Black Cohosh and Menopause: Is It Still Hot?

By David Kiefer, MD, Dr. Kiefer is a Clinical Instructor, Family Medicine, at the University of Washington in Seattle; Clinical Assistant Professor of Medicine at the University of Arizona in Tucson, and Adjunct Faculty at Bastyr University in Seattle; he reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Part 1 of a Series on Black Cohosh

Black cohosh is an herb known by many people for its beneficial effects on the symptoms of menopause, and, more recently, for possible adverse effects partly due to its estrogenic phytochemicals. It is a good example of an herbal medicine with a strong basis in traditional medicine that now has in vitro data as well as numerous clinical trials of varying methodological quality. The purpose of this review is to bring readers up to date about the use of this intriguing herb for hot flashes in menopause.

History and Traditional Use

Black cohosh, also known as black snake root or rattlesnake root, was historically used in North America for snakebite, myalgias, rheumatic conditions, and a variety of gynecological concerns, such as amenorrhea, ovarian pain, and menorrhagia.1 Recently, black cohosh sales in the United States have increased almost on a yearly basis, with one report estimating 2002 sales of $42 million.2 Some experts have attributed this popularity to concerns about hormone replacement therapy during menopause.

Botany and Pharmacology

Black cohosh is native to North America, and its Latin name, Actaea racemosa, was formerly Cimicifuga racemosa (Family Ranunculaceae, the buttercup family).3 Its roots and rhizomes are the plant parts used in current preparations. The roots contain terpene glycosides such as actein and cimifugoside that are thought to account for some of black cohosh's effects, though tannins, alkaloids, resins, fatty acids, caffeic acid, isoferulic acid, and flavonoids (such as formononetin) in the rhizomes may also have some biological activity.2,4

The presence of many other compounds (polyphenols, cycloartane glycosides) in black cohosh has been documented in the scientific literature, having been isolated in small quantities and/or with specialized extraction techniques. It is unclear what physiological effects, if any, these compounds may have.

Mechanism of Action

Numerous mechanisms have been postulated about the effects of black cohosh. Some data indicate that black cohosh decreases luteinizing hormone (LH), acts as a serotonin agonist, and/or is estrogenic, competing for estrogen binding sites, perhaps selectively based on the tissue involved.5 For example, one animal study of the standardized extract BNO 1055 showed some selective estrogen-receptor modifier activity in the hypothalamus, pituitary, and bone, but not in the uterus.6 Other data seem to indicate little estrogenic effect despite binding to estrogen receptors and the associated possibility of estrogen-blocking activity, and no changes to LH, follicle-stimulating hormone (FSH), or prolactin.4

One double-blind study used a vaginal maturity index to examine vaginal smears from 62 postmenopausal women treated with 40 mg daily of the black cohosh extract BNO 1055 (a dried aqueous/ethanolic extract of the rhizome) for three months and found a slight trend (not significant, P = 0.0542) toward the maturation of the vaginal mucosa, casting some doubt on its estrogenic effect.7 In addition, two different doses (39 mg and 127 mg) of an extract of black cohosh was given to 150 women for three months.8 No changes were demonstrated in vaginal cytology or blood hormone levels, prompting the authors to doubt systemic estrogenic effects of black cohosh.

Clinical Trials

Numerous review articles and meta-analyses examine the use of black cohosh for menopausal symptoms.3-5,9 These reviews document the challenges of drawing conclusions from studies that use different black cohosh formulations, prescribed for different periods of time and at different doses. Nonetheless, most authors conclude that there is at least preliminary evidence that black cohosh alleviates some menopause-related symptoms. What this means more specifically is illustrated by some of the recent representative clinical trials.

One double-blind trial randomized 95 women to 40 mg daily of a standardized black cohosh extract (BNO 1055), 0.6 mg conjugated estrogens, or placebo for 12 weeks.10,11 The results, assessed by a menopause rating scale and with an intention-to-treat analysis, showed that both black cohosh and estrogen reduced climacteric complaints when compared to placebo, though the results only approached significance (P = 0.0508 and 0.0513, respectively).10 There was a statistically significant improvement in sleep and a reduction in sweating episodes for both the black cohosh and estrogen groups.11 Adverse effects were mild and similar between the three groups.

Another double-blind, randomized, crossover trial in 132 women taking 20 mg twice daily of a standardized black cohosh extract (standardized to 1 mg triterpene glycosides, similar to Remifemin®) for four weeks failed to find any effect on hot flash score or hot flash frequency compared to placebo.12 The authors did not mention an intention-to-treat analysis, despite the fact that only 107 women completed the first four-week treatment and only 99 completed the crossover treatment. Other possible explanations for these results are the short duration of the trial (four weeks may be insufficient to show an effect) and the low dose employed (some experts recommend more than 20 mg twice daily).

