A Systematic Review Assessing The Safety & Efficacy of Chinese Herbal Medicine (CHM) Reducing Menopause Symptoms

INTRODUCTION

It is still uncertain whether Chinese Herbal Medicine (CHM) for the treatment of vasomotor symptoms in menopausal women is effective or safe. Menopausal women are seeking natural therapies due to concerns associated with adverse effects (AE) of hormone replacement therapy (HRT). I am a Natural Health Specialist in Auckland, New Zealand (NZ) and passionate about menopause in clinic.

What is Menopause?

Menopause is the cessation of reproductive ability and cyclic production of ovarian sex steroids due to loss of ovarian function in a woman that produces vasomotor, somatic, sexual and psychological symptoms (Gartoulla, Islam, Bell & Davie, 2014). Almost 80% of women in western nations and more than 60% of Chinese women experience menopausal symptoms that interfere with their quality of life ((Kronenberg (1994), Nelson (2008)). Diagnosis is confirmed by the cessation of menstruation (excluding hormonal contraceptive use) for more than 12 months (Goolsby, 2001).

Currently, doctors treat menopause with custom-compounded bioidentical HRT, non-hormonal pharmalogics such as (e.g. SSRIs), gabapentin and clonidine (Pace, 2017). There are various HRT brands, preferably a woman will find other options given there are serious side effects that HRT carries. As a guide, the costs of HRT may initially seem lower than seeking naturopathy and Chinese medicine for menopause, however the severity of side effects can outweigh both cost and benefit of HRT.

Symptoms of Menopause

Menopause can present numerous symptoms such as weight gain, hot flashes, night sweating and dryness. Chinese medicine offers numerous remedies to not necessarily reverse the menopause but to support the body to return the body to balance so that hot flash frequency and severity are reduced, metabolism is supported to prevent further weight gain, the excess heat is cleared from the body to reduce the night sweating and dryness. Premature menopause can be supported too for symptomatic reasons but is difficult to treat with Chinese medicine for fertility.

What is Premature Menopause?

Premature menopause is defined as a woman going through menopause before the age of 40 years. Chinese medicine can support premature menopause to reduce the severity of the condition and ease symptoms but it cannot be cured. It can be diagnosed medically, usually through FSH analysis.

What is Perimenopause?

Is when a woman transitions into menopause, she may not be completely menopausal but on the cusp and it can occur for a few years. She may get occasional symptoms such as changes in regularity of menstruation and bleeding quantity. The beginning so hot flashes and night sweating that comes and goes. This occurs as the body makes less oestrogen, in Chinese medicine oestrogen is considered a yin hormone as it makes the body moist and young, so when oestrogen levels drop a woman can become dry and present with heat symptoms such as night sweating and hot flashes. Although taking HRT or synthetic oestrogen alleviates these symptoms, when taken over a long period of time they have been linked to serious side effects such as breast cancer. This is why a course of acupuncture and Chinese herbal medicine with an experienced practitioner is worth doing before trying stronger medications.

Flowers Chinese Herb Menopause
Flowers are commonly used in Chinese herbs for menopause

How To Self-Helf Naturally During Menopause

If you want to understand and learn ways to help your menopause symptoms yourself, read my article here on Natural Support for Menopause.

Definition of Menopause in Traditional Chinese Medicine

CHM is based on traditional Chinese medicine (TCM). TCM theory regards menopause as a natural event in a woman’s life that occurs around 49 years of age. The signs and symptoms experience by a woman at this time vary from night sweating, hot flushes, exhaustion, vaginal dryness to severe hormonal changes (Zhou & Qu, 2007). Menopause is thought to occur after the very gradual decline of kidney jing (essence) over a woman’s life, and manifested in the deficiency of kidney yin or yang, or both, along with the physiological decline of tian gui (heavenly water). An ancient Chinese medicine text, the Huang di Nei Jing Su Wen depicts that this “tian gui” arrives at 14 years of age and is exhausted by the age of 49;

“At the age of 14 the Tian Gui arrives,

the Ren Mai begins to flow,

the Chong Mai is flourishing,

the periods come regularly and she can conceive…

At the age of 49,

the Ren Mai is empty,

the Chong Mai depleted,

the Tian Gui dries up,

the Earth Passage [uterus] is not open,

so weakness and infertility set in”

(Unschuld, 2003, p.84).

TCM treats menopause with either CHM or acupuncture, or both together. Treatment principles generally aim to nourish both the kidney yin and yang, while clearing any deficient heat and addressing any related organ imbalances (Maciocia,1998).

