Reviewed: Jacobson JS, Troxel AB, Evans J, Klaus L, Vahdat L, Kinne D, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of cancer. Journal of Clinical Oncology 2001;19:2739-45.
A randomized, placebo-controlled trial was designed to study the efficacy a black cohosh (Actaea racemosa L., syn., Cimicifuga racemosa (L.) Nutt., Ranunculaceae*) for the treatment of hot flashes in women with a history of breast cancer. Eighty-five women over the age of 18 years previously treated for breast cancer at the Columbia-Presbyterian Medical Center (New York, NY) or one of its affiliates and who reported experiencing daily hot flashes were entered in the trial. Eligible participants had to have completed primary therapy, including chemotherapy and radiation therapy, at least two months before entering the trial. Women were excluded if they were using hormone replacement therapy (HRT) for hot flashes, were pregnant, or were known to have recurrent or metastatic breast cancer. Of the 85 women entered in the study, 59 were using tamoxifen, the anti-estrogenic chemotherapeutic drug used to treat breast cancer.
Participants were randomized to receive either a black cohosh extract equivalent to 20 mg of black cohosh rootstock (Remifemin®; GlaxoSmithKline, Research Triangle Park, NC**) twice daily (for a total daily dose of 40 mg) or placebo twice daily with meals for 60 days. Each woman was asked to record the number of hot flashes and their intensity (1 = mild, 2 = moderate, and 3 = severe) for the three days prior to starting the medication and then again on days 27 to 30, and on days 57 to 60. Before starting the medication and at the conclusion of the study period, each participant was also asked to complete a detailed menopausal symptom index (name and details of the index are not given in the paper) and a visual analog scale rating overall health and well-being. Menopausal symptoms studied were heart palpitations, excessive sweating, headaches, poor sleep, depression, and irritability or nervousness. Blood specimens were collected from 41 women, and analysis of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were completed on the first 37 and 18 women, respectively.
Sixty-eight women provided usable hot flash diary data throughout the entirety of the study (24 in the black cohosh/tamoxifen group, 26 in the placebo/tamoxifen group, 9 in the black cohosh/no tamoxifen group, and 10 in the placebo/no tamoxifen group). Throughout the course of the trial, hot flashes declined in both groups, with an average reduction in the mean number of hot flashes of about 27 percent overall. However, the differences in the mean reduction in hot flashes between groups were not significant (p=0.86 via analysis of covariance adjusting for baseline number and tamoxifen use). Similarly, there were no significant differences between the groups in reduction of hot flash intensity or overall hot flash activity score. The only menopausal symptom significantly reduced in the black cohosh group was excessive sweating (p=0.04). Comparing FSH and LH levels at baseline and completion of the study, FSH level changes were small and not significant in any group (the two groups taking tamoxifen had lower FSH levels at both baseline and completion). Changes in LH levels were also very small with the exception of a rise in levels in the placebo/no tamoxifen group. Three serious adverse events occurred (hysterectomy, breast cancer recurrence, appendectomy): one in the placebo/tamoxifen group and two in the black cohosh/tamoxifen group. Ten minor adverse events were also reported (e.g., constipation, weight gain, cramping, vaginal bleeding, and indigestion) with six occurring in the black cohosh/tamoxifen group.
Approximately two-thirds of breast cancer survivors report experiencing hot flashes following completion of treatment.1 As the number of breast cancer survivors using the anti-estrogenic medication tamoxifen to either treat or prevent breast cancer increases, it is anticipated that the number of these women experiencing menopausal symptoms will rise dramatically.2
While standard estrogen replacement is typically avoided in this group, symptomatic treatment of hot flashes has provided a challenge to healthcare professionals. To date, only megesterol acetate,3 venlafaxine,4 and, on a lesser scale, vitamin E5 and clonidine6 have shown the ability to manage these episodes in well-controlled clinical trials.
