Katherine M. Newton, PhD; Susan D. Reed, MD, MPH; Andrea Z. LaCroix, PhD; Louis C. Grothaus, MS; Kelly Ehrlich, MS; Jane Guiltinan, ND
Acknowledgments: The authors acknowledge all those who contributed significantly to this work, especially the 351 dedicated women who participated in this study. In particular, they thank Linda Palmer, RN, and Jill Seymour, RN, ARNP, for their outstanding work with study participants; David Carrell and Nirmala Sandhu for their excellent programming and data management; Sheree Miller, PharmD, Lead Pharmacist, Investigational Drug Services, University of Washington Medical Center, for packaging and assuring blinding of study medications; and the late Natalie Koether, JD, Pure World, Inc., South Hackensack, New Jersey, for providing black cohosh. The authors also thank the members of the Data and Safety Monitoring Committee: Drs. Gregory Burke (Chair), Ellen Gold, Susan Johnson, and Barry Storer.
Grant Support: This project was funded by the National Institute on Aging and the National Center for Complementary and Alternative Medicine (grant R01AG17057) and by an administrative supplement from the National Institute on Aging (Alternative Therapies For Menopause—A Randomized Trial: Herbal Alternatives Quality Control Supplement).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Katherine M. Newton, PhD, Center for Health Studies, Group Health Cooperative, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Newton: Center for Health Studies, Group Health Cooperative, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101.
Dr. Reed: Obstetrics and Gynecology, Harborview Medical Center, P.O. Box 359865, Seattle, WA 98104.
Dr. LaCroix: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109.
Mr. Grothaus and Ms. Ehrlich: Group Health Center for Health Studies, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101.
Dr. Guiltinan: Bastyr University, 3670 Stone Way North, Seattle, WA 98103.
Author Contributions: Conception and design: K.M. Newton, S.D. Reed, A.Z. LaCroix, L.C. Grothaus, K. Ehrlich, J. Guiltinan.
Analysis and interpretation of the data: K.M. Newton, S.D. Reed, A.Z. LaCroix, L.C. Grothaus, J. Guiltinan.
Drafting of the article: K.M. Newton, S.D. Reed, A.Z. LaCroix, L.C. Grothaus, J. Guiltinan.
Critical revision of the article for important intellectual content: K.M. Newton, S.D. Reed, A.Z. LaCroix, L.C. Grothaus, K. Ehrlich, J. Guiltinan.
Final approval of the article: K.M. Newton, S.D. Reed, A.Z. LaCroix, K. Ehrlich.
Provision of study materials or patients: S.D. Reed.
Statistical expertise: A.Z. LaCroix, L.C. Grothaus.
Obtaining of funding: K.M. Newton, S.D. Reed, A.Z. LaCroix.
Administrative, technical, or logistic support: K. Ehrlich.
Collection and assembly of data: K.M. Newton, L.C. Grothaus, K. Ehrlich.
Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of Vasomotor Symptoms of Menopause with Black Cohosh, Multibotanicals, Soy, Hormone Therapy, or Placebo: A Randomized Trial. Ann Intern Med. 2006;145:869-879. doi: 10.7326/0003-4819-145-12-200612190-00003
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Published: Ann Intern Med. 2006;145(12):869-879.
Caution about taking estrogen for treating postmenopausal vasomotor symptoms has led to increasing substitution of herbal regimens despite few tests of their effectiveness.
The authors randomly assigned 351 perimenopausal or postmenopausal women to herbal treatments (black cohosh, multibotanicals, or multibotanicals plus counseling about dietary soy), estrogen with or without progesterone, or placebo. At 3, 6, and 12 months, patients receiving the herbal interventions had the same change in vasomotor symptoms as those receiving placebo (except for more severe symptoms at 12 months for patients taking multibotanicals plus dietary soy). Estrogen substantially decreased vasomotor symptoms.
Most participants were white and were well-educated.
Herbal regimens did not reduce postmenopausal vasomotor symptoms in this sample of women.
Hormone therapy remains the recommended treatment for vasomotor symptoms, but trials have shown serious risks with even short-term use (1-2). The use of herbs, particularly black cohosh, multibotanical supplements, and dietary soy for menopausal symptoms has grown dramatically (3-6). Few of these approaches have been scientifically evaluated. Women and providers are seeking safe, effective alternatives to hormone therapy. We designed the Herbal Alternatives for Menopause Trial (HALT) to provide rigorous evidence on the efficacy and short-term safety of commonly used naturopathic approaches for management of vasomotor symptoms.
