Treatment of Menopausal Symptoms with Er-xian ...

The American Journal of Chinese Medicine, Vol. 36, No. 2, 233–244 © 2008 World Scientific Publishing Company Institute for Advanced Research in Asian Science and Medicine

Treatment of Menopausal Symptoms with Er-xian Decoction: A Systematic Review H.Y. Chen,* William C.S. Cho,† S.C.W. Sze* and Y. Tong* School of Chinese Medicine, The University of Hong Kong, Hong Kong, China † Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China *

Abstract: The purpose of this systemic review is to assess the efficacy of Er-xian decoction (EXD), a formula of Chinese medicine, in relieving menopausal symptoms. Seven databases were extensively retrieved. The Chinese electronic databases include VIP Information, CBMdisc, and CNKI. The English electronic databases include AMED, CINAHL, Cochrane Library, and MEDLINE. Randomized controlled trials using EXD as a main intervention were included in the study selection. The quality of studies was assessed by Jadad scale and the criteria referred in Cochrane reviewers’ handbook. Two independent reviewers were responsible for data extraction and assessment. Discrepancies were rectified referring to the original articles. The efficacy of EXD treatment for menopausal symptoms was evaluated by metaanalysis. There were 154 articles retrieved according to the search strategy, 677 participants involved in the 5 studies that satisfied the selection criteria. Meta-analysis indicated that administration of EXD significantly relieved at least one menopausal symptom when compared to the control group at a 95% confidence interval (p < 0.01). The curing effect of EXD with all symptoms relieved was significant as compared with the control groups (p < 0.01). The results also indicated that the efficacy of EXD was better than the other non-menopausal hormone therapy (p < 0.01), while there was no significant difference between the EXD and menopausal hormone therapy groups. The EXD is effective in treating menopausal symptoms. However, owing to the low quality of the investigated studies, more randomized controlled trials are needed before evidence-based recommendation regarding the effectiveness of EXD in the management of menopausal symptoms can be provided. Keywords: Menopausal Symptoms; Er-xian Decoction; Randomized Controlled Trial; MetaAnalysis; Alternative Medicine; Chinese Medicine.

Correspondence to: Professor Yao Tong, School of Chinese Medicine, The University of Hong Kong, G/F, 10 Sassoon Road, Pokfulam, Hong Kong. Tel: (+852) 2589-0436, Fax: (+852) 2872-5476, E-mail: [email protected]

233

00574.indd 233

4/4/2008 2:39:33 PM

234

H.Y. CHEN et al.