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Rationale for Another Systematic Review

HRT is currently the most effective and prescribed medical treatment for vasomotor symptoms of menopause, however numerous AE and associations have been reported especially for long-term application; ranging from endometrial hyperplasia, endometrial carcinoma, breast cancer to stroke and venous embolism (Lumsden, 2016, Beral et. al., 2001).

In consequence, a significant proportion of menopausal women are unwilling to use hormone therapy and some have contraindications to the therapy making not only patients, but also physicians progressively curious in complimentary therapies which offer good efficacy and fewer AE (Kang, Ansbacher & Hammoud, 2002).

Problematic symptoms, specifically vasomotor of menopause in Australia affected 50% of women (Gartoulla, Islam, Bell & Davie, 2014). Australia has an ever-growing ageing population; many menopausal women are in the workplace and need alleviation (Davis et. al., 2008). Many Australian women prefer to take and try alternative medicines to ease their menopausal signs and symptoms (Gartoulla, Islam, Bell & Davie, 2014).

This raises questions to the safety and efficacy of complimentary therapies for vasomotor symptoms in menopause.Chinese herbal medicine (CHM) is one of these therapies that has been commonly used in Asia (Scheid, Ward, Cha, Watanabe & Liao, 2010). However, in Australia and other western countries, the evidence for CHM’s effectiveness for menopause remains as sceptical and unconvincing (Huntley & Ernst, 2003)(Lin et al, 2017).

Chinese herbal medicine (CHM) has been used for hundreds of years by women in China to manage these symptoms, however how truly effective are they? The Australian media is sceptical of the quality and safety of Chinese herbs.

For this reason, we aim to assess research pertaining to the efficacy and safety of CHM for the management of vasomotor symptoms in menopausal women. Only two systematic reviews have specifically evaluated CHM for vasomotor symptoms in menopause.

Xu et al (2012) evaluated 23 randomised-controlled trials (RCTs) for the efficacy and side effects of CHM. Their critical analyses found that studies were of low to moderate quality, CHM is effective at least for some symptoms, CHM has less side effects than HRT and need to be confirmed through further well-designed comprehensive research.

Zhu, Liew & Liu (2016) used 22 RCTs and found insufficient evidence that Chinese herbal medicines were any more or less effective than placebo or HRT for the alleviation of vasomotor symptoms. The safety of CHM was inconclusive and they called for better designed RCTs given the quality of evidence ranged from very low to moderate.

Despite the limitation of RCTs on CHM and menopause available (Zhu, Liew & Liu, 2016),the author decided to see whether any better RCTs on the topic had been since conducted, and include any relevant RCTs with an Australian population. It was evaluated how CHM purely compares to a placebo and the effects on vasomotor symptoms given only three high quality RCTs were considered.

Objectives

To evaluate the quality of the available literature in the treatment of menopausal-related vasomotor signs and symptoms with internal Chinese herbal medicine to establish the efficacy and safety of treatment outcomes for menopausal women.

METHODS

Search Methods for Identification of Studies

PICOS was utilised to convert the information into a high-level clinical question here (Table 1). The author used a MeSH search for menopause in the PubMed database (Table 2). The suggestions from the MeSH analysis (Table 2) clarified that menopause, and premenopause would be used for the search terminology along with perimenopause. Postmenopause and premature menopause were omitted and would be classified as exclusion criteria.

Search articles Chinese medicine research
Searching for Chinese herbal medicine research

Search Strategy

The results of this with various combinations of Boolean operator were queried (Table 5). A comprehensive retrieval for studies that evaluated the efficacy and safety of CHM in patients with menopausal vasomotor symptoms was performed in the major English medical database; PubMed. The following subject terms and key words were used in the search: (‘Chinese herb’ OR ‘herbal formula’ OR ‘Chinese herbal medicine’) AND (‘Randomized clinical trial’ OR ‘randomized controlled trial’ OR ‘randomized trial’) AND (‘menopause’ OR ‘premenopause’ OR ‘perimenopause’). The most appropriate search strategy was number 11 (Table 5), given the Boolean Operator combination in American English provided the greatest result of articles. This result of 52 articles were then considered according to inclusion and exclusion criteria (Table 6).

Types of Outcome Measures for Outcome Data

The primary outcome measure considered from the assessed RCTs were the change in vasomotor symptoms, specifically the frequency and severity of hot flushes as this is a standard in menopausal studies (Zhu, Liew & Zhao, 2016). The secondary outcome required was a quality of life assessment for participants, such as the menopause-specific quality of life (MENQOL) Questionnaire (Radtke, Terhorst & Cohen, 2011).

Study Characteristics

Three RCTs were analysed. A total of 256 patients were used for the analysis (128 in the intervention group and 128 in the comparator group). Two studies were conducted on women from Hong Kong and one study on non-Asian Australian women. The duration of trials selected in this review varied from 12 to 24 weeks (Table 7).