HALT was a 1-year double-blind, randomized, controlled trial designed to investigate the effects of 3 naturopathic approaches for vasomotor symptom relief and hormone therapy compared with placebo. Study methods have been described elsewhere (7). The Group Health Institutional Review Board approved this study, and a data and safety monitoring committee monitored it. The study was conducted at Group Health, an integrated health plan in Washington State.
Eligibility criteria were as follows: age 45 to 55 years; late menopausal transition (≥1 skipped menses within the preceding 12 months) or postmenopausal (no bleeding within 12 months, or follicle-stimulating hormone level > 20 IU/mL if patient had undergone hysterectomy without bilateral oophorectomy); and 2 or more vasomotor symptoms per day over 2 weeks (≥6 moderate to severe symptoms). Women in menopausal transition were included because many are highly symptomatic and trial data are lacking for this group. Exclusion criteria were the following: contraindications to hormone therapy; use of hormone therapy or oral contraceptives within 3 months before the trial; use of herbal medicines for menopausal symptoms within 1 month before the trial; soy allergy; bilateral oophorectomy; history of breast cancer; and nonadherence during the run-in period (<80% of capsules taken).
From May 2001 through August 2003, women were recruited by using direct mail. Screening calls determined initial eligibility. Women attended an orientation visit at which eligibility was confirmed, physical measurements were collected, and placebo medication and questionnaires for the 2-week run-in period were provided.
Participants were randomly assigned by using SAS software (SAS Institute, Inc., Cary, North Carolina), stratified by previous hormone therapy and hysterectomy; block sizes within strata ranged from 5 to 25. Treatment assignments were sent to the University of Washington Research Pharmacy, where medications were bottled and labeled with a sequential identification number without treatment group indication. At the randomization visit, vasomotor symptom diaries and medication counts were examined to confirm eligibility and adherence. The study nurse determined the appropriate stratum, assigned the participant the next study number in that stratum without knowledge of group assignment, and distributed study medications.
The publication of results from the Women's Health Initiative (WHI) estrogen–progestin trial (2) raised new concerns about the safety of estrogen therapy. New study participants were given the choice of 5-arm (including hormone therapy) versus 4-arm (no hormone therapy) randomization. Current participants gave consent again, incorporating risk estimates from the WHI, and were given the option of finding out whether they had been assigned to hormone therapy; 16 were unblinded, 1 discontinued use of the study drug, and all remained enrolled. Following publication of the WHI Memory Study (8-9), we informed participants of those findings and restricted randomization to herbs and placebo. No further women were unblinded or discontinued use of the study drug.
Naturopathic medicine provided the model for study interventions. The herbal products, doses, and soy diet were based on approaches used by naturopaths when the study was designed (7). The study groups were as follows: 1) black cohosh (Actaea racemosa or Cimicifuga racemosa, 160 mg daily; 2.5% triterpene glycosides; 70% ethanol extract); 2) multibotanical; 3) multibotanical plus soy diet counseling; 4) conjugated equine estrogen, 0.625 mg daily, with (for women with a uterus) or without (for women without a uterus) medroxyprogesterone acetate, 2.5 mg; and 5) placebo. The multibotanical delivered daily doses of the following: black cohosh, 200 mg; alfalfa (Medicago sativa), 400 mg; boron, 4 mg; chaste tree (Vitex agnus-castus), 200 mg; dong quai (Angelica sinensis), 400 mg; false unicorn (Chamaelirium luteum), 200 mg; licorice (Glycyrrhiza glabra), 200 mg; oats (Avena sativa), 400 mg; pomegranate (Punica granatum), 400 mg; Siberian ginseng (Eleutherococcus senticosus, standardized constituents 0.8% eleutherosides E and B), 400 mg.
Black cohosh was provided by Pure World, Inc., (Hackensack, New Jersey). The multibotanical, ProGyne, was purchased from Progena Professional Formulations (Albuquerque, New Mexico) and encapsulated to study specifications. Both companies follow current good manufacturing practices, and single batches were used. ConsumerLab.com (White Plains, New York) tested the products after the study commenced. Dong quai, false unicorn, and pomegranate were not detected, suggesting that they were of poor quality or did not contain the tested marker compounds. Other marker compounds were detected in the approximate doses as labeled (7). The Appendix Table describes the herbal products in detail.
To facilitate blinding, medications and lactose placebo were encapsulated to provide 2 white and 2 blue capsules to each woman, and medication boxes were labeled with a unique identification number that did not indicate study group.