Introduction Menopause is defined as the permanent cessation of menstrual periods in women for 12 consecutive months and usually begins between the ages of 45 and 55. It is associated with reduced function of the ovaries due to aging, resulting in lower levels of hormones such as estrogen and progesterone (Blake, 2006; The North American Menopause Society). The symptoms of menopause are manifested as vasomotor systems (hot flashes and night sweats), psychological symptoms (sleep disturbance, depression, anxiety, and poor memory), urinary incontinence, as well as vaginal dryness and sexual dysfunction (Barlow and Wren, 2000; Lobo et al., 2000). A Pan-Asia menopause study from 11 Asian countries or regions indicated that 99.4% of the perimenopausal women had experienced the symptoms of menopause during the menopausal transition (Haines et al., 2005). Another survey conducted in 7 European countries reported that almost all perimenopausal women had experienced menopausal symptoms (Genazzani et al., 2006). Menopausal hormone therapy (MHT; in the past, it was called hormone replacement therapy or HRT) is the primary treatment widely prescribed to relieve menopausal symptoms. Brett and Reuben (2003) reported that approximately 24% of women aged 40 years or older were using MHT in the 1999 National Health Interview Survey. In 2002, the Women’s Health Initiatives found that the combined therapy (estrogen-plus-progestin) increased the risk of stroke, breast cancer, and venous thromboembolism (Rossouw et al., 2002). Similar findings were also investigated in the estrogen-alone trial in 2004 (Anderson et al., 2004). Considering these findings, the National Institutes of Health decided to stop the estrogen-plus-progestin and estrogen-alone trials in 2002 and 2004 respectively. The potential risks led to a decline in the use of MHT. Comparing between 2001 and 2003, the number of women taking menopausal hormone prescriptions fell from 26.5 million to 16.9 million in the US (Hing and Brett, 2006). In contrast to the MHT, the use of alternative therapies has increased in recent years, especially for herbal medicine (Albertazzi, 2005; Buick et al., 2005; Chan et al., 2006). About 42–43% of US adults had used at least one form of alternative therapy (Eisenberg et al., 1998; Mackenzie et al., 2003). The proportion of women who used any alternative therapies is 76.1%. Among them, 22.1% of women used it to relieve the menopausal symptoms (Newton et al., 2002). Some of the previous systematic reviews mentioned that no current evidence supports the effectiveness of any complementary and alternative therapy in the management of menopausal symptoms based on clinical trials (Nedrow et al., 2006; Kronenberg and Fugh-Berman, 2002). These reviews presented pitfalls because the papers under scrutiny were limited to discussions of single herb or plant product, not herb mixtures. In fact, there are a number of traditional Chinese herbal formulas that were used to balance the hormonal system. For example, most reviews included the herb dong quai, also know as Radix Angelicae Sinensis. A randomized clinical study of dong quai did not find it to be useful in reducing hot flashes. However, Chinese medical practitioners argued that dong quai should be used in combination with the other herbal medicines to achieve an optimal efficacy.

00574.indd 234

4/3/2008 9:41:20 AM

MENOPAUSAL SYMPTOMS AND ER-XIAN DECOCTION

235

A herbal formula containing dong quai was developed at the Shuguang Hospital affiliated with the Shanghai College of Traditional Chinese Medicine during the 1960s, known as Er-xian (two immortals) decoction (EXD). As an established formula used to treat deficiency of the kidney, EXD is deemed to work effectively in treating menopausal symptoms. The decoction consists of 6 Chinese herbs, Curculigo orchioides Gaertn. (Rhizoma Curculiginis), Epimedium brevicornum Maxim. (Herba Epimedii), Angelica sinensis (Oliv.) Diels (Radix Angelicae Sinensis), Phellodendron chinense Schneid. (Cortex Phellodendri Chinensis), Anemarrhena asphodeloides Bunge (Rhizoma Anemarrhenae), and Morinda officinalis How (Radix Morindae Officinalis). Nian et al. (2006) reported that EXD had antiosteoporotic activity on the basis of biochemical, bone mineral density, biomechanical, and histopathological parameters in ovariectomized rats and it can increase the E2 level in serum. Recent clinical trials reported EXD had a positive effect to relieve menopausal symptoms (Wang et al., 1997; Li et al., 2002; Yu, 2003; Han, 2004). However, most of the clinical trials were based on small sample size. The efficacy of EXD reported in these trials cannot provide strong evidence to confirm the effect unless the clinical trials are based on a large population or combined small sample size trials are statistically analyzed. To address the above question, a systematic review on the effectiveness of EXD in relieving menopausal symptoms was carried out. Methods Articles were retrieved from databases, conference papers, and theses by either electronic or manual search. Only the papers which satisfied the selection criteria were included in the meta-analysis. Based on the selection criteria, the articles were reviewed independently by two reviewers. After selection, the data were extracted by the first reviewer and verified by the second reviewer. Discrepancies were rectified referring to the original articles. Selection Criteria Articles which are included in the study had to meet all of the following criteria: (1) study claimed as a randomized trial; (2) study using EXD as a main intervention; (3) study having at least one controlled group; and (4) articles written in either English or Chinese language. Search Strategy The terms retrieved in databases were menopaus$ ($ indicates a truncation), climacteri$, er xian decoction, er-xian decoction, er xian tang, er-xian tang. The combine search was (menopaus$ OR climacteri$) AND (er xian decoction OR er-xian decoction OR er xian tang OR er-xian tang). Chinese language databases were retrieved with a similar search strategy.