Bias

All three studies were parallel-design randomised controlled trials (RCTs).

Only two studies reported that allocation concealment was implemented, and therefore on this count were considered to have a low risk of selection bias (Haines et. al. 2008; Zhong et. al. 2013). 

RESULTS

When CHM (95% CI 57.2 to 19.6 +- 5.225) was compared with placebo (95% CI 63.83 to 73.97 +- 5.065) for all 3 RCTs, there was no evidence of a difference between groups for MENQOL (scale 0 to 6). There was also no evidence between groups for frequency of hot flushes (95% CI -2.08 to 0.45 +- 0.75) (Table 14). There was no difference across studies for age or sample size (Table 15). Adverse effects were fully reported in the included RCTs and participants in the CHM were found to be less likely to have AE than the placebo (RR=0.84, Table 15). Adverse effects included numerous symptoms such as per rectum bleeding, headache, bloating, stomach-ache and insomnia across both groups (Table 7). It was also 7% less likely for there to be dropouts in the CHM when compared to placebo (RR=0.93, Table 15). Adverse effects were found in both placebo and intervention groups.

Data Extraction & Quality Evaluation

A total of 52 articles were found to have potential relevance for the research question regarding menopause. From these 52, 17 were excluded for the following reasons; there were 2 articles without text or abstract available, 6 were specifically not related to vasomotor symptoms, 1 was duplicate and 8 were not related to Chinese herbal medicine. The remaining 35 articles were assessed for eligibility and 33 were excluded for the following reasons, 2 were premature ovarian failure, 3 only studied a single herb, 1 was not translated into English, 10 were reviews and systemic reviews, 5 had more than one intervention, 3 were pilot studies, 5 studies analysed a patent product and 3 were protocol studies. Thus, 49 trials were excluded after analysis. Only 3 RCTs met all inclusion criteria and were thus considered for qualitative and quantitative analysis for this review (Diagram 1).

The analysed characteristics of the 3 chosen studies (Zhong et. al., 2013; Haines et. al., 2008; Davis et. al., 2001) are presented in Table 2. Two studies were conducted in Hong Kong and one in Australia. Participants were recruited from the outpatient wards of hospitals, and a menopausal society magazine. The sample size of groups ranged from 27 from 51.

Given the condition analysed was vasomotor symptoms of menopause, gender composition of participants was exclusively female. Average age of participants ranged from 46.7 to 57.7. Notably, none of the included studies considered traditional Chinese medicine (TCM) syndrome differentiation. Participants were classified according to vasomotor symptoms medically.

black and white blackboard business chalkboard
Results of Studies on Chinese Herbs for Menopause

Results of Individual Studies

Zhong et. al. (2016) tested the efficacy and safety of er xian tang (EXD), given previous studies presented insufficient evidence to support this CHM formula for the management of menopausal vasomotor symptoms against a placebo for 24 weeks for 108 patients. It was found to be the most superior study analysed in this systematic review, measuring as low risk on all counts in the risk of bias (Table 3). Overall, EXD was found to significantly reduce the frequency and severity of hot flushes, even both menopause rating scale (MRS) (p<0.05) and MENQOL scores (p<0.01) faired favourably when compared with the comparator. One hundred and one participants finished the treatment.

Haines et. al. (2008) examined the effect of dang gui buxue tang against a placebo on menopausal vasomotor symptoms for 12 weeks in Hong Kong Chinese women with 103participants enrolled. Overall risk of bias here was measured as moderate (Table 7) given there were two unclear and one high risks (Table 8). Overall, there was a significant reduction in the number of mild hot flushes per month in the treatment group (p<0.05) but not in the placebo group (p=0.107). Regarding moderate flushes, there was a significant reduction in the placebo group (p<0.05) compared to the treatment group (p=0.471). Regarding vasomotor symptoms in the MENQOL questionnaire, there was also a significant reduction in scoring in the placebo group (p<0.01) but not in the treatment group (p=0.247). Thus, there was no overall difference between the intervention and placebo group, except for dang gui buxue tang being statistically superior to the placebo for mild hot flushes. One hundred subjects finished the treatment.

Davis et. al. (2001) evaluated the effects of their own CHM formula against a placebo for menopausal symptoms in 78 enrolled participants. Overall risk of bias here was measured as high (Table 7) given blinding and allocation as significant items were both unclear, plus another high risk was found (Table 8). There was a reduction in frequency of vasomotor symptoms for the CHM group and also with placebo and although the difference between groups favoured the use of placebo, this was not significant (p=0.09). There were significant reductions in scores for the various domains of the MENQOL questionnaire, however there were no significant differences between the two treatment groups for any domain. Fifty-five menopausal Australian women recruited from an urban population completed 12 weeks of CHM intervention against a placebo.

