Hananja Brice-Ytsma (MNIMH, MSc, DipED, DipTh)
Module Leader, Link Tutor
Archway Clinic of Herbal Medicine
Archway Campus
Highgate Hill
London N19 5LW
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.
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