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The effects of Chinese medicinal herbs on postmenopausal vasomotor symptoms of Australian women

Susan R Davis, Esther M Briganti, Run Q Chen, Fabien S Dalais, Michael Bailey and Henry G Burger
Med J Aust 2001; 174 (2): 68-71.
Published online: 15 January 2001

Research

The effects of Chinese medicinal herbs on postmenopausal vasomotor symptoms of Australian women

A randomised controlled trial

Susan R Davis, Esther M Briganti, Run Q Chen
Fabien S Dalais, Michael Bailey and Henry G Burger

MJA 2001; 174: 68-71
For editorial comment, see Eden

Abstract - Methods - Results - Discussion - Acknowledgements - References - Authors' details

- - More articles on Obstetrics & gynaecology and women's health


 

Abstract

Objective: To evaluate the effects of a defined formula of Chinese medicinal herbs (CMH) on menopausal symptoms.
Design: A double-blind randomised placebo-controlled trial.
Methods: Between August 1998 and April 1999, 55 postmenopausal Australian women recruited from an urban population completed 12 weeks of intervention with either a defined formula of CMH (n = 28) or placebo (n = 27) taken twice daily as a beverage.
Main outcome measures: The primary end-point was change in frequency of vasomotor events (hot flushes and night sweats). The secondary end-points were changes in score for the domains measured in the Menopause Specific Quality of Life (MENQOL) Questionnaire.
Results: There was a reduction in average weekly frequency of vasomotor events with CMH (- 15%; 95% CI, - 31% to + 1%) and with placebo (- 31%; 95% CI, - 42% to - 21%). The difference between groups favoured the use of placebo; however, this was not significant (P = 0.09). Although significant reductions in scores for the various domains of the MENQOL Questionnaire were observed for both CMH and placebo, there were no significant differences between the two treatment groups for any domain. There was evidence for effect modification by previous use of natural therapies for the vasomotor, physical and sexual domains of the MENQOL Questionnaire: women with no prior use of natural therapies for their menopausal symptoms responded to therapy, whereas prior users did not.
Conclusions: The defined formula of CMH was no more effective than placebo in reducing vasomotor episodes in Australian postmenopausal women, or in improving any of the four symptom domains in the MENQOL Questionnaire. Three of the MENQOL Questionnaire domains were modified by prior use of natural therapies. This finding has implications for future studies.

In Australia, more than a third of postmenopausal women are troubled by vasomotor symptoms.1 Although hormone replacement therapy (HRT) eliminates 60% of flushes within three months,2 a significant number of postmenopausal women have absolute or relative contraindications to HRT, or are unwilling to use this therapy.3

Chinese herbal medicine has been used for centuries in China for treating menopausal symptoms, and is still in current use. Clinical trials in China have shown significant effects of Chinese herbal medicine in alleviating menopausal symptoms in Chinese women,4,5 but these effects may not be generalisable. We therefore conducted a double-blind, randomised, placebo-controlled study of the effects of a modified traditional formula of Chinese medicinal herbs (CMH) on vasomotor symptoms in Australian postmenopausal women.


Methods

Study population

Approval for the study was obtained from the Human Research and Ethics Committee of Monash Medical Centre. All patients gave written informed consent. The study was conducted between August 1998 and April 1999.

Inclusion criteria: Patients were recruited through the Jean Hailes Foundation Newsletter, newspapers, radio station interviews and the Medical Unit of the Jean Hailes Foundation. Non-Asian women aged 45 to 70 years, who had lived in Australia for at least 10 years, were postmenopausal (> 12 months' amenorrhoea and follicle-stimulating hormone level > 25 IU/L), and reported at least 14 hot flushes or night sweats per week were eligible for the study.

Exclusion criteria: Women were excluded if they had used HRT, CMH or other natural therapies (evening primrose oil, yam cream, progesterone cream or any other over-the-counter preparation for menopausal symptoms) during the eight weeks before baseline, or if they had preexisting gastrointestinal, renal or liver disease, diabetes mellitus requiring treatment, uncontrolled hypertension, undiagnosed vaginal bleeding, systemic glucocorticosteroid use, or were undergoing cancer therapy. Women who had consumed a high phytoestrogen diet (according to a food frequency questionnaire6) for the four weeks before baseline were also excluded.

