Efficacy and Side Effects of Chinese Herbal Medicine for Menopausal Symptoms: A Critical Review

This study evaluates 23 (9 Chinese and 14 non-Chinese) randomized controlled trials for efficacy and side effects of Chinese herbal medicine on menopausal symptoms. Menopause was diagnosed according to western medicine criteria in all studies while seven Chinese studies and one non-Chinese study further stratified the participants using traditional Chinese medical diagnosis “Zheng differentiation.” Efficacy was reported by all 9 Chinese and 9/14 non-Chinese papers. Side effects and adverse events were generally mild and infrequent. Only ten severe adverse events were reported, two with possible association with the therapy. CHM did not increase the endometrial thickness, a common side effect of hormone therapy. None of the studies investigated long-term side effects. Critical analysis revealed that (1) high-quality studies on efficacy of Chinese herbal medicine for menopausal syndrome are rare and have the drawback of lacking traditional Chinese medicine diagnosis (Zheng-differentiation). (2) Chinese herbal medicine may be effective for at least some menopausal symptoms while side effects are likely less than hormone therapy. (3) All these findings need to be confirmed in further well-designed comprehensive studies meeting the standard of evidence-based medicine and including Zheng-differentiation of traditional Chinese medicine.


Introduction
Women can experience menopausal symptoms beginning in their mid-to-late forties [1]. It has been reported that almost 80% of women in western countries and more than 60% of Chinese women suffer from menopausal problems [2][3][4]. An American survey reports that approximately 25% of women require treatment [5]. Menopausal symptoms can last for 4-5 years or longer and can even be found in 9% of 72-year-old women [1,3,6,7]. Menopausal syndrome not only has an impact on women's quality of life but also is associated with other health problems, for example, cardiovascular disease and osteoporosis in old age [8][9][10].
Clinical manifestations of menopausal syndrome have a multivariate feature, including vasomotor episodes, urogenital problems, sleep disturbance and mood disorders, uterine bleeding, somatic symptoms, vertigo and headaches, palpitations, skin formication, and sexual dysfunction [8,[11][12][13][14][15][16]. Among them, vasomotor symptoms, vaginal dryness, and sleep disturbance are most frequent and thus regarded as the most relevant problems, followed by mood symptoms and urinary complaints [3]. Hormone therapy is taken to be the most effective treatment for menopausal syndrome, but various disadvantages and side effects have been reported, including increased risk of breast and ovarian cancer, endometrial hyperplasia and carcinoma, stroke, and venous thromboembolism, especially for long-term therapy [17][18][19][20][21][22][23][24][25]. Furthermore, a significant proportion of menopausal women have contraindications to or are unwilling to use hormone therapy. Therefore, not only patients but also physicians are increasingly interested in complementary therapies using natural products with good effectiveness and fewer side effects [26,27]. In USA, 82% physicians recommend herbal remedies to their menopausal patients [28].
Chinese herbal medicine (CHM), one of these natural product treatments with less side effect, has been widely used to disperse menopausal problems in China and other Asian countries [29][30][31][32][33][34][35][36]. However, in western society, the evidence of its efficacy is seen as unconvincing [3,[37][38][39]. Though there has been a large number of case reports and pilot clinical trials with various prescriptions in China in the past decades, they do not provide comparable, measurable, and reproducible evidence for efficacy of the treatments. On the other hand, randomized double-blind controlled trials in western medicine framework demand and favor homogeneity of participants, standardization of intervention, and quantitative measurements but lack consideration for Chinese medical Zheng features.
Zheng differentiation (pattern differentiation, 辨 证), a syndrome stratification according to traditional Chinese medicine (TCM) diagnosis methods, plays the central role in the concept and practice of TCM. The logic of this TCM diagnosis differs fundamentally from that of the western scientific thinking. According to the TCM rationale, menopausal syndrome are caused by imaginary dysfunction of several organs such as kidney, liver, heart, and spleen, as well as imaginary pathogenic products induced by that dysfunction such as excessive fire, blood stasis, qi stagnation, and phlegmdampness. The consequence is loss of coordination of qi and blood, disharmony of cold and heat, and imbalance of yin and yang ( Figure 1) [40][41][42][43][44]. A Zheng differentiation of a menopausal case can be, for example, "aging-induced kidney dysfunction" or "kidney-based organ dysfunction" [40]. TCM therapies, both standardized and individualized, are adapted according to this kind of stratification. Efficacy of CHM on menopausal syndrome is thus also expected to rely on Zheng stratification [31,[45][46][47].
In this study, we evaluated more than 2000 published studies on efficacy of CHM for menopausal syndromes and critically analyzed 23 fit to our criteria, focusing on diagnosis, outcome measure, efficacy and side effects/adverse effects. We further discuss the role of Zheng-differentiation.