Regarding vasomotor symptoms in the MENQOL questionnaire, there was also a significant reduction in scoring in the placebo group (p<0.01) but not in the treatment group (p=0.247). Thus, there was no overall difference between the intervention and placebo group, except for dang gui buxue tang being statistically superior to the placebo for mild hot flushes. Hence it was concluded that the defined formula of CHM was no more effective than placebo in reducing vasomotor episodes in Australian menopausal women.

Funding

All three studies declared their funding sources. Zhong et. al. (2016) was supported by the Liu Hao Tsing Foundation and HKU Small Project Funding. Haines et. al. (2008) was funded by the Area of Excellence Grant of the University Grants Committee in Hong Kong. Davis et. al. (2001) was supported by a research grant from the Australasian Menopause Society. There was absence of any potential conflict of interest.

money Chinese medicine study funding
Money is a big factor for research incentives

Risk of Bias Across Studies

Only one study (Zhong et. al., 2016) reported that the overall monthly vasomotor symptom scores were lower in the CHM group compared to the placebo (95% CI -5.52 to -4.06). 

Risk of bias in Individual Studies

The risk ratio was calculated for age, sample size, AE and dropouts across all three RCTs. All RCTs were found to have no difference between intervention and comparator groups for age and sample size. The risk ratio for Davis et. al. (2001) suggested that the number dropouts was likely to have affected the study results whereas those for Haines et. al. (2008) and Zhong et. al. (2016) would not (Table 10).

Limitations

Self-selection bias was present given participants agreed to trial a herbal intervention, expressed negative views on HRT and had high prior expectations to the efficacy of CHM. These kinds of expectations may lead to inaccuracies in reporting in the MENQOL Questionnaire for example. Secondly dosage of Chinese herbs vary and modern dosages are not necessarily correct or the equivalent to the classical prescription. For example Zhong et. al. (2016) prescribed 30g daily whereas Haines et. al. (2008) prescribed 3g daily (Table 7). Thirdly, participant ethnicity varied given two studies were a Hong Kong population and one was an Australian, hence findings may not be generalised. The greatest limitation amongst all three studies was that all forms of CHM were prescribed without considering the participants’ Chinese medicine diagnosis given in TCM a CHM formula is always specified to diagnosis.

DISCUSSION

All RCTs were found to have no difference between intervention and comparator groups for age and sample size. It was slightly less likely for there to be more adverse effects or dropouts in the CHM group compared to placebo. Ultimately, it was inconclusive as to whether MENQOL scores and hot flush frequency faired better in the CHM groups (Table 14).

Strength and Weaknesses of Evidence

Zhong et. al. (2016) resembled a well-designed and thought out study providing low risk of bias on all counts as the authors had extensively researched flaws and needs of past, similar studies. Haines et. al. (2008) was also a well-designed study however the author pertains that its’ major weakness was the dosage of Chinese herbs as being too low to have any significant effect. Across all three RCTs, evidence was not strong enough to support that CHM was superiorly effective to a placebo.

Implications for Clinical Practice

Implications for clinical practice are prescribing an appropriate dosage, 30g of powdered CHM daily is quite high and 3g daily is potentially too low. In clinical practice, the herbalist will almost always prescribe a formula specific to the patients TCM presentation, whereas this was not considered in any of the RCTs. In clinical practice, there is no blinding for patient nor practitioner in clinical practice, and the patient usually decides how long they will take the herbal formula for.

Implications for Research

As always, the major implication for research with TCM is to create a large enough study to have patients in a group of one syndrome, for example liver qi stagnation and then prescribe a general formula for this group. Funding is an issue (what is the purpose of funding a CHM classical formula that cannot be patented?) and the time and effort to create such an RCT is exhaustive.

Limitation of This Systematic Review Project

Two of the studies had the same length of treatment for 12 weeks (Haines et. al., 2008; Davis et. al., 2001) whereas one (Zhong et. al., 2016) went for 24 weeks. Dosages varied from 3g to 30g daily. As always in menopausal studies, the placebo group always responds well, meaning that it is difficult truly to compare the intervention to the placebo.

Comparison with Existing Literature

The author finds that the studies used were of generally high quality when compared to the majority of CHM menopausal studies. Most of which have very small sample sizes, are not blinded nor randomised. Like existing literature, it was found that the efficacy CHM for vasomotor menopausal symptoms is inconclusive and studies with a greater sample size are to be made.

grey haired woman menopause
You can help your menopause symptoms with Chinese medicine

CONCLUSIONS

Despite extensive analysis and consideration, we found insufficient evidence that Chinese herbal medicine was any more or less effective for the relief of vasomotor symptoms for menopausal women. In regards to safety, there were no serious or dangerous effects and although AE appeared lower in the CHM group when compared to the placebo (RR=0.84), the evidence was inconclusive and not clear enough. The quality of evidence ranged from low to moderate quality; there is need for large-scale, well-designed randomised controlled trials.