Randomisation: Subjects were randomised to CMH or placebo using a randomisation chart constructed by randomising numbers 1 to 88 into two groups using Microsoft Excel.7

Study intervention

The defined formula of CMH for the active preparation used in the trial is listed in Box 1. Placebo was cornstarch with a bitter taste enhancer. All herbs are listed with the Australian Therapeutic Goods Administration, and were administered within standard dosage levels. All were screened for heavy metal contamination by Ningbo Daekang Herbs Co Ltd (Ningbo, China) and the National Analytical Laboratories in Melbourne. The CMH and placebo were produced by Ningbo Daekang Herbs Co Ltd as granules soluble in warm water, and each dose was prepackaged in identical aluminium foil sachets. Patients were instructed to drink one sachet of granules dissolved in 200 mL of warm water, twice a day. Both solutions had similar unusual tastes. A four-week supply was dispensed at each treatment visit.

The design did not accommodate the diagnostic and therapeutic principles of Chinese medicine, but was for analysing the therapeutic efficacy of the herbs.

Outcome measures

Demographics, body mass index (kg/m2), medical history, gynaecological history, and use of previous HRT or natural therapies for menopausal symptoms were documented at baseline. The primary end-point of the study was the effect of treatment on the frequency of vasomotor symptoms. Each woman completed a daily diary of the frequency of hot flushes and night sweats for four weeks before the commencement of treatment and for the entire 12 weeks of the study period.

The secondary end-points of the study were the effect of treatment on each of the four domains of the Menopause Specific Quality of Life (MENQOL) Questionnaire and on urinary phytoestrogen excretion. The MENQOL Questionnaire is a validated instrument that tests physical, vasomotor, psychosexual and sexual domains of quality of life.8 It can differentiate between women according to quality of life, as well as measure changes in quality of life. A minimum score of zero corresponds to no symptoms and a maximum score of seven corresponds to extremely bothersome symptoms. The smallest clinically relevant change is a difference in one point within the domains, representing a 15% change.

As dietary history is a poor guide to phytoestrogen ingestion, a potential confounding factor, we also measured urinary phytoestrogen excretion in women participating in the trial. Total urinary daidzein and genistein excretion was measured in 24-hour urine samples at baseline and at Week 12.9 Subjects were asked not to modify their dietary pattern for the study period.

Sample size and statistical analysis

The sample size was calculated based on the primary end-point of change in hot flushes and night sweats. A clinically relevant effect of treatment is considered to be at least a 40% reduction in vasomotor events.10-12 Anticipating a 30% placebo response, for power of 80% and a significance level of 5%, a sample size of 28 subjects in each treatment group was required. This sample size was also adequate to determine a clinically relevant change of score of one point in the MENQOL domains.8

Statistical analysis was performed using Statview.13 For each participant the percentage change from baseline in the frequency of hot flushes and night sweats for each of the 12 weeks of the study period, and the absolute difference in scores between Week 12 and baseline for each domain of the MENQOL Questionnaire, were calculated. Repeated analysis of variance was used to analyse the effects of treatment within and between groups over the study period for these outcomes. The Wilcoxon two-sample test was used to analyse the effect of treatment on the excretion of the phytoestrogen metabolites daidzein and genistein.

Additional analysis was undertaken to determine the effect of baseline characteristics (age, BMI, duration of amenorrhoea, and previous use of HRT or natural therapies for relief of vasomotor symptoms) on the average percentage change in vasomotor symptoms and on the difference in scores for each domain of the MENQOL Questionnaire. This was performed using analysis of covariance. Continuous variables were categorised into two groups based on the median value (age: < 55 years and ≥ 55 years; BMI: ≤ 25 kg/m2 and > 25 kg/m2; duration of amenorrhoea: < 4 years and ≥4 years).


Results

Study population

Of the 78 subjects who were randomised, 28 in the active group and 27 in the placebo group completed the study (Box 2). Baseline characteristics of those who withdrew and those who completed the study were similar, except for the previous use of natural therapies for menopausal symptoms, which was more frequent in those who withdrew. Most withdrawals were owing to taste intolerance and occurred within the first week after randomisation.

There were no significant differences in baseline characteristics between the placebo and CMH treatment groups (Box 3).

