Which of the following steps are ineffective ways to reduce symptoms associated with menopause

NIH-Funded HALT Study Finds Black Cohosh Ineffective for Treating Menopausal Symptoms

By Donald Brown, ND, Dr. Brown is Founder and Director, Natural Product Research Consultants, Inc.; serves on the Advisory Board of the American Botanical Council and the President's Advisory Board, Bastyr University, Seattle, WA; and is an Advisor to the Office of Dietary Supplements at the National Institutes of Health; he is a consultant for Nature's Way, Inc.

Source: Newton KM, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone replacement therapy, or placebo. Ann Intern Med 2006;145:869-879.

Abstract: In a randomized, double-blind, placebo-controlled trial, the effects of black cohosh or a multibotanical combination product with or without a high-soy diet were compared with hormone therapy or placebo for the treatment of vasomotor symptoms associated with menopause. The study was completed with 351 women (ages 45-55 years) with two or more vasomotor symptoms per day; 52% of the women were in menopausal transition (≥ one skipped menses within the preceding 12 months) and 48% were postmenopausal (no bleeding within 12 months, or follicle-stimulating hormone level > 20 IU/mL if the participant had undergone hysterectomy without bilateral oophorectomy).

Women were randomized to one of five groups: 1) black cohosh (Actea racemosa; CimiPure®, 70% ethanol extract standardized to 2.5% triterpene glycosides; Pure World, Inc., Hackensack, NJ) rhizome/root extract, 160 mg/d; 2) an encapsulated multibotanical formulation delivering the following daily doses of these herbs: black cohosh, 200 mg; alfalfa (Medicago sativa), 400 mg; chaste tree (Vitex agnus-castus) berry, 400 mg; dong quai (Angelica sinensis) root, 400 mg; false unicorn (Chamaelirium luteum) root, 200 mg; licorice (Glycyrrhiza glabra) root, 200 mg; oats (Avena sativa) straw, 400 mg; pomegranate (Punica granatum) fruit, 400 mg; Siberian ginseng (Eleutherococcus senticosus) standardized to 0.8% eleutherosides E and B) root, 400 mg; and also 4 mg of boron (multibotanical [ProGyne™]was supplied by Progena Professional Formulations, Albuquerque, NM); 3) multibotanical formula plus a high-soy diet (12-20 g of soy protein per day as instructed by phone counseling); 4) conjugated equine estrogen, 0.625 mg/d, with (for women with a uterus) or without (for women without a uterus) medroxyprogesterone acetate, 2.5 mg/d; or 5) placebo.

The primary outcome measures were change from baseline (measured over a two-week run-in period) to three, six, and 12 months (each measured for four weeks) and change from baseline to 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 Symptoms (WVS) Subscale score. Also evaluated was change from baseline to follow-up (months 3, 6, and 12 and average change) for daytime hot flash rate, night sweat rate, and total Wiklund Menopause Symptom Scale (WMSS) score.

There was a decrease between baseline and three months for the average adjusted number of vasomotor symptoms per day and the WVS subscale score in all groups. There was no statistically significant difference in the average adjusted change in vasomotor symptoms intensity between the herbal interventions (groups 1, 2, and 3) and placebo at three, six, or 12 months, or for the average over all the follow-up time periods. The one exception was that the multibotanical plus soy diet group actually had significantly worse symptom intensity at 12 months compared to placebo (P = 0.016). The average difference in vasomotor symptoms per day between the placebo and herbal treatment groups was less than one symptom per day at three months and less than 0.6 symptoms per day for the average over all the follow-up time periods. Hormone therapy reduced vasomotor symptoms significantly at three months compared to placebo (P < 0.001) as well as vasomotor symptoms per day for the average over all the follow-up time points (P < 0.001). There were no significant differences in the WVS Subscale score between any of the herbal interventions and placebo at three, six, and 12 months or of the average over all follow-up time periods. It was significantly lower for the hormone therapy group compared to placebo at all follow-up time periods.

Additional analyses found no statistically significant differences in hot flashes per day or night sweats per day between any of the herbal interventions and placebo at all time points except at three months when the black cohosh group had 0.38 fewer night sweats per day than the placebo group (P = 0.03). The difference between the herbal treatments and placebo was less than 0.6 hot flashes per day and less than 0.4 night sweats per day at any time points—these differences became smaller when averaged over all time points. This resulted in three fewer hot flashes and one fewer night sweat per day for the hormone therapy group compared to placebo. While differences in the WMSS were significant compared to placebo at all time points for the hormone therapy group, there were no difference at any time point for the herbal intervention groups. Women assigned to hormone therapy reported more breast pain (P < 0.001) and menstrual disorders (P = 0.04) compared to placebo. Other upper and lower gastrointestinal adverse events were similar between all five groups. Too few serious adverse events occurred to make meaningful group comparisons.

