Menopause: The Journal of The North American Menopause Society Vol. 20, No. 7, pp. 000/000 DOI: 10.1097/gme.0b013e31827cd3dd * 2013 by The North American Menopause Society
A randomized, double-blind, controlled trial of a Chinese herbal formula (Er-Xian decoction) for menopausal symptoms in Hong Kong perimenopausal women Linda L.D. Zhong, PhD,1 Yao Tong, PhD,1 Grace W.K. Tang, MD,2 Zhang Jin Zhang, PhD,1 Wai Ki Choi, RN,2 Kin Lok Cheng, BSc,3 Stephen C.W. Sze, PhD,1 Kun Wai, MSc,1 Qing Liu, PhD,1 and Ben X.B. Yu, PhD1 Abstract Objective: The aim of this study is to investigate the effectiveness and safety of a Chinese herbal formula, Er-Xian decoction (EXD), in the treatment of menopausal symptoms among Hong Kong perimenopausal women. Methods: A randomized, double-blind, controlled trial was conducted for 12 weeks among 108 Hong Kong perimenopausal women who reported Menopause Rating Scale (MRS) total scores of 28 or higher. Posttreatment follow-up was performed 3 months after the intervention. The primary outcome measure was the frequency and severity of hot flushes. The secondary outcome measures included the MRS, the Menopause-Specific Quality of Life questionnaire, and serum hormone levels. Results: Among 108 participants, 101 participants finished the study. EXD significantly reduced the mean (SD) frequency of hot flushes from 5.8 (5.0) to 2.2 (3.0) in the treatment group and from 5.0 (3.8) to 2.4 (2.5) in the placebo group (P = 0.04). The mean (SD) hot flush score was also reduced from 19.6 (6.6) to 4.9 (7.8) in the treatment group and from 16.6 (5.4) to 7.0 (6.4) in the placebo group (P = 0.02). The superiority of EXD to placebo was also observed with greater improvement in the total scores for the MRS (P = 0.03) and the Menopause-Specific Quality of Life questionnaire (P G 0.01). There were no differences in serum hormone levels between the EXD group and the placebo group. There were no serious adverse events, and the safety indices of whole blood counts, renal function, and liver function were within the normal range before and after treatment. Conclusions: The Chinese herbal formula EXD is superior to placebo in reducing the frequency and severity of hot flushes and in improving menopausal symptoms in Hong Kong perimenopausal women. It is well tolerated, with no serious adverse events noted during the study period. Key Words: Menopause Y Chinese herbal medicine Y Er-Xian decoction Y Hot flushes Y Quality of life.
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erimenopause is defined as a variable interval beginning a few years beforeVand continuing afterVthe cessation of menstrual periods.1 Perimenopause is characterized by dynamic fluctuations in the levels of sex hormones such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, and progesterone. Associated symp-
Received August 13, 2012; revised and accepted November 6, 2012. From the 1School of Chinese Medicine and2Department of Obstetrics and Gynecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pukfulam, Hong Kong SAR; and 3Department of Clinical Oncology, Queen Elizabeth Hospital, Hospital Authority, Hong Kong SAR. Funding/support: This study was supported by the Liu Hao Tsing. Foundation (research) and HKU Small Project Funding (BA pilot study on the effects of a Chinese herbal formula on menopause[; project code 200907176133). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal_s Web site (www.menopause.org). Financial disclosure/conflicts of interest: None reported. Address correspondence to: Yao Tong, PhD, School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, G/F, 10 Sassoon Road, Pukfulam, Hong Kong SAR. E-mail:
[email protected]
toms include hot flushes, night sweats, uterine bleeding problems, osteoporosis, depression, insomnia, and loss of sexual desire.2,3 Menopausal symptoms are experienced by about 80% of 120 million Chinese women aged 45 to 60 years.4 In Hong Kong, 63.8% of perimenopausal women and 50.7% of postmenopausal women experienced more than 10 symptoms, and 25.5% of perimenopausal women and 21.1% of postmenopausal women experienced more than 20 symptoms, which seriously affected their health and quality of life.5,6 Among all symptoms, the most common complaints included aches or joint stiffness, backaches, and hot flushes. About 21.74% of perimenopausal women experienced hot flushes, 41.3% of perimenopausal women experienced aches or joint stiffness, and 33.7% of perimenopausal women experienced backaches.5,6 The Women’s Health Initiative indicated that hormone therapy (HT) can increase the risks of breast cancer, coronary heart disease, and thromboembolic disease in women with an intact uterus.7 and power were set at 0.05 and 80%, respectively. Forty-two participants were needed in each group. With an estimated 30% dropout rate during 12 weeks of treatment, the number of each group was 54, and 108 participants were needed for this study. Statistical analysis All efficacy and safety analyses were conducted according to the intention-to-treat principle. Missing values were imputed
