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REVIEW ARTICLE
Francesca Borrelli ÆEdzard Ernst
Cimicifuga racemosa
: a systematic review of its clinical efficacy
Received: 15 October 2001 / Accepted in revised form: 1 March 2002 / Published online: 7 June 2002
ÓSpringer-Verlag 2002
Abstract Background:Cimicifuga racemosa has long
been advocated as an alternative to hormone-replace-
ment therapy. However, recent experimental studies and
a clinical trial have raised some questions on its utility.
The aim of this systematic review is principally to
summarise the trial evidence regarding the efficacy of
C. racemosa in the treatment of menopausal symptoms.
In addition, we also explore the evidence relating to the
mechanism of action of this herbal medicine.
Methods: Searches of seven computerised databases
were performed to identify all randomised clinical trials
(RCTs) on C. racemosa as well as animal and in vitro
experiments. No language restrictions were imposed.
Data were extracted by both authors according to
predefined criteria and are summarised in narrative
form.
Results: Four RCTs of C. racemosa as a treatment of
menopausal symptoms were included. They yielded no
compelling evidence for the efficacy of C. racemosa on
menopausal symptoms. The small beneficial effects
observed in some studies could be explained by a central
activity, and an oestrogenic activity cannot be
completely excluded.
Conclusions: In spite of plausible mechanisms of action
of C. racemosa, its clinical efficacy for the treatment of
menopausal symptoms has not been convincingly dem-
onstrated through rigorous clinical trials. Additional
rigorous RCTs and biochemical and chemical investi-
gations are warranted.
Keywords Herbal medicine ÆCimicifuga racemosa Æ
Black cohosh
Introduction
Menopause is characterised by the cessation of men-
struation and by the appearance of many vasomotor,
vaginal and psychological symptoms including hot
flashes, profuse sweating, flushing of the skin, atrophic
vaginitis, irritability and depression. After menopause
the risks of coronary heart disease and osteoporosis in-
crease. These effects are linked to hormonal changes,
including oestrogen deficiency [1]. Currently, hormone-
replacement therapy (HRT) is the most common
pharmacological treatment for relief of menopausal
symptoms. Unfortunately HRT is associated with
endometrial or breast cancer and adverse effects [2, 3, 4,
5]. Therefore, there is a buoyant market for alternative
therapies.
The herbal medicine Cimicifuga racemosa is often
promoted as such an alternative. It is a perennial herb
native to North America commonly known as ‘‘wom-
an’s herb’’. Extracts of the rhizome of C. racemosa have
long been used for the relief of pain during menses or
childbirth and for the treatment of dyspepsia, dysmen-
orrhea, epilepsy, kidney ailments, malaria, rheumatism
and rheumatic pain [6, 7, 8, 9]. Today C. racemosa is the
principal herbal remedy in for menopausal problems.
An ethanolic extract of the rhizome of this plant stan-
dardised to contain 1 mg of triterpenes calculated as 27-
deoxyacteine per 20-mg tablet (trade name Remifemin)
is widely marketed for the relief of climacteric (meno-
pausal) disorders including hot flushes and profuse
sweating. C. racemosa rhizome contains numerous
chemical components including triterpene glycosides
(actein, 27-deoxyactein, cimicifugoside), phenolic acids
(isoferulic acid, fukinolic acid), flavonoids, volatile oils
and tannins. The effects of C. racemosa are believed to
be the result of complex synergistic action of these
components. The aim of this systematic review is (i) to
Eur J Clin Pharmacol (2002) 58: 235–241
DOI 10.1007/s00228-002-0457-2
F. Borrelli
Department of Experimental Pharmacology,
University of Naples ‘‘Federico II’’,
Via D. Montesano 49, 80131 Naples, Italy
E. Ernst (&)
Department of Complementary Medicine,
School of Postgraduate Medicine and Health Studies,
University of Exeter, EX2 4NT, UK
E-mail: E.Ernst@exeter.ac.uk
Tel.: +44-392-430802
Fax: +44-392-424989
summarise the evidence for or against the efficacy of
C. racemosa in providing relief of menopausal symptoms
or other conditions and (ii) to summarise our knowledge
regarding its possible mechanism of action.
Methods
Computerised literature searches were performed to identify all
randomised controlled trials (RCTs) as well as animal and in vitro
experiments on C. racemosa. Databases included Medline, Em-
base, Amed, Phytobase, PubMed, CISCOM (Research Council for
Complementary Medicine, London) and Cochrane Library (all
from their respective inceptions to July 2001). In addition, several
(n=3) manufacturers of C. racemosa preparations were asked to
contribute published or unpublished material, and our own files
were hand searched. Bibliographies of the articles thus located
were scanned for further relevant publications. No language
restrictions were imposed. The search terms used are shown in
Table 1.