Effect of intervention on vasomotor symptoms

The frequency of vasomotor symptoms was reduced in both CMH and placebo groups (CMH: - 15.0%; 95% CI, - 31.1% to + 1.2%; placebo: - 31.4%; 95% CI, - 41.5% to - 21.2%). The difference between the two groups was not significant (+16.4%; 95% CI, + 35.2% to - 2.4%; P = 0.09).

A progressive decline in the frequency of vasomotor symptoms with treatment duration was seen in both groups (CMH, P = 0.001; placebo, P = 0.006). The difference between the two groups was not significant (P = 0.26).

Effect of intervention on MENQOL Questionnaire scores

A reduction in score was seen in all four domains of the questionnaire with both CMH and placebo. This was significant only for the physical (- 1.14; 95% CI, - 1.78 to - 0.50), vasomotor (- 0.57; 95% CI, - 0.89 to - 0.24) and sexual (- 0.69; 95% CI, - 1.10 to - 0.28) domains in the CMH group, and the physical (- 0.74; 95% CI, - 1.41 to - 0.07) domain in the placebo group. However, the difference between the two treatment groups was not significant for any of the four domains.

Effect of baseline characteristics on treatment effect

The effects of baseline characteristics are shown in Box 4. Women with more than four years of amenorrhoea had a significantly greater response to placebo than to CMH (Box 4). A significantly greater reduction in score was seen with CMH compared with placebo in the vasomotor domain of the MENQOL Questionnaire for the baseline characteristics of age < 55 years, BMI ≤ 25 kg/m2, and previous non-users of natural therapies (Box 4).

There was a significant difference in treatment effect between those who had and those who had not previously used natural therapies for the physical, vasomotor and sexual domain scores. A significant difference in treatment effect was also seen for the two age categories and for the two BMI categories for the vasomotor domain score.

Phytoestrogen measurements

No significant change was seen in daidzein or genistein excretion with either CMH or placebo, and there was no difference between the two treatment groups.

Adverse events

The frequency of reported adverse events did not differ between the two groups. Abdominal bloating was reported by three women treated with placebo and one with CMH; two women with CMH reported lower abdominal pain and loose stools. Fifteen women (placebo, 9; CMH, 6) reported headache, joint pain or dizziness.


Discussion

In our study of extracts of CMH administered as granules reconstituted to a beverage, there was no significant or clinically relevant difference in the frequency of vasomotor symptoms between placebo and CMH therapy. Furthermore, there was no significant or clinically relevant difference in the scores for the four domains of the MENQOL Questionnaire. This study was adequately powered to distinguish at least a 40% reduction in the frequency of vasomotor symptoms, as well as a clinically meaningful reduction in the MENQOL domain scores with treatment.

The effect of CMH compared with placebo on the frequency of vasomotor symptoms was not modified by age, BMI, duration of amenorrhoea, previous use of HRT or natural therapies. However, the scores for the physical, vasomotor and sexual domains were modified by previous use of natural therapies: women who had no prior use of natural therapies for their menopausal symptoms responded to therapy, whereas prior users did not. The vasomotor domain was also modified by age and BMI.

It is of interest that prior users of natural therapies showed a clinically relevant greater response to placebo than CMH for the physical, vasomotor and sexual domains. That baseline characteristics, particularly prior natural therapy use, significantly modified the response to treatment in this study is an important observation of relevance to future studies of natural therapies.

That our findings differ from reports of studies conducted in China4,5 is most likely owing to differences in study design. The Chinese studies have not been placebo-controlled, have employed raw herbs, and have allowed for modification of herbal constituents during the studies according to individual responses.4,5 The preparation of medicinal tea from raw herbs is very time consuming, and was deemed a major obstacle to compliance in a non-Asian study population. The granules used in this study were supplied by a company that routinely prepares herbs in this manner for medicinal purposes in China, and there is no evidence to indicate that the granules do not retain the therapeutic properties of the original herbs.

In summary, our study of the effects of CMH versus placebo on vasomotor events and menopausal symptoms in non-Asian Australian women found no overall benefit of the CMH. The modifying effects of prior use of natural therapies is an important positive finding that deserves further investigation and confirmation.



Acknowledgements

The study was supported by a research grant from the Australasian Menopause Society. Cathay Herbal, Sydney, kindly donated the study preparations. We thank Dr Tikky Wattanapenpaiboon of Monash University for assistance in the evaluation of the food frequency questionnaire, and Associate Professor Flavia Cicuttini of Monash University for valuable input to this study. Dr James C G Doery of Monash Medical Centre offered guidance in testing the study herbal preparations for heavy metal contamination. We also thank all the participants.


