Hananja Brice-Ytsma (MNIMH, MSc, DipED, DipTh)

Module Leader, Link Tutor

Archway Clinic of Herbal Medicine

Archway Campus

Highgate Hill

London N19 5LW

http://creativecommons.org/licenses/by-nc-nd/2.0/uk/

Is Cimicifuga racemosa a viable alternative to HRT

Studies on Cimicifuga racemosa have been done since 1950, in the last 5 years
trials have been done under stricter guidelines and have found CR to be effective
in reducing menopausal symptoms, especially in perimenopausal women, with more
severe symptoms. CR looks promising on the effect on the bone metabolism and could
possibly play a role in preventing osteoporosis, more research needs to be done to
indicate the effectiveness. CR has been found to be helpful in menopausal symptoms
in breastcancer patients where estrogen cannot be given and research indicates
that CR has possibly added benefits in its antiproliferative action on cancer
growth, on estrogen dependent tumours as well as on non-estrogen dependent
tumours. The adverse effects on stimulating uterine growth are not present with CR
in the maximum length of trial done for one year, and have not been seen in the
animal trials. With the amount of evidence available the question needs to be
asked why Cimicifuga racemosa is not prescribed regularly. Cimicifuga is easy to
get hold of in the health food shops, and many women will self prescribe.

Hananja Brice-Ytsma

July 2005

Is Cimicifuga racemosa (CR) a viable alternative to HRT

Introduction;

HRT has been used to relieve menopausal symptoms and to prevent disease such as
osteoporosis and dementia, cardiovascular disease.
The women’s Health Initiative (WHI) study was a large clinical trial of
postmenopausal women (age range 50-79) designed to see whether estrogen with or
without progestins could prevent chronic conditions such as heart disease and
dementia. The estrogen with progestins portion of the trial ended early because of
increased incidence of breast cancer. A link was shown between HRT and increases
in blood clots, stroke and heart diseases (Writing Group for the Women’s Health
Initiative Investigators. 2002). Women in the WHI were mostly older (mean age 62)
than those who typically seek HT for vasomotor symptoms (mean age 52). None of the
study participants had severe menopausal symptoms. Benefits were documented such
as a decrease in the risk of hip fracture, colorectal cancer. The women who
continued in estrogen only did not show an increase in breast cancer.

Ultimately the question needs to be addressed if the risks (Writing Group for the
Women’s Health Inititative Investigators 2002) outweigh the benefits, only after
many years, there are studies that provide data which reversed the perception that
HRT works to prevent diseases such as coronary heart disease and dementia.

Many women now try to avoid HRT and are looking for alternatives (Kang et al
2002). The availability and use of alternatives to HRT has

a british study involving about a million women taking HRTprovided information on

long term use (Rossouw et al 2002). Findings suggested that a variety of estrogen–
progestin combination therapies, estrogen and tibolone, increased risks to women
to develop breast cancer. The data suggests that all preparations analysed,
irrespective of the type of the estrogen and the progestins compound or the mode
of administrations bear risks. An increase in fatality of breast cancers was also
found (Beral V 2003). Comparison of HRT with placebo in older women with coronary
heart disease revealed increased rates of venous thromboembolism and biliary tract
surgery without favourable trends in overall rates of cardiovascular diseases
(Hulley et al 2000)

Ultimately the question needs to be addressed if the risks (Writing Group for the
Women’s Health Inititative Investigators 2002) outweigh the benefits, only after
many years, there are studies that provide data which reversed the perception that
HRT works to prevent diseases such as coronary heart disease and dementia.

Many women now try to avoid HRT and are looking for alternatives (Kang et al
2002). The availability and use of alternatives to HRT has grown significantly
(Newton et al 2002). Cimicifuga racemosa is the most used form as an alternative
to HRT (Newton et al 2002).

Cimicifuga racemosa trials;

In 1997, over ten million monthly units of Cimicifuga racemosa extract were sold
in Germany, the United States and Australia (Keenan et al 2003)
The efficacy and safety of Cimicifuga racemosa has been under scrutiny since 1950
where in Germany it became commonly prescribed by gynaecologists for menopausal
symptoms. By 1962 there are 14 clinical studies reported involving 1500 patients,
financed by the supplier the outcome could be interpreted as bias. More trials
have been done, most of these did not fulfil any Good Clinical Practice (GCP)
guidelines (International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human use 1997).