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by the last-observation-carried-forward method. Statistical analysis was performed using the Statistical Packages of Social Sciences for Windows version 16.0. Statistical significance was defined as two-sided P G 0.05. Baseline characteristics were reported as mean (SD) and frequency (%). Baseline differences between groups were assessed with Student’s t test for normally distributed continuous variables and with nonparametric MannWhitney U test for non-normally distributed continuous variables. For categorical variables, W2 test or Fisher’s exact test was used. Comparisons between the placebo group and the EXD group were conducted using analysis of covariance (ANCOVA) with baseline as covariate. All items and domains of the MRS and the MENQOL questionnaire were compared between treatment groups every 4 weeks using ANCOVA, with treatment group as factor in the model and with baseline as covariate. The changes in the scores for the MRS and the MENQOL questionnaire from baseline to 12 weeks were tested with repeated-measures analysis of variance. Within-group differences were assessed with paired t test for normally distributed data and with Wilcoxon sign-rank test for non-normally distributed data. For hormone level and safety indices, ANCOVA was used to compare differences between the two groups, adjusting for baseline covariates. RESULTS Participant flow Participant flow is presented in Figure 1. In total, 557 Chinese women were recruited for preliminary screening via advertisements in local newspapers from April 1, 2009 to January 31, 2011. One hundred twenty-nine women participated in the baseline eligibility screening for randomization. Thirteen women were screened out owing to abnormal liver function, six women were screened out owing to abnormal white blood cell count, and two women were screened out owing to anemia. Seven participants (four participants from the EXD group and three participants from the placebo group) withdrew during the study period (reasons are listed in the flow diagram). One hundred one participants finished the treatment and 12-week posttreatment follow-up. Baseline data The baseline characteristics of the participants are summarized in Table 3. The mean (SD) age was 50.5 (3.1) years for the EXD group and 50.4 (2.8) years for the placebo group. The mean (SD) body mass index was 22.5 (3.1) kg/m2 for the EXD group and 22.1 (2.6) kg/m2 for the placebo group. The duration of cycle irregularity was 16.1 months for the placebo group and 12.2 months for the EXD group. The baseline characteristics of the two groups were balanced (P 9 0.05). Primary outcome assessment The mean (SD) frequency of hot flushes per day decreased from 5.8 (5.0) to 2.2 (3.0) in the EXD group and from 5.0 (3.8) to 2.4 (2.5) in the placebo group during the 12-week treatment period (P = 0.04; Table 4). The mean (SD) severity of hot * 2013 The North American Menopause Society
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ER-XIAN DECOCTION FOR MENOPAUSAL SYMPTOMS
FIG. 1. Flow of participants. EXD, Er-Xian decoction.
TABLE 3. Baseline characteristics Characteristics
Placebo (n = 54)
EXD (n = 54)
Between-group Pa
Age, mean (SD), y 50.4 (2.8) 50.5 (3.1) 0.85 Education, n (%) Primary 11 (20.4) 8 (14.8) 0.60 Secondary 35 (64.8) 36 (66.7) Tertiary 8 (14.8) 10 (16.5) Duration of cycle irregularity, 16.1 (15.6) 12.2 (6.7) 0.61 mean (SD), mo 22.1 (2.6) 22.5 (3.1) 0.44 Body mass index, mean (SD), kg/m2 Hot flush score, mean (SD) 16.6 (5.4) 19.6 (6.6) 0.39 Hot flush frequency, mean (SD) 5.0 (3.8) 5.8 (5.0) 0.35 Total MRS score, mean (SD) 31.4 (2.5) 31.4 (2.8) 0.35 Total MENQOL score, 104.2 (13.4) 105.0 (18.3) 0.80 mean (SD) EXD, Er-Xian decoction; MRS, Menopause Rating Scale; MENQOL, Menopause-Specific Quality of Life. a Results from Student’s t test for normally distributed continuous variables and from nonparametric Mann-Whitney U test for non-normally distributed continuous variables.