REFERENCES

Beral, V., Reeves, G., Bull, D. and Green, J. (2001). Breast cancer risk in relation to the interval between menopause and starting hormone therapy. Journal of the National Cancer Institute, 103(4), 296–305.

Charrois, T.L. (2015). Systematic reviews: what do you need to know to get started? Can J Hosp Pharm,68(2), 144-148.

Davis, S.R., Briganti, E.M., Chen, R.Q., Dalais, F.S., Bailey, M. & Burger, H.G. (2001). The effects of Chinese medicinal herbs on postmenopausal vasomotor symptoms of Australian women. A randomised controlled trial. Med. J. Aust., 174(2), 68.

Gagnier, J.J., Boon, H., Rochon, P., Moher, D., Barnes, J. & Bombardier, C. (2006). Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement. Ann. Intern. Med.,144(5), 364-367.

Gartoulla, P., Davies, S.R., Worsley, R. & Bell, R.J. (2015). Use of complementary and alternative medicines for menopausal symptoms in Australian women aged 40-65 years. Med. J. Aust., 203(3), 146-146e.

Gartoulla, P., Islam, M.R., Bell, R.J. & Davis S.R. (2014). Prevalence of menopausal symptoms in Australian women at midlife: a systematic review. Climeractic,17(5), 529-539.                                                                                                                   doi:10.3109/13697137.2013.865721

Goolsby, M.J. (2001). Management of menopause. J. Am. Acad. Nurse Pract.,13(4), 147-50.                                                                                           doi: 10.1111/j.1745-7599.2001.tb00237

Haines, C.J., Lam, P.M., Chung, T.K.H., Cheng, K.F. & Leung, P.C. (2008). A randomized, double-blind, placebo-controlled study of the effect of a Chinese herbal medicine preparation (dang gui buxue tang) on menopausal symptoms in Hong Kong Chinese women. Climeractic,11(3), 244-251. doi: 10.1080/13697130802073029

Kang, H.J., Ansbacher, R., & Hammoud, M. M. (2002). Use of alternative and complementary medicine in menopause. International Journal of Gynecology and Obstetrics, 79(3), 195–207.

Kronenberg, F. (1994). Hot flashes: phenomenology, quality of life, and search for treatment options. Experimental Gerontology, 29(3-4), 319-336.

Lin, H.Q., Gong, A.G.W., Wang, H.Y., Duan, R., Dong, T.T.X., Zhao, K.J. & Tsim, K.W.K. (2017). Dangui Buxue Tang (Astralagi Radix and Angelicae Sinensis Radix) for menopausal symptoms: A review. Journal of Ethnopharmacology, 199 (6), 205-210. doi: https://doi.org/10.1016/j.jep.2017.01.044

Lumsden, M.A. (2016). The NICE Guideline – Menopause: diagnosis and management. Climeractic,19(5), 426-429.

Maciocia, G. (1998). Obstetrics and gynaecology in Chinese medicine. London, UK; Churchill Livingstone.

Monteleone, P., Mascagni, G., Ginanini, A., Genazzini, A.R. & Simonicini, T. (2018). Symptoms of menopause – global prevalence, physiology and implications. Nature Reviews Endocrinology, 2.                                                                                         doi: 10.1038/nrendo.2017.180

Nelson, H.D. (2008). Menopause. The Lancet, 371(9614), 760-770.

Pace, D. (2017). The menopausal woman: the need for an individualized plan of care. The Nurse Practitioner, 42(12), 43-49.

doi: 10.1097/01.NPR.0000526765.60971.37

Radtke, J.V., Terhorst, L. & Cohen, S.M. (2011). The Menopause-Specific Quality of Life (MENQOL) Questionnaire: Psychometric Evaluation among Breast Cancer Survivors. Menopause. 18(3),289-295. doi: 10.1097/gme.0b013e3181ef975a

Unschuld, P.U. (2003) Huang di nei jing su wen: nature, knowledge, imagery in an ancient Chinese medical text. Berkeley, USA: University of California Press.