00574.indd 235

4/3/2008 9:41:20 AM

236

H.Y. CHEN et al.

Databases A total of 7 databases were extensively searched. The Chinese electronic databases include VIP Information (from 1989 to 2006.10), CBMdisc (from 1978 to 2006.9), and CNKI (from 1979 to 2006.9). The English electronic databases include AMED (from 1985 to 2006.10), CINAHL (from 1982 to 2006.10), Cochrane Library (1993 to 2006.10), and MEDLINE (from 1966 to 2006.10). Data Analysis The Review Manager 4.2 software developed at the Nordic Cochrane Centre was employed for data analysis. The effect data is expressed as relative risk (RR) with 95% confidence interval (CI). Significant difference was considered as p < 0.05. Results There were 154 articles retrieved according to the search strategy. Among them, only 5 articles that satisfied the selection criteria were included. The rest of the articles neither stated randomization in the clinical trials nor had a control group. Characteristics of Study There were 677 subjects included in these 5 studies, 447 were allocated to the treatment group and 230 were allocated to the control group. All the clinical studies were conducted in China and reported in Chinese language. Though the clinical trials claimed randomization in their studies, all of these trials were marked as high risk bias due to the unclear allocation concealment, blindness, and withdrawal/dropout. According to the Jadad scale, all studies were marked as one (Table 1) (Jadad et al., 1996). Among the 5 studies, one trial used EXD alone for treatment (Wang et al., 1997). The rest of the trails used EXD as the main intervention with the adding or dropping of other herbs according to the patients’ specific conditions. Four articles have reported their diagnostic criteria, with all participants diagnosed with menopausal symptoms in these four studies (Wang et al., 1997; Yu, 2003; Han, 2004; Li, 2004). Two of them measured the levels of estrogen, FSH, and LH as a confirmation of diagnosis (Wang et al., 1997; Yu, 2003). The measurement of outcome was solely based on the relief of menopausal symptoms. Three of the measuring criteria were according to published materials (Wang et al., 1997; Yu, 2003; Li, 2004), while the rest were based on self-setting criteria (Han, 2004; Li et al., 2002) (Table 2). The duration of trials selected in this study varied from 2 weeks to 6 months, yet one article did not report the trial duration (Li et al., 2002). Adverse effects of EXD are unclear since no side-effect event was reported in any of the included articles. Three studies used non-MHT as the controls, from which Li et al. (2002) used vitamin therapy, Han (2004) used herbal tablets, and Li (2004) used vitamin therapy combined with

00574.indd 236

4/3/2008 9:41:20 AM

00574.indd 237

B B B B B

Ran. C C C C C

All Con C C C C C

Blind C C C C C

With/Drop

Quality Assessment

Oryzanol 30 mg/tid Vitamin B1 10 mg/tid Nylestriol 1mg/week (ovx) Medroxyprogesterone acetate tablets 2.5 mg/qd

EXD (±)

EXD (±)

EXD (±)

EXD (±)

Li et al. (2002)

Yu (2003)

Han (2004)

Li (2004)

3 and 6 months

14 or 28 days

3 weeks

Not mentioned

60 days

Duration

Symptoms

Symptoms

Symptoms

Symptoms

Symptoms

Outcome Measurement

EXD, Er-xian decoction; ±, indicates Er-xian decoction have some herbs added/dropped according to the participants’ symptoms.