Databases and Search
Strategy. Three Chinese electronic databases including VIP Database for Chinese Technical Periodicals (VIP), Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), and two major international electronic databases (Cochrane Library and MEDLINE) were searched. Specific search strategy for literatures was established for each of the five databases. The search strategy and terms for VIP, CNKI, and CBM were translated from Chinese. The search strategy for MDELINE was developed by modifying a published protocol of CHM for menopausal symptoms from Cochrane library [48]. Details of the search strategies and the abbreviation list are provided in the supplementary information available online at doi:10.1155/2012/568106.

Inclusion and Exclusion
Criteria. Randomized controlled trials of orally taken Chinese herbal medicine, including powders, liquid, pills, tablets, and capsules for treating physical or psychological menopausal symptoms published in Chinese or English were included. Kampo medicine (Japanese branch of traditional Chinese medicine), employing similar prescriptions of Chinese herbal medicine, was also considered [49][50][51]. Menopause included spontaneous ones and those induced by surgery, chemotherapy or radiotherapy. Control groups contained placebo, hormone therapy, other alternative medicine (e.g., SSRIs (selective serotonin reuptake inhibitors), oryzanol), acupuncture, and no treatment. Only studies with outcomes measured by quantitative questionnaires or participant's symptom diaries for menopausal symptoms were included ( Figure 2).

Evaluation.
Two independent specialists (Lian-wei Xu and Man Jia) assessed the abstract and full-text literatures of all potential eligible trials meeting the inclusion criteria and summarized using data extraction forms from the selected studies. One of the two reviewers completed the forms which were subsequently confirmed by the others. Some of missing information was sought by contacting authors of the corresponding publications. The methodological quality of studies was evaluated using Jadad scale [52].
"Efficacy" for a CHM intervention is defined as (1) significant improvement compared to placebo or (2) similar improvement compared to standard therapy for either total scores or subscales of major relevant symptoms such as hot flushes and psychological parameters.

Study Quality.
A total of 2036 randomized controlled trials (RCTs) in Chinese databases and 68 in English databases were retrieved ( Figure 2). Majority of studies were not blinded and many lacked adequate controls or   comparators. Also lack of consideration for dropouts and lack of standardized outcome measures are frequent. The remaining total of 23 studies consisting of 9 Chinese and 14 non-Chinese met the inclusion and exclusion criteria and were further evaluated in following analysis [34,. Jadad score varied from 1 to 4 (mean = 2.8) for the 9 Chinese papers and 2 to 5 (mean = 3.7) for the 14 non-Chinese papers ( Table 2).

Diagnosis and Zheng Differentiation.
In all these 23 RCTs, menopausal syndrome was diagnosed according to the standardized western medical criteria. Seven Chinese studies and one Netherlandish study further stratified the participants according to the TCM Zheng diagnosis ( Figures  2 and 3, Table 1) [67][68][69][70][71][72][73][74]. Seven of studies considered yin deficiency and three specially mentioned kidney deficiency. These Zheng differentiation considered dysfunction of kidney, liver, and imbalanced pathogenic factors excessive liver qi, excessive fire, and blood stasis. The main Zhengs were (1) yin deficiency and excessive fire Zheng, (2) yin deficiency and excessive liver qi Zheng, (3) kidney (yin or yang) deficiency Zheng, and (4) spleen-kidney deficiency with blood stasis Zheng. Among these eight trials, one included all patients meeting western menopausal diagnosis and treated them individually according to the differential Zheng-differentiation [67]. The other seven included only patients meeting certain Zheng-differentiation for which the respective herbal mixture was formulated [68][69][70][71][72][73][74]. None of the studies described details of procedure of the Zhengdifferentiation.