To compare the efficacy and safety of Cimicifuga root with placebo in women with
climacteric complaints the following study was done (Frei-Kleiner 2004). It was a
multicenter, randomised, placebo-controlled, double-blinded, parallel group study
in 122 menopausal women with over 3 hot flashes a day, treated for 12 weeks. The
two main efficacy measures weekly weighted score of hot flashes were severity and
number. Patients filled in a daily diary to record number and severity of the hot
flashes, each day for the whole treatment period. The Kupperman index was assessed
at week–2 on screening, week 0 baseline, week 4, 8, 12 (end of treatment).

In the primary efficacy analysis no significant difference between black cohosh

and placebo could be demonstrated, regarding the two tested main efficacy
variables. However the superiority of Cimicifuga compared to placebo was seen with
respect to symptoms of menopausal disorders in patients with a Kupperman index
over 20. In the active group the Kupperman index decreased by 13 index points, a
reduction of clinically relevance. The two assessment instruments, the Kupperman
index and the Menopause rating Scale (see figure below) correlated markedly and
produced similar results.

The analysis in the subgroup by intensity of the weekly weighted score of hot
flashes showed no difference between active medication and placebo. The conclusion
from this study is that Cimicifuga is effective for patients suffering from
moderate symptoms as supposed to mild symptoms. The active preparation is superior
to placebo, with a trend towards significance as assessed by the Kupperman index.

This is supported by another study (comparable and uncontrolled) which enrolled

only patients with a Kupperman Index of over 20 (Liske et al 2002).

The plant extract was well tolerated during the 3 month trial.

The trouble with menopausal trials is that women might enter at different stages
of their perimenopause with great variety of symptoms. The trial of Frei-Kleiner
et al 2004 illustrates the need to categorize the women according to severity of
symptoms. Women in the trials enter at different stages of their menopause, peri
or post menopausal. The placebo effect is about an average of 30 %. For some
perimenopausal women the natural progression of the menopause will be easy and
won’t have any perimenopausal symptoms at al in others the symptoms may be present
for years. Severity per individual will vary greatly. The above trial shows that
women with and Kupperman Index over 20 benefit most. Therefore one could interpret
this as that perimenopausal benefit the most, since those get the most severe
symptoms.

The most recent trial (Osmers et al 2005) supported the above finding that black
cohosh is effective in relieving climacteric symptoms especially in early
climacteric women (perimenopausal).

This was a randomised, multicenter, double blind clinical trial compared the
efficacy and tolerability of the isopropanolic extract with placebo. A total of
304 patients were receiving 40 mg or placebo daily for 12 weeks. The primary
efficacy measure was the change form baseline on the Menopause Rating scale,
secondary measures included were changes in the sub scores and safety variables.
The effect size was 0.03-0.05 menopausal Rating Scale units, similar to HRT
results. Women in the early climacteric phase benefited most, the hot flush sub
score was the most effective measure. No adverse effects were found.

The two trials have shown the benefit in reducing the Kupperman Index and
Menopausal Rating Scale. HRT has been used to prevent osteoporosis, could
Cimicifuga Racemosa have any effect on bone density?

A study by Wutke et al 2003, was comparing Cimicifuga racemosa with HRT and
placebo, looking at climacteric complains and effects on vagina and bone
metabolism and effect on the uterus. A double blind, placebo and estrogen
controlled, multicenter study in parallel groups. Good Clinical Practice
guidelines were applied, and conducted in accordance with the Helsinki declaration
(World Medical Association Declaration of Helsinki 1996). This was the first time
Cimicifuga racemosa was investigated in a randomised three armed ,double-blind,
and GCP controlled. Comparison included placebo and a positive control in the form
of Conjugated Estrogens (CE). At start of treatment patients were selected,
characteristics concerning age, height, weight, and the intensity of climacteric
symptoms were comparable in all treatment groups. Treatment consisted of 40 mg of
herbal drug, or 0.6mg CE, or placebo. Menopausal Rating Scale (MRS) was used as
efficacy criterion (Hauser et al 1994).