Gengnian An 5 tablets/tid

Oryzanol 20~40 mg/tid Vitamin B1 10~20 mg/tid Vitamin E 200~1,000 mg/tid Gengnian Kang 2~4 tablets/tid

Diazepam 5 mg/qd Oryzanol 20 mg/tid Diethylstilbestrol 0.125 mg/bid

Controlled Intervention

EXD

Intervention

Table 2. Characteristics of Included Studies

Wang et al. (1997)

Study

46 60 35 30 59 230

50 179 40 60 118 447 677

Control N

Treatment N HRB HRB HRB HRB HRB

TS 1 1 1 1 1

JSS

Diagnostic and outcome measurement criteria of traditional Chinese medicine

Guideline for Chinese New Drugs in Clinical Research

Guideline for Chinese New Drugs in Clinical Research

Self-setting

Self-setting

Outcome Assessment Criteria

Ran, randomization; All Con, allocation concealment; Blind, blindness; With/drop, withdrawal/dropout; B, inadequate; C, unclear; HRB, high risk bias; TS, total score; JSS, Jadad scale score.

Total

Wang et al. (1997) Li et al. (2002) Yu (2003) Han (2004) Li (2004) Subtotal

Study

Table 1. Quality Evaluation of Included Studies

MENOPAUSAL SYMPTOMS AND ER-XIAN DECOCTION 237

4/3/2008 9:41:21 AM

238

H.Y. CHEN et al.

herbal tablets as the controls. For the other two studies, MHT was used as the controls. Wang et al. (1997) selected MHT combined with diazepam and vitamin, while Yu (2003) used MHT only. Meta-Analysis Measurement of the outcome was based on the relief of menopausal symptoms. Wang et al. (1997) reported that all patients had a relief of at least one menopausal symptom in both the EXD treatment group (n = 50) and the MHT combined with diazepam and vitamin control group (n = 46). The menopausal symptoms of 8 participants in the EXD treated group and 9 participants in the MHT combined with diazepam and vitamin control group completely disappeared. There was no significant difference between the 2 groups after 60 days treatment. Li et al. (2002) reported that the menopausal symptoms of 119 participants in the EXD treated group (n = 179) and 1 participant in the vitamin treated group (n = 60) were completely relieved, but 12 participants in the EXD treated group and 23 participants in the vitamin treated group showed no effect at all. The effectiveness of EXD was significantly higher than the control group (93.4% vs 63.3%, p < 0.01). The curing effect of EXD was statistically improved when compared to the controls (66.5% vs 1.3%, p < 0.01). Yu (2003) reported that the menopausal symptoms of 16 participants in the EXD treated group (n = 40) and 11 participants in the MHT control group (n = 35) were completely relieved, but 3 EXD treated participants and 4 MHT treated participants had no effect after 3 weeks treatment. There was no significant difference between the EXD treated group and the control group (92.5% vs 88.6%, p > 0.05) after treatment. Han (2004) found that the menopausal symptoms of 53 participants in the EXD treated group (n = 60) and 10 participants in the herbal tablets treated group (n = 30) were completely relieved. There were some relief of menopausal symptoms for most of the participants in the EXD treated group, only 4 participants had no effect at all after treatment. The effectiveness of EXD was significantly higher than herbal tablets (100% vs 86.7%, p < 0.01). Li (2004) reported that the menopausal symptoms were completely relieved for 20 participants after a 3 months treatment and 42 participants after a 6 months treatment with EXD (n = 118). However, no effect was reported by 69 participants with 3 months treatment and 9 participants with 6 months treatment. Only 2 participants in the combined vitamin and herbal tablets treated control group (n = 59) had their menopausal symptoms completely relieved after a 3 months treatment, while 5 participants achieved the complete relief after a 6 months treatment. However, no effect was reported by 47 participants with 3 months treatment and 31 participants with 6 months treatment. The effectiveness of the EXD treated group was 42% and 92% for the 3 months and 6 months groups, while the effectiveness was just 20% and 47% for the 3 months and 6 months control groups. The effect of EXD was statistically higher than combined vitamin and herbal tablets (p < 0.05).