Van der Sluijs, C.P., Bensoussan, A., Chang, S., & Baber, R. (2009). A randomized placebo-controlled trial on the effectiveness of an herbal formula to alleviate menopausal vasomotor symptoms. Menopause.16(2), 336-344.                           doi: 10.1097/gme.0b013e3181883dc1

Xu, L.-W., Jia, M., Salchow, R., Kentsch, M., Cui, X.-J., Deng, H.-Y., Sun, Z.-J. & Kluwe, L. (2012). Efficacy and side effects of Chinese herbal medicine for menopausal symptoms: a critical review. Evidence-Based Complementary and Alternative Medicine, 2012(568106), 19.
http://dx.doi.org/10.1155/2012/568106

Zhong, L.L., Tong, Y., Tang, G.W., Zhang, Z.J., Choi, W.K., Cheng, K.L, Sze, S.C., Wai, K., Liu, Q. & Yu, B.X. (2013). A randomized, double-blind, controlled trial of a Chinese herbal formula (Er-Xian decoction) for menopausal symptoms in Hong Kong perimenopausal women. Menopause, 20(7), 767-76.

doi: 10.1097/GME.0b013e31827cd3dd.

Zhou, J. & Qu, F. (2007). The effect of Chinese medicinal herbs in relieving menopausal symptoms in ovariectomized Chinese women. Journal of Science and Healing, 3(5), 478-484. doi: https://doi.org/10.1016/j.explore.2007.06.002

Zhu, X., Liew, Y. & Zhao, L.L. (2016). Chinese herbal medicine for menopausal symptoms. Cochrane Gynaecology and Fertility Group.doi: 10.1002/14651858.CD009023.  

APPENDICES

Table 6. Study Inclusion and Exclusion Criteria regarding Chinese Herbal Medicine (CHM) and Menopause-related Signs and Symptoms
INCLUSION EXCLUSION
Study published within the last twenty years (1998-2018). Study older than twenty years (1998 or older)
Participants diagnosed as any stage and type of premenopause, perimenopause or menopause. Participants diagnosed as postmenopausal, ovarian insufficiency, premature menopausal: ovarectimized, primary amenorrhoea or no diagnosis.
Participants were adult and females. Participants that were men, teenagers or paediatric.
Studies published in English. Studies published in Chinese or any language other than English.
Full text studies. Conference Abstracts.
Data Type must have included Primary Data. Data Type referred to Secondary or other types of data.
Study Design must be original, a RCT. Must have a placebo as the control group. Reviews, Editorials, Letters and Pilot studies, non-randomised controlled trials, theoretical protocols, evidence-based and systematic reviews.
Outcome measures analysed change in vasomotor symptoms such as hot flushes and night sweats. Non-vasomotor outcome measures such as emotional (depression), cholesterol, bone density, functional dyspepsia or cardiovascular disease.
Uses the MENQOL questionnaire to analyse outcomes of the intervention. Studies that evaluated patented prescription formula that were a brand name, were not traditional or were combined with supplements.
The main intervention had to be CHM vs placebo. Other interventions such as acupuncture, hormone therapy and psychotherapy.
CHM that consisted of a formula using Chinese medicine classified herbs. Studies analysing single herbs or herbs pertaining from a Western formula or origin.
Intervention is a CHB formula and comparator is placebo. Three or four arm studies comparing 3 to 4 interventions
Sample size per group at least 20. Sample size of each group less than 20.

 

Table 7. Characteristics of the Three Included RCTs
Trial Number RCT 1 RCT 2 RCT 3
YEAR STUDY PUBLISHED 2013 2008 2001
AUTHORS Zhong LL, Tong Y, Tang GW, Zhang ZJ, Choi WK, Cheng KL, Sze SC, Wai K, Liu Q & Yu BX. Haines CJ, Lam PM, Chung TK, Cheng KF & Leung PC. Davis SR, Briganti EM, Chen RQ, Dalais FS, Bailey M & Burger HG.
INTERVENTION              (Chinese herb dose/day) Chinese herbal formula Er-Xian Decoction (EXD) (30g/day) Chinese herbal formula Dang Gui BuXue Tang (DBT) (3g/day) CHM granule formula (dosage not specified)
COMPARATOR Placebo Placebo Placebo
RISK OF BIAS Low Moderate High
PRIMARY OUTCOME MEASURES Change in frequency of vasomotor symptoms (hot flushes). Change in frequency of vasomotor symptoms (hot flushes & night sweats). Change in frequency of vasomotor symptoms (hot flushes & night sweats).
SECONDARY OUTCOME MEASURES MRS, MENQOL Questionnaire & serum hormone levels. Changes is score of MENQOL Questionnaire. Changes is score of MENQOL Questionnaire.
RANDOMISATION Block randomization, 1:1 ratio, sequence generated by Random Allocation Software version 1.0.0. Computer-generated randomisation code list in blocks of 10. Microsoft Excel randomisation chart (numbers 1 to 88) in two groups.
BLINDING Complete blinding of subjects and all staff. Complete blinding of subjects and all staff. Not mentioned.
STUDY LENGTH 24 weeks, 8 week baseline 12 weeks, 2 week baseline 12 weeks, 4 week baseline
HERBAL FORMULA INGREDIENTS (g) Xian Mao 12