References

  1. Dennerstein L, Smith AM, Morse C, et al. Menopausal symptoms in Australian women. Med J Aust 1993; 159: 232-236.
  2. Abraham S, Perz J, Clarkson R, Llewellyn-Jones D. Australian women's perception of hormone replacement therapy over 10 years. Maturitas 1995; 21: 91-95.
  3. Waldman TN. Menopause: when hormone replacement therapy is not an option. Part 1 [review]. Women's Health 1998; 7: 559-565.
  4. Yao SA. Review on the research and development of Chinese medicine in menopausal syndrome (in Chinese). J Tradit Chin Med 1994; 35: 112-114.
  5. Li CJ. Menopausal symptoms. In: Dai DY, editor. Current application and research of Chinese medicine and pharmacology: gynecology. Shanghai: Shanghai University of Traditional Chinese Medicine Publishing House, 1995; 174-182.
  6. Wahlqvist M, Kouris-Blazos A, Hsu-Hage B, et al. Food habits and health status of Anglo-Celtic Australians. A questionnaire on food frequency. Melbourne: Monash University.
  7. Microsoft Excel 95 [computer program]. Redmond: Microsoft Corporation, 1995.
  8. Hilditch JR, Lewis J, Peter A, et al. A menopause specific quality of life questionnaire: development and psychometric properties. Maturitas 1996: 24; 161-175.
  9. Dalais FS, Rice GE, Wahlqvist ML, et al. Effects of dietary phytoestrogens in postmenopausal women. Climacteric 1998; 1: 124-129.
  10. Murkies AL, Lombard C, Strauss BJ, et al. Dietary flour supplementation decreases postmenopausal hot flushes: effect of soy and wheat. Maturitas 1995; 21: 189-195.
  11. Poller L, Thomson JM, Coope J. A double-blind cross-over study of piperazine oestrone sulphate and placebo with coagulation studies. Br J Obstet Gynaecol 1980; 87: 718-725.
  12. Hailes JD, Nelson BJ, Schneider M, et al. Conjugated equine oestrogen versus placebo in the management of menopausal symptoms. Med J Aust 1981; 2: 341-342.
  13. Statview [computer program]. Abacus Concepts Inc, Berkeley, CA, 1995.

(Received 28 Aug, accepted 1 Oct, 2000)


Authors' details

The Jean Hailes Foundation, Melbourne, VIC.
Susan R Davis, FRACP, PhD, Associate Professor and Director of Research;
Run Q Chen, MA, Master's Student;
Henry G Burger, AO, FRACP, FAA, Consultant Endocrinologist.

Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC.
Esther M Briganti, MB BS, FRACP, Senior Lecturer;
Michael Bailey, MSc, Statistical Consultant.

International Health and Development Unit, Monash University, Clayton, VIC.
Fabien S Dalais, PhD, Senior Research Officer.

Reprints will not be available from the authors.
Correspondence: Associate Professor S R Davis, The Jean Hailes Foundation, 173 Carinish Road, Clayton, VIC 3168.
suedavisATnetlink.com.au


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1: The defined formula of the Chinese medicinal herbs
Pharmaceutical name Chinese name Dose*

Rehmannia glutinosa
Cornus officinalis
Dioscorea opposita
Alisma orientalis
Paeonia suffruticosa
Poria cocos
Citrus reticulata
Lycium chinensis
Albizzia julibrissin
Zizyphus jujuba
Eclipta prostrata
Ligustrum lucidum
Shu Di Huang
Shan Zhu Yu
Shan Yao
Ze Xie
Dan Pi
Fu Shen
Chen Pi
Di Gu Pi
He Huan Pi
Suan Zao Ren
Han Lian Cao
Nu Zhen Zi
15
10
12
8
8
12
5
20
15
10
15
10

*Dose in grams of dried herb per day.
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2: Flow diagram of participation in the study
figure 2

CMH = Chinese medical herbs. HRT = hormone replacement therapy.
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3: Baseline characteristics of study participants
Baseline characteristics Placebo Chinese medicinal herbs P