00574.indd 238

4/3/2008 9:41:21 AM

MENOPAUSAL SYMPTOMS AND ER-XIAN DECOCTION

239

The meta-analysis results indicated the efficacy of EXD, at least one menopausal symptom was significantly relieved compared to the control groups (p < 0.01) (Fig. 1). The curing effect of EXD, with all symptoms relieved, was significant as compared to the control groups (p < 0.01). The heterogeneity was presented (p = 0.05) (Fig. 2). The results also indicated that the efficacy of EXD was better than the other non-MHTs (p < 0.01), while there was no significant difference between the EXD and MHT treated groups (Fig. 3). Discussion Menopausal symptoms are cluster symptoms including the manifestation of hot flashes, night sweats, changes of temper, etc. Menopausal hormone therapy is the primary treatment to relieve menopausal symptoms in Western medicine. However, the side-effects drive menopausal women to approach alternative therapies. Chinese medicine, such as EXD, may give them a better solution. The study is to investigate the effect of EXD in treating menopausal symptoms in 3 main Chinese language databases and 4 main English language databases. Five of 154 articles meeting the selection criteria were identified. Meta-analysis is the combination of results from two or more individual studies using the statistical technique. It not only increases the precision of a treatment effect by combining similar studies but also settles controversies arising from apparently conflicting studies (Higgins and Green, 2006). In our systematic review, meta-analysis showed that the total effect of EXD was significant as compared to the control groups. The curing effect of EXD also indicated an advantage of treating menopausal symptoms. Compared to non-MHT, the effect of EXD in treating the menopausal symptoms was significant. The EXD did not show a significant difference when compared with MHT. The pooled results gave relatively strong evidence that EXD was effective in treating menopausal symptoms. Though MHT was beneficial in alleviating menopausal symptoms, there were some risks. When facing the dilemma of MHT, EXD may provide menopausal women an effective way to settle the issue. In the review of 154 articles, none reported any clinical trial following the format of Consolidated Standards of Reporting Trials (CONSORT) (http://www.consort-statement. org/). One of the 5 studies used the completed formula of EXD as treatment. The other 4 studies claimed that EXD was used as a basic formula with the adding or dropping of some herbs according to the patients’ specific conditions. According to the theory of Chinese medicine, diagnosis and treatment were based on an overall evaluation of the patient's conditions. Since every patient had different conditions, it would be contradictory to the personalized approach of Chinese medicine if an individual patient was treated with a fixed herbal formula without any adjustment in dose and herbs. However, the changes of dose and herbs may cause bias, and affect the credibility of data in the trials. This is a major obstacle to design a clinical trial for Chinese medicine to satisfy both of the Chinese medicine theory and the Good Clinical Practice (GCP) requirements, a widely used gold standard of clinical trials in the world (ICH Expert Working Group, 1996).

00574.indd 239

4/3/2008 9:41:21 AM

00574.indd 240

50/50 167/179 37/40 60/60 109/118

Treatment n/N 46/46 37/60 31/35 26/30 28/59

Control n/N

1

2

5

Favours control

10

124

11/35 10/30 5/59

0.2

0.5 Favours treatment

0.1

1

2

5 Favours control

RR (fixed) 95% CI

2.47 [1.71, 3.56]

100.00

10

1.27 [0.69, 2.36] 2.65 [1.58, 4.43] 4.20 [1.75, 10.05]

36.97 42.02 21.01

Weight %

RR (fixed) 95% CI

1.44 [1.29, 1.61]

Not estimable 1.51 [1.23, 1.85] 1.04 [0.90, 1.21] 1.16 [1.00, 1.34] 1.95 [1.48, 2.56]

RR (fixed) 95% CI

Figure 2. The curing effect of Er-xian decoction was significantly different as compared to the control groups (p < 0.01).

Total (Treatment), 26 (Control) Totalevents: events:111 111 (Treatment), 26 (Control) 2 2 Chi = 5.89, df = l = I?= 66.0% Test Testfor forheterogeneity: heterogeneity: Chi?= 5.89, df2=(p2