The German Commission E has approved the use of black cohosh root for climacteric (menopausal) symptoms, including hot flashes.7 A review of eight German clinical trials on the use of black cohosh for treatment of symptoms of menopause published in the Journal of Women's Health concluded that the herb is both safe and effective and a suitable alternative to estrogen-replacement therapy in those women whom estrogen therapy is either refused or potentially harmful (e.g., some breast cancer patients).8
Small clinical trials completed in the 1980s in Germany using the Remifemin® extract (Schaper and Brummer GmbH, Salzgitter, Germany) suggest that black cohosh not only reduces hot flashes effectively but also compares favorably to HRT and anti-anxiety medications (e.g., diazepam) for symptom relief.9 One trial compared black cohosh extract (80 milligrams per day) with conjugated estrogens (0.625 milligrams per day) or placebo in 80 menopausal women.10 After 12 weeks, women taking black cohosh had a significantly greater reduction in scores on a standard measure of menopausal symptoms known as the Kupperman Index. This index rates severity of hot flashes, outbreaks of sweating, sleep disorders, nervousness/irritability, dizziness, difficulty in concentrating, joint pains, headaches, and heart palpitations. Side effects were virtually absent in the black cohosh group. Another trial compared black cohosh (similar dose but liquid preparation) with conjugated estrogens (same dose as above) or Valium (2 mg/day) in 100 menopausal women.11 After 12 weeks of treatment, hot flashes and other symptoms on the Kupperman Index were more effectively reduced in the black cohosh group. It should be noted that women taking black cohosh had a greater reduction in depression and anxiety also.
Although the German Commission E previously reported estrogen-like (phytoestrogen) actions as well as suppression of LH for black cohosh based on earlier pharmacological experiments,12 a more recent trial with 152 women ages 43 to 60 years, found no effects of the Remifemin® extract (40 or 127 mg/day) on either LH or FSH levels over six months.13 After three months of treatment, both dosages of black cohosh were found to be equal to each other in reducing symptoms on the Kupperman Index.14 Self-rating scales and physician evaluation supported these results. No serious side effects were noted at either dose. A later report on the same subjects reported no changes in endometrial thickness following six months of black cohosh at either dose.15
Based on these results, the researchers at Columbia University felt that black cohosh may provide a safe and effective treatment option for breast cancer survivors experiencing menopausal symptoms, including hot flashes. Their study is the first to examine the effects of this phytomedicine in women with a history of breast cancer. While sweating, which is likely related to the perception of heat in women experiencing hot flashes, was significantly reduced in those taking the black cohosh extract, other symptoms that also seemed to be reduced in earlier trials with menopausal women without a history of breast cancer, are reduced at a rate no different than placebo. It should be noted that sweating is often reported as the most significant symptom of menopause.
There are some shortcomings of the trial. While the investigators express concern about a large drop-out rate with a longer study period (the drop-out rate was high at 18.8 percent), the 60-day trial is 30 to 120 days shorter than previous studies with black cohosh for treating hot flashes. With the large placebo response noted in this trial, a longer study period is needed to determine efficacy of the study medication.
While it is hard to avoid, the confounding factor of tamoxifen versus no tamoxifen treatment essentially breaks the already small study population down to extremely small groups for statistical analysis. While it is possible that black cohosh cannot overcome the hot flashes caused by tamoxifen, looking at a larger group of women not taking tamoxifen would have helped strengthen the data analysis.
Finally, the investigators report on individual menopausal symptoms but do not provide a collective 'menopausal score' such as that used in earlier black cohosh studies using the Kupperman Index (which combines 10 menopausal symptoms). Due to the complexity of symptoms affecting women during menopause, this overall symptom score would have been interesting to compare between the treatment and placebo groups.
While advocates of black cohosh will point to the lack of hormonal effect of black cohosh as evidence that the herb is safe for women with a history of breast cancer or who may have a family history of breast cancer, I would like to see a follow-up study which examines the effect on LH and FSH on this population for a longer period of time (e.g., six months). It is also important that women in this population be informed that the study used only 40 mg of the Remifemin® extract daily. While the earlier pharmacological study found no evidence of a hormonal effect at 127 mg/day, the study was completed with women reporting no history of breast cancer.
Although larger and longer clinical trials are needed, these new data suggest that black cohosh may not effectively treat menopausal symptoms, such as hot flashes in women who are breast cancer survivors, particularly those taking tamoxifen (although reports of sweating were significantly reduced in women using black cohosh). While not a definitive comment on the safety of black cohosh in this population, the study does suggest that black cohosh does not affect LH and FSH, therefore supporting an earlier study that found no estrogen-like activity in women without a history of breast cancer.
* Note: Actaea racemosa L. replaces Cimicifuga racemosa (L.) Nutt. as the taxonomically preferred Latin binomial for black cohosh.
** Note: The Remifemin® product is an isopropanolic-aqueous extract of black cohosh rootstock manufactured in a standard production procedure with constant monitoring of the content of active compounds (triterpene glycoside). Each tablet contains extract to be equivalent to 20 mg black cohosh rootstock. The product is produced by Schaper and Brummer GmbH & Co., Salzgitter, Germany and licensed to GlaxoSmithKline in the United States for sale under the same registered trade name.
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