Xian Ling Pi 12

Ba Ji Tian 9

Dang Gui 9

Zhi Mu 10

Huang Bai 10

Huang Qi 15g

Dang Gui 3g

(5:1 ratio)

Shu Di Huang 15, Shan Zhu Yu 10, Shan Yao 12, Ze Xie 8, Mu Dan Pi 8, Fu Shen 12,Chen Pi 5, Di Gu Pi 20,
He Huan Pi 15, Suan Zao Ren 10, Han Lian Cao 15 & Nu Zhen Zi 10.
AGE INTERVENTION 50.5 52.8 56.3
COMPARATOR 50.4 51.3 54.1
SAMPLE SIZE (DROPOUTS) INTERVENTION 50 (4) 50 (11) 28 (11)
COMPARATOR 51 (3) 50 (5) 27 (12)
HOT FLUSH FREQUENCY INTERVENTION P=0.04 p<0.01 p<0.05
COMPARATOR p=0.02 p=0.062 p<0.05
TOTAL MENQOL SCORES INTERVENTION p<0.01 p=0.353 Reduction in score for both, but difference between two groups was not significant.
COMPARATOR p<0.01 p=0.654
MAIN RESULTS EXD was found to significantly reduce the frequency and severity of hot flushes, and MRS and MENQOL scores faired favourably when compared with placebo. Despite a significant improvement in mild vasomotor symptoms in DBT group, in general there were no consistent changes in vasomotor symptoms between the DBT and placebo group. No significant or clinically relevant difference in the frequency of vasomotor symptoms nor for MENQOL scores between placebo and intervention.
ADVERSE EFFECTS INTERVENTION Mild diarrhoea (n = 1), headache (n = 2), worsening of depression (n = 2), and stomach ache (n = 1). Per rectum bleeding (n=1). Abdominal bloating (n=1), lower abdominal pain and loose stools (n=2). Headache, joint pain or dizziness (n=6).
COMPARATOR Headache (n = 1), worsening of insomnia (n = 2), and worsening of hot flushes (n = 3). All adverse events were reported to be mild. Hepatic enzyme increase (n=1). Abdominal bloating by 3 subjects. 9 women reported headache, joint pain or dizziness.

 

  Table 8. Risk of Bias Assessment Within Studies
BIAS AUTHOR’S JUDGEMENT SUPPORT FOR JUDGEMENT
ZHONG et al 2013 Random sequence generation (selection bias) Low risk “A random sequence was prepared by the staff of The University of Hong Kong School of Chinese Medicine clinical centre, who had no connection with the study”.
Allocation concealment (selection bias) Low risk “Block randomisation was carried out in a 1:1 ratio according to the sequence generated with Random Allocation Software version 1.0.0.”.
Blinding of participants and researchers                              (performance bias) Low risk “The participants, investigators, nurses, all other participating medical staff, and assessors remained unaware of intervention assignments throughout the trial”.
Blinding of outcome assessment (detection bias) Low risk Participants and researchers were not aware of who was taking the intervention and who was not.
Incomplete outcome data (attrition bias) Low risk “Dropouts were both low in placebo and treatment groups”. Four in intervention and 3 in comparator.
Selective reporting                    (reporting bias) Low risk 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.
Other bias Low risk None found or mentioned.
HAINES et al 2001 Random sequence generation (selection bias) Low risk “Each subject was allocated to one of the two treatment groups according to a computer-generated randomization code list in blocks of 10.”
Allocation concealment (selection bias) Low risk “No staff having contact with the subjects was aware of the treatment allocation and the code was not broken for any subjects during the study.”
Blinding of participants and researchers              (performance bias) Low risk Participants and researchers were not aware of who was taking the intervention and who was not.
Blinding of outcome assessment               (detection bias) Unclear risk Not specified.
Incomplete outcome data (attrition bias) High risk 16 people dropped out of the study. Five from intervention and 11 from comparator.
Selective reporting                    (reporting bias) Low risk “The primary outcome measurement was the change in reporting of vasomotor symptoms. Secondary outcome measurements were changes in scoring of quality of life using MENQOL and adverse events occurring during the study period.”
Other bias Unclear risk Authors mention that they were unsure whether the CHM dose was accurate as to what was classically prescribed.
DAVIS et al 2008 Random sequence generation (selection bias) Low risk “Subjects were randomised to CMH or placebo using a randomisation chart constructed by randomising numbers 1 to 88 into two groups using Microsoft Excel”
Allocation concealment (selection bias) Unclear risk No mention of allocation concealment.
Blinding of participants and researchers              (performance bias) Unclear risk No mention of blinding participants nor researchers.
Blinding of outcome assessment (detection bias) Low risk The granules were made to look the same (i.e. intervention and comparator). Placebo was granulised corn starch with a bitter flavour. All were contained in aluminium sachets.
Incomplete outcome data (attrition bias) High risk Given 23 participants dropped out of this study and it was not clear on which groups they came from.
Selective reporting                    (reporting bias) Low risk “Primary outcome was change in frequency of vasomotor events (hot flushes and night sweats). Secondary outcomes were changes in score for the domains measured in the Menopause Specific Quality of Life. (MENQOL) Questionnaire.”
Other bias Low risk No other biases were noted.