flushes decreased from 3.0 (0.7) to 1.6 (0.8) in the EXD group and from 3.0 (0.8) to 2.3 (0.8) in the placebo group during the 12-week treatment period (P = 0.01; Table 4). The mean (SD) total hot flush score decreased from 19.6 (6.6) to 4.9 (7.8) in the EXD group and from 16.6 (5.4) to 7.0 (6.4) in the placebo group during the 12-week treatment period (P = 0.02; Table 4). Secondary outcome assessment Total MRS scores and different domains of MRS scores Changes in total MRS scores are presented in Table 4. A significant reduction in total MRS scores was demonstrated within and between the placebo group and the EXD group. After the 12-week treatment period, the mean (SD) total MRS score significantly decreased from 31.9 (2.8) to 16.7 (7.2) in the EXD group and from 31.4 (2.5) to 19.2 (6.9) in the placebo group (P = 0.03). Each domain showed significant reduction before and after treatment (P G 0.05). In the Menopause, Vol. 20, No. 7, 2013
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ZHONG ET AL TABLE 4. Comparison of main outcome measures within and between the EXD group and the placebo group Placebo (n = 54) Outcome measures
Mean (SD)
Within-group P b
EXD (n = 54) Mean (SD)
Within-group P b
Between-group P a
Hot flush frequency Baseline 5.0 (3.8) 5.8 (5.0) 0.35 Endpoint (12 wk) 2.4 (2.5) G0.01 2.2 (3.0) G0.01 0.04 Follow-up (3 mo) 2.9 (0.6) 0.5 2.2 (0.8) 0.53 0.01 Hot flush severity Baseline 3.0 (0.8) 3.0 (0.7) 0.86 Endpoint (12 wk) 2.3 (0.8) G0.01 1.6 (0.8) G0.01 0.01 Follow-up (3 mo) 3.0 (0.7) G0.01 2.1 (0.8) 0.15 0.03 Hot flush scores Baseline 16.6 (5.4) 19.6 (6.6) 0.39 Endpoint (12 wk) 7.0 (6.4) G0.01 4.9 (7.8) G0.01 0.02 Follow-up (3 mo) 9.4 (2.5) G0.01 7.9 (3.7) 0.01 0.06 Total MRS scores Baseline 31.4 (2.5) 31.9 (2.8) 0.35 Endpoint (12 wk) 19.2 (6.9) G0.01 16.7 (7.2) G0.01 0.03 Follow-up (3 mo) 29.7 (3.5) G0.01 23.0 (4.5) G0.01 G0.01 Total MENQOL scores Baseline 104.2 (13.4) 105.0 (18.3) 0.80 Endpoint (12 wk) 68.9 (19.0) G0.01 57.2 (19.6) G0.01 G0.01 Follow-up (3 mo) 99.0 (15.6) G0.01 72.6 (19.4) G0.01 0.02 EXD, Er-Xian decoction; MRS, Menopause Rating Scale; MENQOL, Menopause-Specific Quality of Life. a Results from analysis of covariance with baseline as covariate (EXD vs placebo). b Results from paired t test examining effects within the group: baseline versus 12-week follow-up, and 12-week follow-up versus 3-month follow-up.
psychological domain (from 11.7 (1.5) to 5.7 (3.0) in the EXD group and from 11.4 (1.7) to 7.0 (3.2) in the placebo group) and somatovegetative domain (from 8.2 (1.1) to 3.3 (2.6) in the EXD group and from 8.3 (1.1) to 5.9 (2.6) in the placebo group), there were significant differences between and within the EXD group and the placebo group (P G 0.01; Fig. 2). However, in the urogenital domain (from 12.4 (1.6) to 6.7 (2.7) in the EXD group and from 11.7 (1.6) to 7.3 (2.8) in the placebo group), there was no significant difference between groups after the 12-week treatment period (P = 0.18).
Total MENQOL scores and different domains of MENQOL scores Changes in total MENQOL scores across the study period are summarized in Table 4. A significant reduction in total MENQOL scores was noted within and between the placebo group and the EXD group. After the 12-week treatment period, the mean (SD) total MENQOL score was significantly decreased between the EXD group and the placebo group (from 104.2 (13.4) to 68.9 (19.0) in the placebo group and from 105.0 (18.3) to 57.2 (19.6) in the EXD group; P G 0.01).
FIG. 2. Total MRS scores and different MRS domains between EXD and placebo. MRS, Menopause Rating Scale; EXD, Er-Xian decoction.
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ER-XIAN DECOCTION FOR MENOPAUSAL SYMPTOMS
FIG. 3. Different domains of the MENQOL questionnaire between EXD and placebo. MENQOL, Menopause-Specific Quality of Life; EXD, Er-Xian decoction.