The soy food intervention was modeled after a successful 5-a-day intervention (10). We chose soy foods because of uncertainty about the efficacy of isoflavone supplements and because naturopaths commonly recommend whole soy foods. Participants received 5 telephone calls from a clinical dietitian and a 34-page booklet recommending 2 soy food servings per day (12 to 20 g of soy protein) (7). Other participants received 1 telephone call and a similar booklet reinforcing fruit and vegetable intake. Participants were instructed not to discuss dietitian calls with study nurses and were unaware that soy counseling was linked to the multibotanical.
The primary outcomes were change from baseline (measured over 2-week run-in period) to 3, 6, and 12 months (each measured for 4 weeks) and change from baseline to the average for all follow-ups with regard to the mean frequency and intensity of vasomotor symptoms (daytime hot flashes plus night sweats) and the mean Wiklund Vasomotor Symptom Subscale score (11-12). We also evaluated change from baseline to follow-up (months 3, 6, and 12 and average change) for daytime hot flash rate, night sweat rate, and the total Wiklund Menopause Symptom Scale score. Symptom diaries and global ratings of menopause symptoms are almost universally used in studies of vasomotor symptoms. Participants used a vasomotor symptom diary to record daytime hot flashes and night sweats, rating intensity as mild, moderate, or severe (scale, 1 to 3), as recommended by the U.S. Food and Drug Administration (13). Women completed the Wiklund Menopause Symptom Scale, rating the severity of 13 menopausal symptoms (sweats, hot flashes, sleep disturbance, fatigue, vaginal dryness, depression, headache, irritability, muscle/joint pain, breast tenderness, nervousness, palpitations, and dizziness/fainting on a scale of 0 (none) to 10 (severe) (11). Soy food intake was monitored by using a self-reported, validated soy food questionnaire (14).
Participants returned to the research clinic at 3, 6, and 12 months. Questionnaires were collected, and study medication was dispensed. Medication adherence counts were conducted by staff without participant contact and without knowledge of treatment assignment. Study nurses encouraged adherence and monitored adverse events during monthly telephone calls and at visits. Adverse events were identified through participants' responses to the question, “Have you had any medical problems or been hospitalized?” Responses were recorded and adverse events were followed until they were resolved. The study nurse determined intensity (mild, moderate, or severe) and whether the event was serious (yes or no). Events were reviewed by the study physician, who determined whether the event was study related, without knowledge of group assignment. Adverse events were coded by using the Coding Symbols for Thesaurus of Adverse Reaction Terms(15).
The Data and Safety Monitoring Committee reviewed study progress and unblinded outcome and safety data 5 times.
The study was powered to detect an effect of herbs halfway between the expected effects of hormone therapy and placebo, an outcome that we hypothesized would be meaningful.
Treatment effects, the difference between each treatment group and the placebo group with regard to the mean change from baseline, and the associated 95% CIs and P values were estimated by using a multivariate mixed model (PROC MIXED in SAS). We used an unstructured covariance matrix for the repeated measures, with separate parameter estimates for women in the hormone therapy group, since this structure best fit the data. Mixed models increase statistical power because of their ability to use all follow-up data and to better handle missing data. Although retention rates were very high, mixed-model analysis allowed us to use a true intention-to-treat approach, including data from all 351 randomly assigned women (n = 349 in adjusted analyses because of missing covariate data). The two Wiklund measures were analyzed after square-root transformation to normalize their distributions.
Mixed models were evaluated with and without adjustment for covariates. All models included a term for randomization protocol (4-arm vs. 5-arm). The adjusted models also controlled for age, body mass index (BMI), hysterectomy, menopausal status (menopausal transition vs. postmenopausal), and previous hormone therapy. All covariates except for BMI were selected a priori because of their hypothesized correlations with study outcomes and exposures. Results from the adjusted and unadjusted models were identical; we present only the adjusted results.
We also tested whether treatment effects differed by 4-arm versus 5-arm randomization (arm-by-treatment interaction). Since they did not differ, we present the results based on all randomly assigned women. An “as-treated” sensitivity analysis, restricted to women who took at least 80% of their study medications, was conducted, but results were similar and are not presented. Finally, we used mixed models to test whether the effect of each treatment varied in a statistically significant manner with BMI (nonobese [BMI < 30 kg/m2] vs. obese), hysterectomy, menopausal status, previous use of hormone therapy, and baseline symptom rate (<7 symptoms per day vs. ≥7 symptoms per day).
Adverse events rates were compared between each group and placebo by using chi-square tests or Fisher exact test (if expected count was <5). The study biostatistician conducted all analyses.
This study was funded by the National Institute on Aging and National Center for Complementary and Alternative Medicine. These agencies did not participate in the design, conduct, or analysis of the study or in decisions to submit the manuscript for publication. The National Institute on Aging did participate in decisions related to recruitment redesign in response to the release of the WHI findings and had a representative who attended all Data and Safety Monitoring Committee meetings.