Comments

Funded by a grant from the National Institute on Aging and the National Center for Complementary and Alternative Medicine, the Herbal Alternatives for Menopause Trial (HALT) was a much anticipated collaboration between Group Health, the University of Washington, Fred Hutchinson Cancer Research Center, and Bastyr University in the greater Seattle area. The study was designed to "investigate the effects of three naturopathic approaches for vasomotor symptom relief and hormone replacement therapy compared with placebo." As most readers are probably aware at this juncture, not only were the results negative but a corresponding editorial in the Annals of Internal Medicine1 and stories in the mainstream press largely focused on the fact that black cohosh was ineffective for treating hot flashes. Upon publication of the study, herbal and integrative medicine experts (e.g., Mary Hardy, MD, Francis Brinker, ND, and Gail Mahady, PhD) questioned the design as well as the results of the study and suggested that it was inconsistent with previous positive studies with black cohosh.2 One of the lead investigators in the HALT study, Jane Guiltinan, ND, responded by pointing out that non-industry sponsored black cohosh trials that were placebo-controlled trials were largely negative.3

Of course, yours truly was one of those "experts" with an opinion. First and foremost, I'm disappointed in the design of the study. While I'm the first to acknowledge the fact that naturopathic interventions are hard to study in a controlled clinical trial, there were too many variables and too many groups in this study. By dividing the total number of subjects across five treatment arms, the statistical power of the study suffers. To their credit, the investigators acknowledge this limitation in their paper by writing, "The study was too small to detect small changes in symptom frequency (less than 1.5 hot flashes per day)." As noted in the summary above, the study set a criteria for inclusion at a minimum of two hot flashes per day, a relatively low level at which reductions are more difficult to produce or monitor.

Also of concern is the choice of black cohosh extract and the dosage chosen. With preclinical safety data, positive and negative clinical trials, as well as postmarketing surveillance data on established extracts such as Remifemin® (Schaper and Bruemmer, Salzgitter, Germany, imported by Enzymatic Therapy, Green Bay, WI) and Klimadynon® (BN 1055, Bionorica, Neumarkt, Germany, imported by Bionorica USA, Eugene, OR), why would the researchers choose to use an extract with no data whatsoever? It's interesting to note that in a three-month open-label, monitoring study of Remifemin, a dose comparison of 40 mg/d and 127 mg/d found a similar effect on vasomotor symptoms associated with menopause.4 With 40 mg/d clearly established in earlier trials as an efficacious dose, it's not clear why the higher dose of 160 mg/d was chosen for this study.

I'm also confused by the addition of the multibotanical product. Perplexing is the fact that the investigators discovered after the study had started that laboratory analysis failed to detect any dong quai, false unicorn, or pomegranate in the product. That disconcerting fact aside, I'm unaware of any data or even historical rationale that supports the use of ingredients such as chaste tree or dong quai for vasomotor symptoms associated with menopause. Why not use a more established comparison supported by clinical research such as red clover?

So, what we're left with is a study that really tells us very little other than the fact that hormone therapy effectively treats hot flashes and that there is a large placebo response (about 30% in this trial) in this study population. If the critique is that previous positive black cohosh studies are biased and industry-sponsored (so are most drug studies by the way), then why not complete a definitive U.S. study with black cohosh that uses an established extract? The opportunity for high-quality and objective research exists with funding from agencies such as the National Institute on Aging and the National Center for Complementary and Alternative Medicine. However, based on the track record of either poorly designed studies and/or poorly chosen products/ingredients for those studies, isn't it time for a critical view of how government funds are being spent on CAM research?

Conclusion

Although the above study clearly shows superiority of hormone therapy for the management of vasomotor symptoms of menopause such as hot flashes, many female patients in this population are aware of the health risks associated with taking hormones. Unfortunately, this study fails to provide a clear answer for alternatives such as black cohosh, a high-soy diet, and a multibotanical product. The results of this study must be taken in the context of all black cohosh trials—many showing efficacy at 40 mg/d for commercially available products—however, a critical view of this study points to the need for government-funded trials that build on work already done on alternative therapies such as black cohosh instead of ill-advised attempts to reinvent the wheel.

References

1. Magione CM. A randomized trial of alternative medicines for vasomotor symptoms of menopause [editorial]. Ann Intern Med 2006;145:924-925.

2. Black cohosh trial not representative of previous research showing positive results [press release]. Austin, TX: American Botanical Council; Dec. 21, 2006.

3. Appleton J. Is black cohosh effective for hot flashes? Portland, OR: Healthnotes Newswire, Jan. 4, 2007.

4. Liske E, et al. Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): A 6-month clinical study demonstrates no systemic estrogenic effect. J Women Health Gender-Based Med 2002;11:163-174.

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