In the vasomotor domain (from 10.7 (3.5) to 7.9 (5.4) in the placebo group and from 9.8 (4.3) to 5.3 (4.7) in the EXD group; P = 0.05), psychosocial domain (from 26.4 (4.8) to 17.1 (8.6) in the placebo group and from 27.1 (5.9) to 13.4 (9.2) in the EXD group; P = 0.01), and physical domain (from 55.5 (8.6) to 37.3 (15.9) in the placebo group and from 56.2 (10.1) to 30.9 (15.7) in the EXD group; P = 0.04), there were significant differences within and between the EXD group and the placebo group after the 12-week treatment period (Fig. 3). However, in the sexual domain, there was no significant difference between groups after the 12-week treatment period (from 11.6 (3.9) to 6.7 (4.6) in the placebo group and from 12.1 (3.7) to 6.1 (3.0) in the EXD group; P = 0.29).
Serum hormones and blood pressure Serum FSH, LH, estradiol, and progesterone levels were checked at baseline and after the 12-week treatment period. The differences within and between the EXD group and the placebo group are listed in Table 5. There was no significant difference between and within the EXD group and the placebo group. There was also no significant difference in blood pressure changes between and within the EXD group and the placebo group (Table 5). Assessment of blinding and compliance Success of blinding was evaluated by asking participants which treatment they thought they had received at each
TABLE 5. Comparison of serum hormones and blood pressures within and between the EXD group and the placebo group Placebo (n = 54) Serum hormones, IU/L
Mean (SD)
Within-group P b
EXD (n = 54) Mean (SD)
Within-group P b
Between-group P a
Follicle-stimulating hormone Baseline 52.4 (32.5) 66.2 (42.6) 12 wk 52.7 (34.8) 0.70 68.9 (41.9) 0.63 Luteinizing hormone Baseline 24.5 (14.0) 27.4 (17.4) 12 wk 23.5 (14.0) 0.63 28.4 (15.5) 0.49 Estradiol Baseline 245.9 (326.7) 169.8 (191.6) 12 wk 185.9 (180.6) 0.36 202.2 (530.4) 0.60 Progesterone Baseline 3.4 (7.4) 3.7 (10.0) 12 wk 4.0 (8.2) 0.26 3.0 (8.4) 0.38 Systolic blood pressure Baseline 117.3 (17.1) 117.5 (17.5) 12 wk 118.7 (14.0) 0.78 118.5 (16.1) 0.66 Diastolic blood pressure Baseline 70.5 (12.2) 67.5 (11.2) 12 wk 70.2 (8.6) 0.99 71.8 (9.4) 0.76 EXD, Er-Xian decoction. a Results from analysis of covariance with baseline as covariate (EXD vs placebo). b Results from paired t test for normally distributed data and from Wilcoxon sign-rank test for non-normally distributed data.
0.06 0.28 0.33 0.16 0.14 0.66 0.88 0.52 0.98 0.94 0.19 0.47
Menopause, Vol. 20, No. 7, 2013
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ZHONG ET AL
consultation and on follow-up. Overall, 35.2% (38 of 108 participants) correctly identified their treatment, whether CHM or placebo (57.9% in the EXD group and 42.1% in the placebo group), as compared with 53.7% correct guesses by the investigator (62.1% in the EXD group and 37.9% in the placebo group). Compliance at 12-week treatment was fair, with three withdrawing from the placebo group and four withdrawing from the EXD group (Fig. 1). The overall compliance with medication among the remaining participants was good. Ninetyone percent of participants were found to have taken at least 80% of scheduled doses via counting of the remaining medication sachets. Safety and adverse events Whole blood count, renal function, and liver function were checked at baseline and after treatments. There were no differences in these safety indices between and within the EXD group and the placebo group. Both EXD and placebo were well tolerated. There were no serious adverse events (eg, requiring hospital admission). In the EXD group, the adverse events reported were mild diarrhea (n = 1), headache (n = 2), worsening of depression (n = 2), and stomachache (n = 1). In the placebo group, the adverse events reported were headache (n = 1), worsening of insomnia (n = 2), and worsening of hot flushes (n = 3). All adverse events were reported to be mild. DISCUSSION EXD is composed of Rhizoma curliginis, H. epimedii, R. morindae officinalis, Radix anemarrhenae, C. phellodendri, and R. angelicae sinensis. Experimental research has been conducted extensively in the last 50 years and has focused on the phytochemistry and pharmacological action of EXD. Our past studies indicated that EXD relieved the menopausal syndrome by increasing endocrine and antioxidant functions through activation of the aromatase and catalase (CAT) detoxifying pathways.26 Another study also revealed the action of EXD in prolonging antiosteoporotic effects and the aging of the hypothalamus-pituitary-target gland axis.37