Clinical trials of C. racemosa were included in this review only if
performed randomised, blind and controlled. Clinical trials for any
indication were included. Animal and in vitro experiments on
C. racemosa were included only if performed to evaluate its
oestrogen-like activity. Studies of this plant in combination prod-
ucts were excluded.
Data were validated and extracted in a standardised, predefined
manner (Table 2). The methodological quality of clinical studies
was assessed using the scoring system developed by Jadad and
colleagues (Table 2) [10].
Results
Several clinical studies examined the effect of C. race-
mosa in menopausal women [11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. Only four of
these met our inclusion/exclusion criteria [21, 22, 24, 29].
Key data of RCTs are summarised in Table 3. All trials
scored at least two of five points on the Jadad score.
Three studies reporting positive results in favour of
C. racemosa scored two, three and two points, respec-
tively [21, 22, 24]. One negative trial scored five points
[29]. The trials are described in some detail below. All
trials used a commercial product of C. racemosa, Rem-
ifemin (dosage 40–80 mg).
The first RTC on Remifemin was conducted by
Warnecke on 60 women with menopause in 1985 [21].
The women received 40 drops twice daily of C racemosa
(80 mg/day), conjugated oestrogens (0.625 mg/day) or
diazepam (2 mg/day) for 4 months. The outcome mea-
sures were: modified Kupperman menopausal index,
self-evaluation depression scale, Hamilton anxiety scale
and vaginal epithelium status. C. racemosa produced a
decrease in climacteric complaints and oestrogen-like
stimulation of the vaginal mucosa similar to conjugate
oestrogens. Cytological examinations of vaginal epi-
thelium proliferation revealed a similar percentage of
eosinophilic epithelial cells with C. racemosa and
conjugated oestrogens. The women treated with
C. racemosa extract had a greater percentage of pyknotic
nuclei than those on conjugated oestrogens. Greater
improvements in neurovegetative symptoms were noted
in the experimental group.
A double-blind trial with 80 women aged between
46 years and 58 years compared the effects of a stan-
dardised C. racemosa extract both with placebo and low-
dose oestrogen [22]. The women received two tablets of
extract (80 mg), conjugated oestrogens (0.625 mg) or
identical placebo twice daily for 3 months. The outcome
measures were: Kupperman menopausal index, mea-
suring mainly neurovegetative symptoms, Hamilton
anxiety scale for psychological complaints (both re-
corded every 4 weeks) and proliferation status of vaginal
epithelium (recorded at the beginning and the end of the
study). At the end of treatment all groups showed im-
provements compared with baseline. Since the oestrogen
dose proved to be too low, only the difference between
placebo and C. racemosa were evaluated. C. racemosa
significantly improved all parameters under investiga-
Table 1. Terms used for computer search and number of papers found. n.r. not reported, CISCOM Research Council for Comple-
mentary Medicine, London
Search terms Embase Amed PubMed
or Medline
Phytobase CISCOM Cochrane
Library
Cimicifuga racemosa (botanical name) 70 21 n.r. 8 4
Black cohosh (common English name) 9 18 n.r. 5 1
Actaea racemosa (first botanical name) 4 1 n.r. 2 0
Actein (active ingredient) 3 6 n.r. 1 0
Cimicifugoside (active ingredient) 11 8 n.r. 2 0
Cimicifugic acid (active ingredient) 6 4 n.r. 2 0
Fukinolic acid (active ingredient) 6 4 n.r. 2 0
Remifemin (trade name) 15 6 n.r. 0 0
Cimisan 2 0 n.r. 0 0
Cimicifuga (common Italian name) 120 58 n.r. 21 5
Traubensilberkerze (common German name) 4 0 n.r. 1 0
Wanzenkraut (common German name) 0 0 n.r. 0 0
Black snakeroot (common English name) 0 0 n.r. 0 0
Bugbane (common English name) 0 0 n.r. 0 0
Rattleroot (common English name) 0 0 n.r. 0 0
Rattletop (common English name) 0 0 n.r. 0 0
Rattleweed (common English name) 0 0 n.r. 0 0
236
tion, compared with placebo. The final score of the
menopausal index in women treated with the extract was
below 15, which the author considered to be a clinically
relevant result.