Three main factors in the MRS were compared; Factor one consisted of hot flushes,
sweating, heart complaints and sleep disorders, factor two were depressive moods,
nervousness, irritability and impaired performance, memory, factor three, were
disorders of sexuality, urinary symptoms, vaginal dryness, joint and muscle
symptoms.

Hormonal levels were measured as well as the levels of CrossLaps (metabolic

products of bone-specific collagen-1alpha1marker for bone degradation,) and the
levels of bone-specific alkaline phosphatase (marker for bone formation) (see
figure 2, Wutke et al 2003).

A statistically significant improvement of bone metabolism can be seen with CE and

CR, both compounds being equally active.

Other tests done were transvaginal ultrasound to measure endometrial thickness and
vaginal smear to determine the maturity index of vaginal epithelium.

Endometrial thickness compared from pre-treatment baseline until the end of the
treatment remained unchanged with placebo and Cimicifuga. With CE an increase of
more than 1 mm was found. Vaginal smear; CE had a significant effect on the amount
of superficial cells in the vaginal smear, the amount of superficial cells were
slightly stimulated by Cimicifuga and decreased in the placebo group. In reducing
the climacteric symptoms CE and CR were as effective, when compared to placebo.
The symptoms under factor 2 were distinctly improved with CR, less obvious with
CE. From diary evaluation, positive effects were seen on frequency of waking at
night with CR compared to placebo, by week 12. By week 8 and 12 positive effects
seen on early waking with CR compared to placebo.

Analysis of the markers on bone metabolism in the serum of postmenopausal women

indicated that CR and CE had comparable beneficial effects. CrossLaps had
increased in the placebo group, and decreased under CR and CE at week 12,
indicating decreased activity of the osteoclast cells, responsible for bone
degradation. The bone-specific alkaline phosphatase, the marker for bone
formation, remained unchanged in the placebo, significantly increased under CR and
remained unchanged under CE, indicating increased activity of the osteoblast cells
responsible for bone formation.

No adverse effects reported.

The lack of stimulation of CR on the uterus confirmed previous studies that CR

does not stimulated uterine weight.

CE increased these parameters.

CR does not stimulate the uterus, so unlikely that CR will stimulate the uterus to
develop uterine cancer. Whereas progestins has been added to estrogen to prevent
the development of endometrial cancer, progestins are not needed in CR.

Estrogens in the vagina stimulates acidity in the vaginal environment, preventing

ascending infections (Stoll 1987). The increase of superficial cells in vaginal
smears of patients treated with CE indicating estrogenic effects, similar effect
was noted with CR, which will lead to lowering pH therefore preventing ascending
infections as well as increase in lubrication upon sexual activity.

Placebo effect on any trials affecting menopausal complaints overall is always

significant, most susceptive in trials have been the hot flushes, placebo had the
least impact on the urinary symptoms, vaginal dryness, joint and muscle. In this
trial CE and CR are comparable on the total MRS score, compared to placebo. CR and
CE improved the muscle and joints evaluation (see figure 3 and 4). In bones
beneficial effects on bone turnover were apparent therefore might indicate that CR
can have preventative action in osteoporosis.

Cimicifuga racemosa in breast cancer patients;

The population of postmenopausal breast cancer survivors is rising, including the

use of tamoxifen as adjuvant therapy. The possible link of breast cancer with
estrogen makes the use of HRT undesirable. The use of tamoxifen is associated with
an increase in specific vasomotor and gynaecological symptoms (Day et al1999) and
can have significant adverse effect on the quality of life.

Medication other than estrogen has to be used to control symptoms among breast
cancer survivors. The vasomotor symptoms as a consequence of tamoxifen are more
common in women before the menopause then afterwards; 25 % of post menopausal
patients reported hot flushes while in premenopausal women hot flusher were
higher, up to 74% and mostly severe (Hernandez Munoz 2002)

One randomised clinical trial of CR in breast cancer patients has failed to show
improvement of the overall Kupperman index (Jacobson et al 2001). The study
involved 69 women, most were taking tamoxifen, and the trial lasted for 60 days.
The study design was a two armed randomisation, double blind and placebo
controlled. Stratified on tamoxifen and no tamoxifen taken

The aim of the study was to measure the frequency and intensity of hot flashes.
The women here were permitted to use nonhormonal medication while participating
but were instructed not to initiate new therapy for hot flashes. The primary
efficacy end point was mean numbers of hot flashes at 57-60 days. Additionally
analysis was performed using data from the menopausal symptoms index. Both groups
reported decreases in the number and intensity of hot flashes. The mean overall
decrease was approximately 27%.