We mailed 157 493 informational brochures and received 3443 responses (Figure 1). The baseline visit was attended by 509 women; of the 398 eligible women, 351 consented and were randomly assigned as follows: black cohosh (n = 80); multibotanical (n = 76); multibotanical plus soy counseling (n = 79); conjugated equine estrogen with medroxyprogesterone acetate (n = 29 women with a uterus) or without medroxyprogesterone acetate (n = 3 women without a uterus, all receiving unopposed estrogen); or placebo (n = 84). We enrolled 159 women under the 5-arm randomization scheme and 192 under the 4-arm randomization scheme; 147 of 183 women who were given a choice selected the 4-arm protocol. Ninety-two percent of women completed the study (327 of 351), and 87% (306 of 351) were taking study medication at 12 months.
Reasons for discontinuing therapy are not mutually exclusive. All participants received allocated intervention. *In the original enrolled plan, all participants were enrolled in 1 of 5 groups. †After publication of the Women's Health Initiative (WHI) estrogen–progestin (E + P) trial (2), women were given the option of 4-arm (without conjugated equine estrogen [CEE]) or 5-arm randomization. ‡After publication of the WHI Memory Study (8-9), randomization to CEE was stopped and only 4-arm randomization (that is, random assignment to herb or placebo, excluding hormone therapy) was used. BMD = bone mineral density; FSH = follicle-stimulating hormone; HT = estrogen with or without progestin; MPA = medroxyprogesterone acetate, 2.5 mg (women without a uterus were randomly assigned to CEE only); soy = counseling to increase dietary soy; TSH = thyroid-stimulating hormone.
Baseline characteristics were similar across treatment groups, with the exception of BMI (Table 1). On average, BMI was lower in the black cohosh group than in the placebo group and was higher in the hormone therapy group than in the placebo group. Average age was 52.2 years; 93% of participants were white, and all had at least a high school education. Women averaged 6.5 vasomotor symptoms per day (SD, 3.7; range, 1.4 to 24), and 34% averaged at least 7 symptoms per day at baseline. Average symptom intensity was 1.8 (on a scale of 1 to 3); 29% of participants reported symptom intensity averaging at least 2.0. The average Wiklund Menopause Symptom Scale score was 2.3 (SD, 1.2; range, 0.2 to 6.5) and the average Wiklund Vasomotor Symptom Subscale score was 4.5 (SD, 2.0; range, 0.8 to 10). Of 183 women (52%) who were in menopausal transition at baseline, 79 (46.6%) achieved 12 months of amenorrhea during the study.
Among women assigned to the soy food intervention, 77% completed 3 or more telephone calls (mean, 3.6). At baseline, women reported an average of 0.6 serving of soy per day. On average, women in the multibotanical plus soy intervention increased dietary soy by 1.1 servings per day between baseline and 3 months, compared with 0.1 serving per day in the other 4 groups.
The average adjusted number of vasomotor symptoms per day (Figure 2) and the Wiklund Vasomotor Symptom Subscale score (Figure 3) decreased between baseline and 3 months in all groups. There were no statistically significant differences in the average adjusted change in vasomotor symptoms per day or in vasomotor symptom intensity between the herbal interventions and placebo at 3, 6, or 12 months, or for the average over all the follow-up time points, with 1 exception: At 12 months, the multibotanical plus soy intervention had higher (worse) symptom intensity relative to placebo (P = 0.016) (Table 2). The average difference in vasomotor symptoms per day between the placebo and herbal treatments groups was less than 1 symptom per day at 3 months and less than 0.6 symptom per day for the average over all the follow-up time points. The average adjusted difference for hormone therapy compared with placebo was −4.55 (95% CI, −6.51 to −2.59) vasomotor symptoms per day at 3 months (P < 0.001) and −4.06 (CI, −5.93 to −2.19) vasomotor symptoms per day for the average over all the follow-up time points (P < 0.001) (Table 2).
Adjusted for age (continuous), body mass index (kg/m2, continuous), hysterectomy (yes or no), previous use of hormone therapy (HT) (yes or no), menopausal status (menopausal transition vs. postmenopausal), and randomization arm (4-arm without hormone therapy vs. 5-arm with hormone therapy).
There were no statistically significant differences in the Wiklund Vasomotor Symptom Subscale score between any of the herbal interventions and placebo at 3, 6, or 12 months or for the average over all the follow-up time points (Table 2). The Wiklund Vasomotor Symptom Subscale score was statistically significantly lower with hormone therapy than with placebo at all follow-up time points.