Number
Age (years)*
Body mass index (kg/m2)*
Duration of amenorrhoea (years)*
Previous use of hormone
   replacement therapy
Previous use of natural therapies
Frequency of hot flushes or
   night sweats, per week*
MENQOL domains
  Physical domain*
  Vasomotor domain*
  Psychosexual domain*
  Sexual domain*
27
54.1 (52.6, 55.5)
26.1 (24.3, 27.9)
4.6 (3.0, 6.2)

44.4%
37.0%

46.6 (35.4, 57.8)

5.6 (4.9, 6.2)
4.0 (3.3, 4.8)
3.9 (3.3, 4.6)
3.4 (2.5, 4.3)
28
56.3 (54.3, 58.3)
25.7 (23.9, 27.5)
5.8 (3.9, 7.7)

53.6%
35.7%

46.2 (38.75, 53.7)

5.5 (5.2, 6.5)
3.8 (3.1, 4.5)
3.6 (3.0, 4.2)
3.3 (2.4, 4.3)

0.07
0.75
0.34

0.50
0.92

0.94

0.57
0.67
0.45
0.95

*Values are mean (95% confidence limits).
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4: Effect of Chinese medicinal herbs (CMH) compared with placebo on frequency of vasomotor symptoms and MENQOL domain scores, by baseline characteristics*
Mean reduction in MENQOL domain score (95% confidence limits)
Mean reduction in vasomotor
symptoms (95% confidence limits) Physical Vasomotor Psychosexual Sexual

Age
+8.1% (-16.5%, +32.8%)
-0.74 (-1.91, +0.42)
-0.94 (-1.74, -0.14)
-0.22 (-1.00, +0.57)
-0.72 (-2.82, +1.38)
≥55 years +17.9% (-10.7%, +46.5%) -0.36 (-1.76, +1.03) +0.51 (-0.56, +1.58) +0.10 (-0.77, +0.96) -0.14 (-1.30, +1.03)
Body mass index
≤25 kg/m2 +7.1% (-21.4%, +35.5%) -1.16 (-2.57, +0.25) -0.85 (-1.61, -0.08) -0.17 (-1.01, +0.68) -1.00 (-2.66, +0.65)
>25 kg/m2 +26.2% (-0.48%, +52.9%) +0.28 (-0.92, +1.48) +0.42 (-0.73, +1.58) +0.13 (-0.68, +0.95) +0.18 (-1.46, +1.82)
Amenorrhoea
< 4 years +4.8% (-24.6%, +34.2%) -0.28 (-1.72, +1.17) -0.31 (-1.67, +1.06) +0.18 (-0.81, +1.16) +0.52 (-1.59, +2.62)
≥4 years +26.8% (+3.8%, +49.9%) -0.49 (-1.70, +0.72) -0.09 (-0.61, +0.42) -0.08 (-0.70, +0.54) -0.96 (-2.08, +0.16)
Previous use of hormone replacement therapy
No +12.1% (-14.4%, +38.6%) -0.69 (-2.02, +0.65) -0.24 (-1.47, +1.00) +0.03 (-0.74, +0.80) +0.17 (-1.74, +1.40)
Yes +22.4% (-6.3%, +51.2%) -0.05 (-1.37, +1.27) -0.16 (-0.75, +0.43) +0.02 (-0.90, +0.95) -0.59 (-2.43, +1.26)
Previous use of natural therapies for symptoms of menopause
No +11.1% (-11.2%, +33.3%) -1.16 (-2.35, +0.02) -1.09 (-1.68, -0.49) -0.33 (-1.07, +0.41) -1.19 (-2.75, +0.37)
Yes +26.1% (-10.0%, +62.3%) +0.93 (-0.38, +2.24) +1.30 (-0.06, +2.67) +0.63 (-0.29, +1.56) +1.15 (-0.33, +2.64)

*Values are the percentage or point difference between CMH and placebo (CMH effect minus placebo effect). As vasomotor symptoms and all domain scores improved for both treatment groups, a negative value indicates a greater effect from CMH and a positive value indicates a greater effect from placebo. For shaded values, 95% confidence limits do not include 0. For boxed values, there is a significant difference in treatment effect between the two categories (P
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Received 22 November 2018, accepted 22 November 2018

  • Susan R Davis
  • Esther M Briganti
  • Run Q Chen
  • Fabien S Dalais
  • Michael Bailey
  • Henry G Burger


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