The most debilitating symptom of sweating had improved significantly in the

treatment groups (P= 0.4). No changes in hormonal levels were noted (FSH and LH).
The main draw back in this study is the length of the study being only two months
most clinical trials with CR were done for three months or longer. There were more
older women in the treatment group, over fifty were in the CR groups. This could
have an effect on the outcome, since the CR has been found in other trials to be
most beneficial in the early perimenopausal symptoms.

Concomitant administration of CR and adjuvant tamoxifen therapy showed no negative

influences on cancer recurrence of cancer spread, although the trial was only two
months and therefore we cannot draw conclusions for long-term use.
Another trial on 136 breast cancer survivors aged 35-52 had a more promising the
result (Hernandez, Munoz and Pluchino 2003). After treatment for the cancer with
segmental or total mastectomy, radiation therapy and adjuvant chemotherapy,
participants were in open label randomly assigned to receive tamoxifen 20mg per
day (n46) or tamoxifen 20 mg plus 20 mg CR (n90). Clinical assessment was done
every two months. The primary end point was to record the number and the intensity
of hot flushes.

The main reason for eligibility was the premenopausal status with regular
menstruation and normal duration of cycle and breast cancer diagnosis with ER-
positive tumour. Pap smear, intravaginal ultrasound were performed, repeated 6
months later and successively every year to measure endometrium thickness.

The study design was two armed, randomised and open, and patients were instructed
not to initiate new therapies for hot flushes while participating in the study.

Hot flushes were considered severe when five or more sudden episodes of heat are
experienced during the day accompanied by sweating and sleep disturbances, feeling
irritation and anxiety. Moderate was described as a few episodes of heat with
discrete sweating. The intervention group started treatment with CR 14 days before
tamoxifen. At the end of the study after 12 months, in the CR group 46.7% were
free of hot flushes while only 24.4% suffered form severe symptoms compared to the
tamoxifen only group where 73.9% suffered from severe hot flushes and 26.1% from
moderate. No side effects noted.

The main difference between this trial and the one above is the fact that CR was
taken over twelve months as supposed to over two months. Patients were overall
younger and had more severe symptoms, CR could have a greater benefit in those
patients then in older patients as seen from the clinical trials above.

Cimicifuga racemosa; is it estrogenic?

All the above trials showed a lack of uterine stimulation, pointing to lack of
estrogenic activity, however the positive action found could point to estrogenic
activity and has led to speculation that CR is contraindicated in breast cancer,
or possible negative effects leading to uterine cancer.

Animal studies have found no increase in uterine weight, but a suppression of LH

was seen. (Jarry et al. 1985) An in vitro test with CR found a displacement of
estradiol form binding sites in human endometrium cytosol preparation , indicating
estrogenic activity, however CR was not able to displace radioactive –labelled
estradiol form either ERAlpha or ERBeta (Jarry et al 2002), confirmed by similar
observations in other studies (Liu et al and Amato et al).

CR extracts have been reported to have seronotin receptor blocking activity (Liao
et all 1995), and other investigators have demonstrated that certain activities of
CR extract such as decrease of body temperature, prolong action of ketamine
induced sleeping time and reduction of hot flush equivalent in rats could be
blocked by dopamine receptor antagonists, suggesting a dopaminergic mechanism of
action.

Jarry et al 2003 in vitro test were able to separate the dopaminergic compounds
and to distinquish between dopaminergic activity and oestrogenic activity, both
activities were well separated and concluded that in CR both are contributing to
the overall pharmacological profile.