There were no statistically significant differences in hot flashes per day or night sweats per day between any of the herbal interventions and placebo at 3, 6, or 12 months or for the average over all the time points, with 1 exception: At 3 months, the black cohosh group had 0.38 less night sweat per day than the placebo group (CI, −0.72 to −0.04; P = 0.030) (Table 3). The difference between the herbal treatments and placebo was less than 0.6 hot flash per day and less than 0.4 night sweat per day at any time point; the differences in the average over all the time points were even smaller. The differences in hot flashes per day and night sweats per day between hormone therapy and placebo were statistically significant at all times points; over all follow-up time points, the average difference was nearly −3 hot flashes per day and nearly −1 night sweat per day (Table 3).
There were no statistically significant differences in the Wiklund Menopause Symptom Scale score between any of the herbal interventions and placebo at 3, 6, or 12 months or for the average over all the time points (Table 3). All differences between hormone therapy and placebo were statistically significant at all times (Table 3).
As-treated analyses, limited to women with at least 80% adherence, and separate analyses for women in the 4-arm and 5-arm randomization schemes, yielded similar results (data not shown). Results did not vary (no statistically significant treatment by subgroup interaction) when results were examined by baseline number of vasomotor symptoms (<7 vs. ≥7 per day), 4-arm versus 5-arm randomization scheme, baseline menopausal status, previous use of hormone therapy, hysterectomy (yes or no), or BMI (not obese [<30 kg/m2] vs. obese) (data not shown).
Women assigned to hormone therapy reported more breast pain (P < 0.001) and menstrual disorders (P = 0.04) compared with placebo (Table 4). There were no statistically significant differences between any of the 4 groups and placebo in the proportion of women with upper or lower gastrointestinal symptoms; nausea and vomiting; fatigue, asthenia, or malaise; or headaches or migraine. Too few severe adverse events occurred to make meaningful group comparisons (1 case of endometrial cancer in the multibotanical plus soy group 2.8 months after randomization; 1 case of breast cancer in the multibotanical group 4.7 months after randomization).
Over the 12-month follow-up period, the overall study sample on average took 86% of their pills; among individual study groups, adherence was 88% for black cohosh, 80% for multibotanical, 87% for multibotanical plus soy, 87% for hormone therapy, and 82% for placebo. These adherence figures include all 351 women; adherence was set to 0 for those who dropped out or stopped using study medication (Table 4). The primary reasons for discontinuation of study medication use or study withdrawal were no symptom relief (n = 10), other symptoms (n = 8), or change in health status (n = 8) (Figure 1).
In this large, randomized, double-blind trial, none of the 3 herbal treatments had clinically meaningful effects on any of the primary outcomes. As expected, hormone therapy resulted in a clinically important decrease in vasomotor symptom frequency and Wiklund scores throughout 1 year of treatment.
At least 5 randomized, placebo-controlled trials of black cohosh and menopausal symptoms have been published (16-20). All were short-term (≤12 weeks), and most were small, typically randomly assigning 30 to 60 women per group. Among 5 trials that examined frequency of hot flashes (16-19, 21, the only trial reporting a positive effect for black cohosh also found no effect of conjugated equine estrogen versus placebo (18); this result raises concerns about the validity of the findings. When menopause rating scales were used, 2 trials reported a positive effect of black cohosh (16, 18, 3 reported no difference from placebo (17, 19, 21, and 1 did not report main trial effects (20). The only trial that investigated a multibotanical containing black cohosh found no differences in vasomotor symptom frequency or menopause scale scores compared with placebo (22). Thus, the totality of the evidence does not consistently support a short-term effect of black cohosh on menopausal symptoms.
Effects of herbal products, such as black cohosh, may be sensitive to dose, extraction method, plant type, and coadministration of other herbs. The total daily triterpene glycoside dose in our black cohosh product was 5 mg, comparable to the 2 to 4 mg found in Remifemin (Schaper & Brümmer GmbH, Salzgitter, Germany), the most widely used product. Like Remifemin, our black cohosh (fingerprinted and verified to be Actaea racemosa) (7) was standardized to 27-deoxyactin. Remifemin is an isopropyl alcohol extract, whereas the products we tested are ethanol extracts. The implications of these different extraction techniques are unknown.
The literature on the other ingredients in the multibotanical is limited. Randomized trials have shown no improvement in vasomotor symptoms with dong quai (23) or Siberian ginseng (24). We are unaware of any study that has examined how the other components of the multibotanical affect vasomotor symptoms, although similar formulas are prescribed by naturopathic clinicians (7) and sold as over-the-counter supplements.
