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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
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More articles on Obstetrics & gynaecology and women's health
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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.
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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.
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| Methods |
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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.
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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.
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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).
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| Results |
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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).
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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).
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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.
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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.
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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.
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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.
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| Discussion
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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.
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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.
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- Dennerstein L, Smith AM, Morse C, et al. Menopausal symptoms in
Australian women. Med J Aust 1993; 159: 232-236.
-
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.
-
Waldman TN. Menopause: when hormone replacement therapy is not an
option. Part 1 [review]. Women's Health 1998; 7:
559-565.
-
Yao SA. Review on the research and development of Chinese medicine
in menopausal syndrome (in Chinese). J Tradit Chin Med 1994;
35: 112-114.
-
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.
-
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.
-
Microsoft Excel 95 [computer program]. Redmond: Microsoft
Corporation, 1995.
-
Hilditch JR, Lewis J, Peter A, et al. A menopause specific quality of
life questionnaire: development and psychometric properties.
Maturitas 1996: 24; 161-175.
-
Dalais FS, Rice GE, Wahlqvist ML, et al. Effects of dietary
phytoestrogens in postmenopausal women. Climacteric 1998;
1: 124-129.
-
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.
-
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.
-
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.
-
Statview [computer program]. Abacus Concepts Inc, Berkeley, CA,
1995.
(Received 28 Aug, accepted 1 Oct, 2000)
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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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| | Back to text | | | | | Back to text | | |
| 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 |
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| *Values are mean (95% confidence
limits). |
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| | Back to text | | |
| 4: Effect of Chinese medicinal herbs (CMH)
compared with placebo on frequency of vasomotor symptoms and MENQOL domain
scores, by baseline characteristics* |
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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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| | Back to text |
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