 

Table 9. Overall Study Rating
Low risk A low risk study has the least bias and the results are considered valid. This kind of study gives a valid approach to allocate patients to alternative treatments, has a low dropout rate; and uses appropriate means to prevent bias, measure outcomes, analyse and report results.
Moderate risk Moderate risk is a study that is susceptible to some bias but probably not enough to invalidate the results. The study may be missing information, making it difficult to assess limitations and potential problems (that are classified as unclear risk). As the moderate risk category is broad, studies with this rating vary in their strengths and weaknesses.
High risk A high risk rating indicates significant bias that may invalidate the results. These studies have serious errors in design, analysis, or reporting, have large amounts of missing information or discrepancies in reporting. The result of a high risk study is at least as likely to reflect flaw in the study design as to indicate true differences between the compared interventions. At most, one-half of the individual quality items are rated as high or unclear risk.
Unclear risk Insufficient information about the sequence generation process to permit judgement of ‘Yes’ or ‘No’

 

Table 10. Risk Ratio for Dichotomous Data within Studies
Zhong et. al (2016) Haines et. al. (2008) Davis et. al. (2001)
Age 1 1.03 1.04
Sample Size 1.02 1 1.04
Dropouts 1.33 2.2 0.08
Adverse Effects 1 1 0.75

 

Table 11. Analysis of Variance Results between Groups (AGE)
Data Summary
Groups N Mean Standard Deviation Standard Error
Zhong et. al. (2016) 2 50.45 0.0707 0.05
Haines et. al. (2008) 2 52.05 1.0607 0.75
Davis et. al. (2001) 2 55.2 1.5556 1.1
ANOVA Summary (AGE)
Source Degrees of Freedom DF Sum of Squares SS Mean Square MS F-Stat P-Value
Between Groups 2 23.3633 11.6817 9.8719 0.0479
Within Groups 3 3.55 1.1833
Total: 5 26.9133
Table 12. Analysis of Variance Results between Groups (SAMPLE SIZE)
Data Summary
Groups N Mean Standard Deviation Standard Error
Zhong et. al. (2016) 2 50.5 0.7071 0.5
Haines et. al. (2008) 2 50 0 0
Davis et. al. (2001) 2 27.5 0.7071 0.5
F-statistic value = 1035.51986 P-value = 0.00006
ANOVA Summary (AGE)
Source Degrees of Freedom DF Sum of Squares SS Mean Square MS F-Stat P-Value
Between Groups 2 690.3333 345.1667 1035.52 0.0001
Within Groups 3 1 0.3333
Total: 5 691.3333
Table 13. Analysis of Variance Results between Groups (DROPOUTS)
Data Summary
Groups N Mean Standard Deviation Standard Error
Zhong et. al. (2016) 2 3.5 0.7071 0.5
Haines et. al. (2008) 2 8 4.2426 3
Davis et. al. (2001) 2 11.5 0.7071 0,5
F-statistic value = 5.07904 P-value = 0.10887
ANOVA Summary (DROPOUTS)
Source Degrees of Freedom DF Sum of Squares SS Mean Square MS F-Stat P-Value
Between Groups 2 64.3333 32.1667 5.079 0.1089
Within Groups 3 18.9996 6.3332
Total: 5 83.333

 

Table 14. Data Synthesis Between Studies for Hot Flush Frequency & MENQOL – 95% CI
Total Frequency Hot Flushes (CHM) 95% CI -2.08 to 0.45 ± 0.75
Total MENQOL (Endpoint for CHM) 95% CI 57.2 to 19.6 ± 5.225
Total MENQOL (Endpoint for Placebo) 95% CI 63.83 to 73.97 ± 5.065

 

Table 15. Risk Ratio for Dichotomous Data between Studies (CHM vs Placebo)
Risk Ratio
Age 1.02
Sample Size 1.0
Dropouts 0.93
Adverse Effects 0.84

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