Preclinical experiences show that CR has no proliferative effects on human mammary

tumour cells(Hostanska et al 2004). Black cohosh and its main components
triterpene glycosides and phenolic substances are potent inducers of apoptosis
(Hostanksa et al 2004).

It was found that CR had antiproliferative action on human prostate cancer cells,
which was observed under basal as well as E2 and DHT stimulated conditions (Jarry
et al 2005).

Studies on T47D breast cancer cells and another study with MCF-7 cells had
antiproliferative effects (Dixon-Shanies et al 1999, NeBelhut et al 1993)

In vitro proliferation of estrogen dependent breast cancer cell lines was

inhibited in dose dependent manner (Nesselhut et al 1993), and CR prevented the
stimulation of estrogen dependent cancer cells when estrogen was added in vitro
Tamoxifen and CR may act synergistically to black estrogenic proliferation of
breast cancer cells, because the combined inhibitory effect was greater than the
sum of the effect of each substance alone (Nesselhut et al 1999)

Test on the estrogen receptor alpha, shown that CR has antiestrogenic activity,
which could support the possibility that CR has selective estrogen receptor
modulator activity or have more than one component leading to the
antiproliferative activity.

Animal studies have shown lack of mammary tumor-stimulating effects of CR extract.

Freudenstein et al 2002 showed in a 6 weeks CR treatment, in doses up to 100-fold
the human therapeutic dose, did not exert growth-promoting effects on DMBA-induced
mammary tumors in ovariectomized rats. There was no effect on uterine
proliferation of and affect on FSH or LH found.

Estrogen replacement in the rats show and higher prevalence of multiple mammary
tumor growth and malignant adenocarcinomas as compared tot the CR treated and
control animals. By comparing the estrogen treated animals compared with the CR
extract and control groups, one can verify the sensitivity of the experimental
model in the measure of estrogenic parameters. Whereas the estrogen replacement
resulted in increase in uterus size, increased prolactin and decreased LH and FSH,
the model illustrated the lack of estrogen like adverse events after CR treatment.
The data in this study suggested a trend toward reduce tumor growth in CR treated
animals. This supports the safe use of CR in estrogen sensitive patients for which
HRT is contraindicated

Occasionally side effects have been reported when taken higher doses then
recommended , such as gastrointestinal discomfort, vertigo, headache nausea
vomiting impaired vision.

In human studies with the fluid extract up to 890mg a day was given without
evidence of toxic effects (Beuscher 1995). Other test on rats have failed to shown
chronic toxicity at about 90 times the human dose equivalent. Studies on
mutagenicity, teratogenicity and carcinogenicity have proven negative (Beuscher
1995).

Dosage needed for effectiveness;

One clinical trial compared 40 mg CR versus 127 mg CR per day on 152 women (Liske
et al 1998), decrease in Kupperman-menopause Index was observable after 2 weeks of
CR, similar results in safety and efficacy were observed in both dosages, after 6
months a positive response was seen in 90% of the patients, no chances sere seen
in hormone levels of LH, FSH, SHBG, Prolactin, estradiol, CR was effective, but no
difference found in either CR group, thus 40 mg is enough to find effect. Current
recommendation is based on this trial, however the dosage used in most clinical
trials have been 80mg of CR.

Conclusion;

Studies on Cimicifuga racemosa have been done since 1950, in the last 5 years
trials have been done under stricter guidelines and have found CR to be effective
in reducing menopausal symptoms, especially in perimenopausal women, with more
severe symptoms. CR looks promising on the effect on the bone metabolism and could
possibly play a role in preventing osteoporosis, more research needs to be done to
indicate the effectiveness. CR has been found to be helpful in menopausal symptoms
in breastcancer patients where estrogen cannot be given and research indicates
that CR has possibly added benefits in its antiproliferative action on cancer
growth, on estrogen dependent tumours as well as on non-estrogen dependent
tumours. The adverse effects on stimulating uterine growth are not present with CR
in the maximum length of trial done for one year, and have not been seen in the
animal trials. With the amount of evidence available the question needs to be
asked why Cimicifuga racemosa is not prescribed regularly. Cimicifuga is easy to
get hold of in the health food shops, and many women will self prescribe.

http://creativecommons.org/licenses/by-nc-nd/2.0/uk/

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