CHM Interventions and Control.
One study used hydrophilic concentration of individualized CHM prescribed according to the Zheng-differentiation of each participant [67]. All the other 22 used standard patented Chinese medicine of classical, modified classical or empirical prescriptions or single herb in granules, capsules, oral liquid, powder, or tablets (Table 1). Nineteen trials used mixed herbs while the other four used single herb ( Figure 3, Table 1).
The duration of the interventions was between eight weeks and two years ( Table 1). One study had followup until four weeks after termination of the treatment [67].

Outcome
Measure. All the 23 included trials used quantitative methodology to score and measure the extent of the menopausal symptoms and quality of life (Table 1). Kupperman Index and modified Kupperman Index are the most frequently used systematic measures (in 11/23 studies), especially in Chinese studies (8/9). Five Chinese trials employed the Chinese Medical Symptoms Scale corresponding to the TCM Zheng-differentiation. Other studies applied various scales including Greene Climacteric Scale, Menopause Rating Scale, Menopause Specific Quality of Life, Short-Form 36 Health Survey (SF-36), Pittsburgh Sleepiness Quality Scale, and Hamilton Depression Scale. Some of the trials provided scores of each symptom or domain separately while others gave the total scores for these standardized questionnaires. Six non-Chinese studies measured vasomotor symptoms by patient diary.
3.5. Efficacy. All 9 Chinese and 8/14 non-Chinese studies reported positive effects of CHM while the other 6 non-Chinese studies did not find effectiveness. Positive effects included significant improvement (in total scores or in subscales of major relevant symptoms) compared to placebo and similar improvement compared to standard hormone therapy or other recognized alternative medicine. Reduction of hot flushes was the most frequently reported positive effect followed by improvement in total scores, benefits in depression, and other psychological measures. Generally, non-Chinese studies reported more details than Chinese ones.
Among the 9 Chinese studies, 5 employed placebo, 3 employed HRT, and one used Vit E plus oryzanol as positive comparators [61,62,[68][69][70][71][72][73][74]. Majority of the Chinese studies reported only total scores of questionnaires but no data for subscales. Most studies declared that CHM improved scores of menopausal symptoms in comparison to placebo or reached similar effect of that of positive comparators (oryzanol or HRT). Only Wang et al. reported rather confusing results that CHM reduced total score of modified Kupperman index in the 8th week but not in the 12th week of the treatment [70].
One non-Chinese study observed significant improvement for Greene's scales for the CHM treatment group in comparison to baseline. However, most of these positive effects were significantly weaker than those of the Paroxetine treatment. The authors, thus, could not reach a conclusion for the efficacy of the CHM [57].
A total of 5 non-Chinese studies reported no efficacy ( Figure 3). All these 5 studies employed placebo or no treatment as the comparators. Four studies reported substantial but similar improvements in both CHM and placebo groups [34,53,55,56]. One did not find improvement at all in five major domains in CHM, HRT, and no treatment groups [54].
Eight out of the 9 Chinese studies and one non-Chinese study stratified patients according to their TCM-Zheng [67]. For example, Kwee et al. reported that individualized CHM for menopausal patients with Zheng-differentiation led to 29% reduction of average score of hot flushes compared to placebo [67]. In the study of 442 patients with yin deficiency and excessive liver qi, CHM mixture Jing Qian Ping granules significantly improved total scores of modified Kupperman Index and Chinese Medical Symptoms Scale compared to placebo (Table 1) [71].
Two of the 4 studies with single herb reported efficacy while the other two did not ( Figure 3).
A meta-analysis for efficacy of CHM was not feasible due to the variety of measurements of outcomes and the heterogeneity of the trials.