Lehmann-Willenbrock and Riedel [24] studied the
effect of estriol, conjugated oestrogens, oestrogen–gest-
agen sequential therapy or a C. racemosa extract on 60
hysterectomised women who all had at least one intact
ovary and complained of climacteric symptoms. The
extract (two tablets, 80 mg/day) was administered twice
daily for 6 months. The dose of estriol and conjugated
oestrogens was 1 mg/day and 1.25 mg/day, respectively,
while the dose of oestrogen–gestagen was not specified.
The outcome measures were: modified Kupperman in-
dex and serum concentrations of follicle-stimulating
hormone (FSH) and luteinising hormone (LH). These
variables were measured after 4, 8, 12 and 24 weeks. In
Table 2. Jadad scoring system to measure methodological quality
of clinical trials
Each ‘yes’ 1 point; each ‘no’ 0 points
A. Study described as randomised (includes the use of words
such as random, randomly and randomisation)?
B. Study described as double-blind?
C. Description of withdrawals and dropouts?
D. Method of generating the sequence of randomisation
described and appropriated (table of random numbers,
computer-generated etc.)?
E. Method of double-blinding described and appropriated
(identical placebo, active placebo, dummy etc.)?
Deduct 1 point if
F. Method to generate the sequence of randomisation described
and inappropriate (patients were allocated alternately,
or according to their date of birth, hospital number etc.)
G. Method of double-blinding described and inappropriate
(e.g. comparison of tablet versus injection with no double
dummy)
Table 3. Clinical studies. CE coniugated oestrogens, EG oestrogen + gestagen, FSH follicle-stimulating hormone, LH luteinising
hormone
First author,
year
(reference)
Jadad
score
Design Patients
(number)
Dosage
of extract
Control
treatments
(dosage)
Length of
treatment
(months)
Outcome
measures
Main
results
Comments
Warnecke,
1985 [21]
2 Randomised,
open trial
(3 groups)
60 Meno-
pausal
women
40 Drops
twice
daily
(80 mg)
CE (0.625
mg/day),
diazepam
(2 mg/day)
3 Modified
Kupperman
menopausal
index; self-
evaluation
depression
scale;
Hamilton
anxiety scale;
vaginal
epithelium
status
C. racemosa
improved
all parameters
and increased
vaginal
ephitelium
proliferation
as well as CE
Open study,
no placebo
control
Stoll,
1987 [22]
3 Randomised,
double-blind
trial (3 groups)
80 Women
with
climacteric
complaints
Two tablets
twice daily
(80 mg)
Placebo,
oestrogen
(0.625
mg/day)
3 Kupperman
menopausal
index;
Hamilton
anxiety scale;
vaginal
epithelium
status
C. racemosa
improved
all parameters
compared
with placebo
Lack of
oestrogen
effects
Lehmann-
Willenbrock,
1988 [24]
2 Randomised,
open trial
(4 groups)
60 Hyste-
rectomised
women with
at least one
intact ovary
Two tablets
twice daily
(80 mg)
Estriol
(1 mg/day),
CE (1.25
mg/day),
EG
6 Modified
Kupperman
menopausal
index; FSH
and LH levels
In all groups
Kupperman
index
decreased.
Differences
between
groups
were not
significant.
Only CE and
EG reduced
FSH and
LH levels
Open study,
no placebo
group
Jacobson
2001 [29]
5 Randomised,
double-blind
trial (2 groups)
26 Breast
cancer
survivors
One tablet
twice
daily
(40 mg)
Placebo 2 Menopausal
symptom
index; FSH
and LH levels
In all groups
menopausal
symptoms
improved.
No effect on
FSH and LH.