We reviewed 16 randomized clinical trials that tested whole soy or soy isoflavone supplements for vasomotor symptoms (25-40). Most were 12-week trials (range, 4 to 52). Eight studies found statistically significant improvements in at least 1 menopause symptom measure (26-28, 31, 33, 35, 37, 39. The magnitude of benefit was a 25% to 55% decrease in frequency or severity of menopause symptoms. Only 3 short-term studies evaluated dietary soy and vasomotor symptoms (38-40); 1 found a statistically significant improvement in vasomotor symptoms after 12 weeks of a soy- and flax-enriched diet (39).
To our knowledge, ours is the longest and largest placebo-controlled, double-blind trial to date, and we included both placebo and hormone therapy as benchmark comparison groups. Findings from our study indicate that trials longer than 12 weeks are necessary to evaluate the sustainability of effects. Adherence and retention were high. We included women in the menopausal transition, and women with 2 or more vasomotor symptoms per day (compared with the 7 to 8 required in Food and Drug Administration–monitored drug trials (13)), because women with fewer symptoms are a key target for herbal therapies. Our findings were similar for women with 7 or more versus fewer than 7 symptoms per day. Although we found no evidence of significant side effects, only a larger and longer trial could provide reassurance in this regard. Our results are generalizable to white, relatively well-educated women who have an average of at least 2 vasomotor symptoms per day. We conducted independent testing of the herbal products; no contaminants were found, and key constituents were present in the amounts specified by the manufacturers (7).
An important question in a trial that does not find statistically significant treatment effects is whether the negative findings were due to a true lack of clinically important effects or a lack of statistical power. The confidence intervals for our primary outcome of symptoms per day can be used to determine the effect size that can be “ruled out” by our results (Table 2). Over all 3 follow-up time points, one can rule out reductions beyond 1.5 symptoms per day from black cohosh and 1.0 symptom per day from the multibotanical treatments. Whether these are clinically important effects is debatable, but we would argue that most women would not think so. It is important to emphasize that these are the largest possible effects that are consistent with our data. Our best estimates of effect are far less; the average reduction in symptoms per day over the entire follow-up period was less than 0.01 symptom per day, combining results for the 3 herbal groups, all of whom received black cohosh.
Treatments used in naturopathic practice motivated our choice of interventions. The whole-person approach used by most naturopathic physicians differs significantly from the treatments selected for our study, and this might have affected response to therapy. Time spent with the patient on counseling about diet, exercise, and emotional issues related to menopause; dose revisions; and additional supplements are important aspects of the naturopathic strategy for managing menopausal symptoms. We could not replicate this approach.
In summary, there is a pressing need for safe and effective interventions for vasomotor symptoms. Regrettably, this trial and the totality of the evidence indicates that black cohosh used in isolation, or in a multibotanical product, has little potential to play an important role in relief of vasomotor symptoms.
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Video News Release - Black Cohosh No Better than Dummy Pill for Hot Flashes and Night Sweats of Menopause
Jonathan P. Krueger
December 19, 2006
why between-subjects design?
Is there some reason a within-subjects design was not used? It would appear to be suited to the phenomenon, which is reversible and observable within months. Why not have all subjects experience all conditions, say two months per condition, ordered at random for each subject?The power would be better, the results cleaner, and we'd be able to answer a question this study cannot: do some subjects repond reliably, even if the overall response is weak?
China Clinical Trials Coordination Center
December 20, 2006
Interpretation of the "negative" result
I read the paper with interest about the excellent work completed by Dr. Newton and her colleagues. We have just finished a pilot study of a black cohosh ethanol abstract in Beijing and are on the track of a national wide multi-centered RCT. The double-blinded pilot study enrolled 120 Chinese women with climacteric symptoms who were stratified into perimenopausal and postmenopausal arms, according to the standard of STRAW. Each arm was divided into 3 interventional groups, i.e. black cohosh (BC) low dose (1# bid), BC high dose (1# tid) and placebo, with 20 cases in each group. The primary outcome was Kupperman Index (KI) evaluated before the study and at the 2 and 4 weeks after the treatment. We also used menopause rating scale (MRS) as secondary outcome when it was first introduced in China and validified by this study. Although some of the results of this pilot study were "negative" (even there existed difference between BC and placebo groups), similar as shown in Dr. Newton et al's study, we were very careful to accept the null hypothesis, which we believed that the sample size we calculated before the study was not powerful enough to detect the difference.
