pharmacy 2014; 20: 43-44. [In Chinese]. [Google Scholar]
- 9.Tian LL. [Zhibai Dihuang decoction combined with Xiaochaihu decoction for menopausal syndrome after endocrine therapy on breast cancer]. Chinese Remedies & Clinics 2021; 21: 1582-1584. [In Chinese]. [Google Scholar]
- 10.Sheng LN. [Research on intervention of yangyinshugan soup of against perimenopausal syndrome after endocrine therapy on breast cancer]. Yunnan University of Chinese Medicine 2014. [In Chinese]. [Google Scholar]
- 11.Sui RQ. [Clinical observation on treatment of breast cancer with perimenopausal syndrome during endocrine therapy by enriching water and nourish wood prescription]. Nanjing University of Chinese Medicine 2019. [In Chinese]. [Google Scholar]
- 12.Sun C. [The research of traditional Chinese medicine in the treatment of perimenopausal syndrome caused by the treatment of breast cancer]. Shandong University of Traditional Chinese Medicine 2009. [In Chinese]. [Google Scholar]
- 13.Wu WZ. [Clinical effect observation of Ganmai dazao decoction combined with Tian wang buxin dan in the treatment of mammary cancer class perimenopausal syndrome]. China Modern Medicine 2014; 21: 70-71,74. [In Chinese]. [Google Scholar]
- 14.Zhu LM, Zhang QJ, Guo LJ, Shi HX, Mao ZJ, Xu ZY. [Effect of Ruyaning prescription on quality of life and immune function of postmenopausal patients with breast cancer undergoing endocrine therapy]. MOD of Tradit Chin Med & Materia Medica-World Sci & Tech 2020; 22: 4352-4359. [In Chinese]. [Google Scholar]
- 15.Xie NL. [Effect of Ruyaning prescription on quality of life and immune function of postmenopausal patients with breast cancer undergoing endocrine therapy]. Nanjing Uni of Chin Med 2014. [In Chinese].
- 16.Xiao H, Xi J, Fang NQ. [Modified Zhibai Dihuang decoction alleviating the adverse reactions of letrozole in endocrine therapy for breast cancer]. Contemporary Med 2019; 25: 9-12. [In Chinese]. [Google Scholar]
- 17.Liu DY. [Clinical observation of Chaishao Dihuang decoction combined with Letrozole in the treatment of LuminalA breast cancer after menopause (kidney deficiency and liver depression syndrome)]. Hunan Uni of Chin Med 2019. [In Chinese].
- 18.Zhou JM, Wu Z. [Efficacy of Zishen Ningxin decoction in the treatment of breast cancer complicated with kidney Yin deficiency-associated perimenopausal syndrome]. Chin J of Clin Onco & Rehab 2020; 27: 572-574. [In Chinese]. [Google Scholar]
- 19.Wu XM, Luo HT, Liu MH, Wang LQ. [Study on Chinese medicine way of Hefa (Harmonic herbs) in the treatment of menopausal syndrome after endocrine therapy of breast cancer]. J of Clin Res 2021; 38: 1334-1337. [In Chinese]. [Google Scholar]
- 20.Guo J, Shi HJ, Zhang L. [Treatment of 60 cases of breast cancer combined with perimenopausal syndrome with Yiwei decoction]. Shaanxi J of Tradit Chin Med 2015; 36: 1599-1600. [In Chinese]. [Google Scholar]
- 21.Li YM, Ma CC, Zhan QX. [Effect of modified Fangji Dihuang decoction on insomnia after endocrine therapy for breast cancer]. World J of Integr Tradit & Westr Med 2022; 17: 5. [In Chinese]. [Google Scholar]
- 22.Rahmat E, Chung Y, Nam HH, Lee AY, Park JH, Kang Y. Evaluation of marker compounds and biological activity of in vitro regenerated and commercial Rehmannia glutinosa (Gaertn.) DC. Roots subjected to steam processing. Evid Based Complement Alternat Med 2022; 2022: 1506703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Zhang RX, Li MX, Jia ZP. Rehmannia glutinosa: review of botany, chemistry and pharmacology. J Ethnopharmacol 2008; 117: 199-214. [DOI] [PubMed] [Google Scholar]
- 24.Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898. [DOI] [PubMed] [Google Scholar]
- 25.Li L, Wang R, Zhang A, Wang L, Ge Q, Liu Y, et al. Evidence on efficacy and safety of Chinese medicines combined Western medicines treatment for breast cancer with endocrine therapy. Front Oncol 2021; 11: 661925. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Li Y, Zhu X, Bensussan A, Li P, Moylan E, Delaney G, et al. Herbal medicine for hot flushes induced by endocrine therapy in women with breast cancer: a systematic review and meta-analysis. eCAM 2016; 2016. [DOI] [PMC free article] [PubMed]
- 27.Zhang YY, Wang JM, Wu XH, Song LL, Guan YC. [Study on protective effect of Catalpol from Dihuang (Rehmanniae radix) on tissue damage]. Chin Arch of Tradit Chin Med 2022; 40: 76-79. [In Chinese]. [Google Scholar]
- 28.Liu J, Du J, Li Y, Wang F, Song D, Lin J, et al. Catalpol induces apoptosis in breast cancer in vitro and in vivo: involvement of mitochondria apoptosis pathway and post-translational modifications. Toxicol Appl Pharmacol 2022; 454: 116215. [DOI] [PubMed] [Google Scholar]
- 29.Lin C, Lu Y, Yan X, Wu X, Kuai M, Sun X, et al. Catalpol protects glucose-deprived rat embryonic cardiac cells by inducing mitophagy and modulating estrogen receptor. Biomed Pharmacother 2017; 89: 973-982. [DOI] [PubMed] [Google Scholar]
- 30.Lim DW, Kim YT. Dried root of Rehmannia glutinosa prevents bone loss in ovariectomized rats. Molecules 2013; 18: 5804-5813. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Jiang Y, Fan L. Evaluation of anticancer activities of Poria cocos ethanol extract in breast cancer: in vivo and in vitro, identification and mechanism. J Ethnopharmacol 2020; 257: 112851. [DOI] [PubMed] [Google Scholar]
- 32.Cheng S, Castillo V, Sliva D. CDC20 associated with cancer metastasis and novel mushroom–derived CDC20 inhibitors with antimetastatic activity. Int J Oncol 2019; 54: 2250-2256. [DOI] [PubMed] [Google Scholar]
- 33.Lee JH, Austin JR, Burdette JE, Murphy BT. Secoiridoids from Dogwood (Cornus officinalis) potentiate progesterone signaling. J Nat Prod 2021; 84: 2612-2616. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Zhang P, Lai X, Zhu MH, Long M, Liu XL, Wang ZX, et al. Saikosaponin A, a triterpene saponin, suppresses angiogenesis and tumor growth by blocking VEGFR2-mediated signaling pathway. Front Pharmacol 2021; 12: 713200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Li C, Guan X, Xue H, Wang P, Wang M, Gai X. Reversal of P-glycoprotein-mediated multidrug resistance is induced by saikosaponin D in breast cancer MCF-7/adriamycin cells. Pathol Res Pract 2017; 213: 848-853. [DOI] [PubMed] [Google Scholar]