No difference
between
groups
Length of
treatment
too short
237
Animal experiments In vitro experiments
First author,
year (reference)
Test(s) used Main result First author,
year (reference)
Test(s) used Main result
Gizicky 1944 [30] Uterine weight,
ovary weight
CR increased
uterine and
ovary weight
Jarry 1985 [33] ER binding assay A fraction bound
to ER
Foldes 1959 [13] Uterine weight,
induction of oestrus,
sedative effect,
changes in ovaries
and thyroid function
CR increased
the uterine weight
and induced oestrus
Duker 1991 [25] ER binding assay Whole extract did not
bind to ER. Some
fractions bound
to ER
Siess 1960 [31] Uterine weight,
induction of oestrus
No effect
was observed
Nesselhut 1993 [42] Cell proliferation CR inhibited cell
proliferation at
concentration
>2.5 lg/ml
Jarry 1985 [32] FSH levels,
LH levels,
prolactin levels
A fraction reduced
LH levels
Jarry 1996 [43] OPS CR inhibited OPS
in porcine
Jarry 1985 [33] LH levels CHCl
3
fraction
reduced LH levels
Harnischfeger
1996 [44]
ER binding assay,
cell proliferation
CR bound to ER,
increased the cell
proliferation at 1–5
lg/ml and decreased
it at >10 lg/ml
Duker 1991 [25] LH levels CR reduced
LH levels
Eagon 1996 [45] ER binding assay CR did not bind
to ER
Einer-Jensen
1996 [34]
Vaginal
cornification,
uterine weight
CR did not show
estrogenic effects
Zava 1998 [46] ER/PR binding
assay, T47D cell
proliferation
CR did not bind to
ER/PR and did not
modify cell
proliferation
Eagon, 1997 [35] Uterine weight,
c-myc expression,
serum CP levels
and hepatic
CP mRNA levels
CR root increased
uterine weight
and CP levels
Lohning 1998 [47] MCF-7 cell
proliferation
CR increased cell
proliferation
to 0.1–10 lg/ml.
100 lg/ml were
ineffective
Eagon 1999 [36] Uterine weight,
LH levels
CR increased
uterine weight and
decreased LH levels
Lohning 1999 [38] Basal and TRH
stimulated PS
CR reduced both
basal and TRH
stimulated PS
Jarry 1999 [37] LH levels, uterine
weight and ERa,
IgF1, C3, collagen I,
osteocalcin
expression
CR either reduced
LH levels, collagen I
and osteocalcin
expression or
increased ERa
expression
Dixon Shanies
1999 [48]
T47D cells
proliferation
CR inhibited cell
proliferation to
0.1–1 % v/v
Lohning 1999 [38] Body temperature,
ketamine-induced
sleeping
CR decreased
body temperature
and prolonged
sleeping time
Eagon 1999 [36] ER binding assay CR bound ER
Freudenstein
2000 [39]
Number and size
of tumours, FSH,
LH, prolactin levels,
organ weights
CR did not show
oestrogen effects
Jarry 1999 [37] ER binding assay,
luciferase
expression in a
MCF7-a-andb
ER expressing
subclone
CR bound to ER
and activated the
transcription of
oestrogen-regulated
genes
Nisslein 2000 [40] PYR and DPD
levels, femoral
density
CR reduced
PYR/DPD levels
and bone loss
Freudenstein
1999 [49]
MCF-7 cells
proliferation
CR inhibited
cells proliferation
Liu 2001 [41] Days of oestrus,
uterine and
ovary weight
CR increased the
days of oestrus
Liu 2001 [50] ER aand b
binding assay
CR did not show
activity
Liu 2001 [41] MCF-7 cells
proliferation,
ER expression
CR increased
cells proliferation
and ER expression
Table 4. Animal and in vitro experiments to investigate the Cim-
icifuga racemosa (CR) mechanism of action. ER oestrogen recep-
tor, PR progesterone receptor, LH luteinising hormone, FSH
follicle-stimulating hormone, OPS ovarian-progesterone secretion,
PYR pyridinoline, DPD deoxypyridinoline, CP ceruloplasmin, PS
prolactin secretion, n.d. not described, n.c. no comment
238
all groups, a decrease of the modified Kupperman index
was observed within 4 weeks after the onset of therapy.
There was no significant inter-group difference regarding
the Kupperman index at the end of therapy. Only con-
jugated oestrogens and oestrogen–gestagen sequential
therapy significantly modified the serum concentration
of FSH and LH.
A recent RCT included 26 female breast cancer
survivors [29]. Each woman took one tablet of C. race-
mosa (Remifemin 40 mg) or placebo twice daily with
meals for 60 days. At the start and completion of the
study, patients completed a detailed menopausal
symptom index (heart palpitations, excessive sweating,
headaches, poor sleep, depression and irritability or
nervousness). The number and intensity of hot flashes
were recorded in a diary 3 days before baseline, on
days 7–30 and on days 57–60. FSH and LH levels were
measured in a subset of patients at both the start and
the end of the medication phase. The results showed
that both the treatment and placebo groups improved.
No statistically significant differences in blood levels of
FSH and LH were noted. Except for a reduced number
of sweating episodes, no significant beneficial clinical
effects of C. racemosa compared with placebo were
observed.