I've noticed in Dr. Newton et al's study that they calculated the sample size based on an assumption that the effect of herbs was halfway of HRT. It is not surprised to see that the black cohosh group failed to show a "P<0.05" when it didn't reach the standard effect size even though the 95% CIs shifted to the left side of zero and inferred a small sample size. Seems Dr. Altman's words ring again beside our ears absence of evidence is not an evidence of absence. I have also noticed that Dr. Newton and her colleagues also admitted that their study result didn't rule out the differences between treatment groups smaller than 1.5 vasomotor symptoms per day.
We have never used Wiklund Vasomotor Symptom Subscale in China. But we found an interesting result in our study when we used both KI and MRS as outcomes, of which the KI seemed more "sensitive" to detect the treatment effect than MRS. We postulated that it was possible due the "weight" factor given to the score of vasomotor symptoms in KI which might "amplify" the effect comparing scored by MRS. It is interesting to know if any other researchers find similar phenomena.
Our study showed that the BC treatment brought more adverse events than placebo to the participants, mainly headaches. It was also shown in many other studies on BC. I was surprised to find that BC treatment had similar safety profile as placebo in Dr. Newton et al's study. We used a pharmaceutical product with major components specified, provided by a local manufacturer. Dr. Newton didn't mention whether the components contained in the BC product were standardized.
We appreciate that Dr. Newton or any other medical professionals with experience of using BC may share information with us.
Dr. Baoming Ge
Altman DG, Bland JM. Absence of evidence is not evidence of absence. BMJ 1995;311:485
Dr. Ge is the medical director of a CRO, located in Beijing, China.
Private medical practitioner
December 29, 2006
A misguided trial of Cohosh
Neither black nor blue Cohosh is indicated in any herbal/homeopathic text book for menopausal vasomotor symptoms sothat this trial is of no value in this respect. Unfortunately not one of your auhors is mentioned as being a fully qualified physician as well as a fully qualified and certified homeopath, in which case it would have been a far more useful to have compared homeopathically prepared Sepia,Sulphur,Lachesis or Pulsatilla.
The time is really long overdue for orthodox medicine to take a genuine look at the enormous potential for other therapies
The misunderstanding of herbal/homeopathic potential
Jonathan R. Byron
Dosage Low, Conclusions Sweeping
The dosages used in this study (160 mg daily of black cohosh root or 200 mg daily of black cohosh and other botanicals) are much lower than that taken by many women. Some commonly used supplements contain 500 mg or more of C. racemosa root per capsule, and multiple capsules are taken per day. It is not unusual to see a daily dose that is ten times larger than that used in this experiment. Assuming there is a dose-dependency to previously demonstrated phytoestrogen properties of black cohosh, it is unfortunate that this study only looked at relatively low doses. This study made a sweeping conclusion (that black cohosh "shows little potential as an important therapy for relief of vasomotor symptoms") that may or may not be true, but which is not supported by the study design. Research to evaluate ethnobotanical practices should start with a better understanding of those practices.
mid western univ
December 27, 2006
Was an excellent article, clearly illustrating the benefits of Black Cohosh, Multibotanicals, Soy, Hormone Therapy in menpause. My congrats to the authors.
Robert E. Kaeufeler
Max Zeller Soehne AG
January 19, 2007
Are conclusions of the HALT-study on herbal remedy really sound?
It is important that the authors' claim regarding the efficacy of black cohosh be considered in the context of an unusually high placebo response and an unclearly defined black cohosh dose. Even allowing for natural symptom regression over time, the placebo response in this study warrants further scrutiny. There was a consistent reduction in symptoms in the placebo group in the first 6 months (reduction from baseline in all other groups became stable after 3 months) and over a 1-year period only one patient in this group discontinued due to lack of symptom relief. This drop out rate was even proportionally less than among patients in the HRT group. Unusually high placebo responses in clinical trials can mask true drug responses and may be due to flaws in study design or implementation. Changes introduced following the publication of the WHI study led to 16 patients being unblinded and may also have been responsible for marked baseline differences observed among treatment groups, in particular between the HRT group and the others. The validity and clinical relevance of the findings of this study may also be undermined by the dosage and type of black cohosh extract used. Although the authors state that the effects of herbal products may be sensitive to dose and extraction method, they have not addressed these issues in the study. The amount of triterpene glycosides which is discussed constitutes not at all to the active substance of black cohosh and authors have not specified the extract used in the study according to current and international regulatory guidelines and standards . This study therefore does not negate the results of previous studies that have demonstrated the efficacy of black cohosh. The WHI study had previously shown an increased risk of cardiovascular disease and breast cancer in women using HRT . In light of new evidence which suggest that the recent fall in the incidence of breast cancer rates in the United States may be due to a reduction in hormone use , black cohosh should continue to be considered an alternative treatment of menopausal symptoms.