Safety and Adverse Effects.
Eight trials systematically examined the endometrial thickness after the interventions and none of them found abnormal increase of thickness of endometrium by CHM. In contrast, increase of thickness of endometrium was reported in patients receiving hormone therapy which was used as a positive comparator in one study [62].
Nineteen trials monitored standard physiological functions and investigated adverse events or side effects of CHM (Table 1) [34,[53][54][55][56][57][58][59][60][61][63][64][65][66][67][68][69][70][71][72][73]. Six trials (32%) reported no serious side effects or adverse events. Six of the remaining thirteen trials reported some adverse events which were, however, similar to those in corresponding placebo groups. Only one study reported more diarrhea in CHM group than in placebo ( Table 1). The most common side effect was gastrointestinal symptoms including abdominal bloating Evidence-Based Complementary and Alternative Medicine  Evidence-Based Complementary and Alternative Medicine    or pain, epigastric discomfort, and stomach disorder in 8, followed by diarrhea in 7, headache in 4, nausea in 3, breast distension or pain in 2, abnormal vaginal bleeding in 2/19, and dizziness in 2 studies. Only 10 severe adverse events were reported by three trials, among a total of 1837 participants (Table 2). One adverse event was per rectum bleeding, which may be possibly associated to the hot feature of Dang Gui Bu Xue Tang (DBT) [55]. Wiklund et al. reported 7 severe adverse events and stated that one of them was likely related to the CHM medication. However, no detailed information was available regarding feature of this event [58]. Two other serious adverse events were found in high dose of CHM of Grady et al.'s trial. One was idiopathic pancreatitis and the other one had occurred before the trial [59]. The paper did not mention the relationship between CHM intervention and idiopathic pancreatitis.
The longest trial over two years did not report serious adverse events [72]. None of the other studies investigated long-term side effect.

Efficacy, Study Quality and Zheng Differentiation.
To date, more than 2000 studies have been carried out concerning efficacy of CHM for menopausal syndrome, mostly in China and published in Chinese journals. However, only very few meet some of the standards of evidence-based medicine. We could only select 9 Chinese and 14 non-Chinese studies for evaluation.
All Chinese studies reported effectiveness for CHM. However, these studies have generally low quality and lacked detailed data. In addition, the fact that Chinese journals traditionally publish only positive results seriously reduces reliability of the reported efficacies.
Non-Chinese studies have generally better quality. However, most of these studies have the drawback of lacking consideration of Chinese medical features, especially Zheng-differentiation, the essential soul of TCM theory and practice. As in western medicine, CHM is also prescribed according to diagnosis which is based on a different way of interpretation and consideration of symptoms and endogenic/exogenic factors in a disordered and disharmonized menopausal female body ( Figure 1). Thus, efficacy of CHM relies on Zheng-differentiation and may be less prominent in non-Chinese studies which do not apply Zhengdifferentiation. Authors of a study carried out on American women indeed discussed that the lack of consideration of sho (similar to Zheng-differentiation) for participants may have contributed to the negative results [34].
Zheng-differentiation is a basic skill of TCM professionals who, however, often lack experience in randomized, blinded, and placebo-controlled clinical trials meeting the standard of evidence-based medicine in western countries. Cooperation of TCM and western medicine professionals is, thus, desirable for future studies on efficacy of CHM for menopausal in Chinese and non-Chinese females. Such studies will also help elucidating the role of Zheng-differentiation in TCM in general.

Side Effect and Adverse
Events. An important feature of CHM is the lack of increase of endometrial thickness, a common side effect of hormone therapy [62]. This can be well seen in several of the evaluated studies.
Other side effects of CHM are infrequent and generally mild. Among a total of 1837 treated cases, only ten severe adverse events were reported, though for eight of them there was no evidence of causal relation with the used CHM. Only two adverse events may have been related to the some components of the respective CHM: nausea in one case may be related to Ginseng [58] and per rectum bleeding in another case to the hot nature of Dang Gui Bu Xue Tang [55]. The most frequent side effects were mild gastrointestinal symptoms.
The observation periods of the evaluated studies were generally short (around 12 weeks). Thus, long-term side effects known for CHM remain a central issue for future studies.

Conclusion
Large number of studies have been carried out on efficacy of CHM for menopausal syndrome, but most of them lack adequate quality. CHM may be effective for at least some menopausal symptoms while its side effects are likely less than those of hormone therapy. However, all these findings need to be confirmed in further well-designed comprehensive studies which meet the standard of evidencebased medicine and include Zheng-differentiation of TCM. Cooperation of western medical and TCM professionals is essential.