A total of 14 animal and 15 in vitro studies of
C. racemosa met our inclusion/exclusion criteria [13, 25,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51]. Key data of all studies are sum-
marised in Table 4. Experimental studies were per-
formed on the capacity of C. racemosa to modulate
either the plasma hormone levels (LH, FSH), the uterine
weight and induction of oestrus in animals or the cell
proliferation, the oestrogen-receptor expression and
competitive binding assay in vitro. The results fail to
yield a uniform picture as the mechanism of action of
C. racemosa.
Discussion
C. racemosa was approved by the German Commission
E for premenstrual discomfort, dysmenorrhea or cli-
macteric (menopausal) neurovegetative ailments. The
data summarised above do, however, not conclusively
demonstrate its efficacy. Most clinical trials were not
well designed. Some were not controlled or randomised
and included heterogeneous subject samples [11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 23, 25, 26, 27, 28]. Only four
RCTs were located [21, 22, 24, 29]. Three of these trials
suggested that an extract of C. racemosa had therapeutic
benefit on menopausal symptoms improving the
Kupperman menopausal index and Hamilton anxiety
scale [21, 22, 24]. Trials with active controls suggested
that the extract had similar effects to oestrogen
replacement therapy [21, 24]. Neither of these studies
was designed as an equivalence trial in the strict sense. In
the third trial, placebo and oestrogen showed almost the
same beneficial effects on the Kupperman index and
Hamilton anxiety scale [22]; and the ineffective oestro-
gen dosage (0.625 mg/day) used was similar to the
dosage (0.625 mg/day) used by Warnecke [21]. It there-
fore seems possible that the beneficial effect observed by
Warnecke [21] and Lehmann-Willenbrock and Riedel
[24] was due to a placebo effect.
The recent RCT by Jacobson et al. [29] suggested
C. racemosa to be ineffective on menopausal symptom
index. A large placebo response in menopausal symp-
toms and no significant difference between the placebo
and C. racemosa were observed in this RCT. The only
significantly reduced number of sweating episodes was,
according to the authors, a chance finding. The lack of
effect of C. racemosa is unlikely to be due to the short
duration of therapy (2 months); in a previous RCT,
Lehmann-Willenbrock and Riedel [24] reported notice-
able benefits of C. racemosa within 4 weeks The lack of
rigorous long-term studies is, however, a clear limitation
of the evidence available to date.
Early animal studies on an extract of C. racemosa had
postulated ‘‘oestrogen-like’’ activity as evidenced by an
increase in uterine weight and an induction of oestrus
[13, 30]. Further studies [25, 32, 33, 37] suggested that
C. racemosa contained three synergistically acting com-
pounds able to reduce serum LH levels and bind to
oestrogen receptors (so as to increase the amount of
oestrogen in the blood which decreases the menopause
symptoms). Actein and cimicifugoside were believed to
be partly responsible for the reduction in LH, while the
isoflavone formononetin was thought to bind to oes-
trogen receptors. However, recent investigations imply
that C. racemosa contains compounds that act by a
mechanism that does not involve oestrogen receptors
[39, 46, 50]. The effects seem partly to be due to a central
activity mediated by dopaminergic-2 receptors rather
than to an oestrogenic activity [38]. Some investigators
have found that an extract of C. racemosa inhibited the
proliferation of human oestrogen receptor-positive
breast cancer cells (T47D and MCF-7) [42, 48, 49] and
increased oestrogen receptor levels [37, 41]. Since dop-
aminergic agonists also cause a significant decrease in
the proliferation of MCF-7 cells [51] and D1-like dop-
amine receptors mediate the in vitro transcriptional ac-
tivation of oestrogen receptors by dopamine [52, 53], the
effect of the extract could be due to the presence of
dopaminergic substances. This theory is further sup-
ported by chemical studies reporting that ethanolic and
isopropanolic extracts do not contain the isoflavone
formononetin and the flavone kaempferol [54, 55]. These
substances are concentrated in the aerial parts of the
plant. As some of the early experiments did not use
standardised extracts, the detection of formononetin and
the effect of C. racemosa on oestrogen receptors and LH
levels observed in these investigations could be due to
contaminants.
In conclusion, the notion that C. racemosa has ben-
eficial effects on menopausal symptoms is not supported
by the evidence of rigorous RCTs. If an effect on
menopausal symptoms exists, it is probably due to an
239
action discrete from oestrogen receptor activity. Further
work is needed to test the efficacy of C. racemosa for
menopausal symptoms and to assess its long-term
effects. In addition, more work is required to identify the
pharmacologically active compounds of C. racemosa
and their actions.
Acknowledgements The authors wish to thank the University of
Naples Federico II for its support.
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