1. CPMP/QWP/2819/00 Rev 1
2. Rossouw, J.E., et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. Jama, 2002. 288(3): p. 321-33.
3. Ravdin, P.M., et al. A sharp decrease in breast cancer incidence in the United States in 2003. in San Antonio Breast Cancer Symposium. 2006.
The author is Medical Director of Max Zeller Soehne AG, Switzerland. The company produces its own black cohosh extract Ze 450.
Katherine M. Newton
March 22, 2007
We would like to reply to two points made in this review. First, is the issues of the select nature of the populations we studies, and resulting generalizability. We do not disagree with this point which applies to virtually any study. However, it is important to note that we made conscious choices to increase the generalizability compared to many of the currently published studies. We included women who were in the menopause transition as well as post-menopausal women, we included women with as few as 2 hot flashes per days vs. the 7 or more per day that is often required, and we included women with and without a uterus. The fact that our results were consistent across these different characteristics is, we believe, a point in favour of generalizability. It should also be clarified that we did not mail 150,000 letters to women with qualifying symptoms. Rather, the mailings went to presumably age-eligible women, but we could not target those with hot flashes specifically. And women received 2-3 mailings over time, so the number of women approached was closer to 60,000. The large number of mailings was necessary because the number of women with qualifying hot flashes who were willing to accept randomization in a clinical trial, and not already taking an alternative therapy or HT, is relatively small. The population base is far superior to studies enrolling women who present for symptoms, who represent just the tip of the iceberg.
It is suggested that a better evaluation of compliance with the soy intervention would have been urine or plasma phytoestrogens. We agree, and we will be publishing these results in the future.
Katherine M. Newton, PhD Associate Director for Research Group Health Center for Health Studies 1730 Minor Ave., Ste 1600 Seattle, WA 98101 Phone: 206-287-2973 FAX: 206-287-2871 Email: email@example.com
Susan D. Reed, MD, MPH Associate Professor of Obstetrics and Gynecology School of Medicine University of Washington Seattle, WA
Andrea Z. LaCroix, PhD Professor of Epidemiology Public Health Sciences Division, Fred Hutchinson Cancer Research Center Seattle, WA
I am the first author of this manuscript.
Katherine M Newton
Group Health Center for Health Studies
June 20, 2007
Treatment of Vasomotor Symptoms of Menopause with Black Cohosh, Multibotanicals, Soy, Hormonal Thera
We do not agree with Mr. Krueger that a within-subject design would have been preferable. A valid crossover study requires sufficient time for the effects of one drug to "wash out" before treatment on a second drug is begin. The time needed for the effects of herbal treatments to wash out is unknown so a crossover study would be subject to the criticism that the effects of one drug contaminated the effects of the others. Exposing each woman to all treatments would have required 14 months of participation, introducing unnecessary logistical and analytic complexity. This approach would have negated our opportunity to evaluate bone mineral density and to examine adverse events associated with longer duration of therapy. Menopausal symptoms change through time, further complicating the interpretation of crossover studies. Dr. Ge raises one of the principle limitations of many studies of alternative therapies for menopause symptoms, the use of generalized scales to summarize the menopause experience. These scales use a single question or small sets of questions for each outcome (hot flashes, mood, etc). As Dr. Ge observed, changes in scale scores are usually driven by vasomotor symptoms. We believe it is preferable to use validated, outcome- specific instruments (hot flash diaries and sternal skin conductance for vasomotor symptoms, PHQ-9 for depression, etc). Our study was powered to rule out differences between treatment groups greater than 1.5 vasomotor symptoms per day, a change we consider quite small.
One cannot conclude that there was a large placebo effect in the HALT study simply because symptoms decrease from baseline to month 3 in the placebo group. Subjects were excluded if they did not have at least 2 symptoms per day. We expected symptoms to decline from baseline to month 3 due to regression to the mean. Also, change in the placebo group was minimal from months 3 to 12 so it is incorrect to claim that there was a placebo effect after month 3.
Black cohosh was standardized to 2.5% triterpine glycosides. The doses we used were those most frequently used by naturopathic physicians in Seattle at the time, were consistent with manufacturer recommendations, and are considerably higher than doses currently recommended by many manufacturers (40-80mg). We are unaware of recommendations for doses as high as 1000-1500mg and consider such a practice inadvisable. Dr. Byron may be confusing the dose of dried root with that for standardized extract.
Hematology/Oncology, Neurology, Obesity, Headache, Breast Cancer.
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