In another randomized study, a menopause symptom diary was used in 64 women to compare 40 mg of an isopropanolic aqueous extract of black cohosh to transdermal estrogen over three months.13 Both treatments significantly (P < 0.001) reduced the frequency of hot flashes, vasomotor symptoms, anxiety, and depression over the three study months. The lack of a placebo group severely limits interpretation of these results, especially given the relatively high placebo response in menopause trials.

A double-blind trial examined 304 women randomized to 40 mg of an isopropanolic black cohosh extract (brand name Remifemin) or placebo for three months using a menopause rating scale.14 An intention-to-treat analysis showed that the black cohosh group had a statistically significant improvement (P < 0.001) in menopause symptoms, especially for those women recently menopausal. The adverse effects were similar between the two groups.

Another double-blind, randomized, placebo-controlled trial further specified a sub-population among the 122 menopausal women studied for which black cohosh may be useful.15 Using an intention-to-treat analysis of hot flash scores, a menopausal rating system, and the Kupperman Index (a rating scale to quantify menopausal severity), an average of 42 mg daily of an ethanolic extract caused a statistically significant decrease in hot flash scores and number, but only for women with moderately intense menopausal symptoms (Kupperman Index > 19). Again, there was no difference in adverse events between the placebo group and the black cohosh group.

Two recent trials provide some insight on the use of black cohosh in the context of breast cancer survivors. A two-month, placebo-controlled trial in 85 women who had completed primary treatment for breast cancer were randomized to receive black cohosh or placebo.16 Fifty-nine women were also on tamoxifen. Only 69 women completed the trial. An intention-to-treat analysis revealed that both treatment and placebo groups reported fewer hot flashes, and there was no statistical difference in blood levels of LH and FSH between the two groups. The product specifications were not described by the researchers, though patients took one tablet twice daily. There was a statistically-significant decrease in sweating in the treatment group as compared to placebo. Otherwise, no benefit or problems with black cohosh were reported. One criticism was that the treatment period was not long enough to show an effect.

In another trial, 136 breast cancer survivors were randomized to receive either tamoxifen 20 mg daily or tamoxifen 20 mg plus 20 mg twice daily of a standardized black cohosh extract (BNO 1055) for one year, resulting in a statistically significant decrease (P < 0.01) in the number and severity of hot flashes in the black cohosh group.17 Of note, there was no placebo arm to this trial. No serious adverse events were reported.

There are problems with each of these trials, and more research is needed to determine the safety of black cohosh in breast cancer survivors; clarification should focus on such parameters as the use of black cohosh when estrogen receptor status is positive or over longer periods of time, before clinicians can definitively and safely use black cohosh in this demographic.

Dosage and Formulation

Clinical trials have generally used extracts standardized to the terpene glycoside content, with doses ranging from 40 mg to 160 mg daily. The two main standardized products are Remifemin (in the past a 60% ethanol hydroethanolic extract, now a 40% isopropyl alcohol extract) and BNO 1055 (Klimadynon®, a 58% aqueous ethanolic extract).3 Black cohosh tinctures are available; there is a wide variety of published doses, from 2 mL twice daily of a 1:1 tincture (90% alcohol) to 0.5-2.0 mL daily of a 1:10 tincture (60% alcohol).1,4 Some experts point to the negative clinical trials using 20 mg twice daily as evidence that higher doses, such as 40 mg twice daily, may be necessary for an effect.

Adverse Effects, Contraindications, and Drug Interactions

A recent review of clinical trials found that the adverse effects associated with black cohosh use are usually mild, rare, and reversible (most commonly gastrointestinal upset). The researchers also noted an overall paucity of information about herbal side effects, making it difficult to draw definitive safety conclusions.

The causality of more serious conditions, such as hepatotoxicity, is unclear.18 There have been several cases of hepatotoxicity reportedly associated with black cohosh use.19 A workshop sponsored by the National Center for Complementary and Alternative Medicine and the National Institutes of Health Office of Dietary Supplements in November 2004 examined the safety and efficacy of black cohosh and commented on its hepatotoxicity.20 The hepatotoxicity reports associated at that time with black cohosh occurred in some cases with products containing only black cohosh, in other cases with a combination of botanicals, and still others with unidentifiable herbal products. The experts involved in the workshop recommended checking liver function tests prior to and during clinical trials involving black cohosh, and screening out people with pre-existing liver disease.

Concerns about endometrial hyperplasia in the face of possible estrogenic effects prompted a one-year prospective open-label study in 400 women taking 40 mg daily of the standardized extract BNO 1055.21 The study failed to find abnormalities as demonstrated by endometrial biopsy.21

An isolated case of toxic myopathy was also observed in a 54-year-old woman taking Remifemin.22

In Germany, partly due to the lack of data, black cohosh use is approved only for a duration of six months.2

Conclusion

Black cohosh is a commonly used herb and one grounded in traditional medicine. Although data are mixed about whether black cohosh has estrogenic effects, in vitro studies of black cohosh point to a variety of phytochemical constituents and physiological effects that could explain its potential benefits in alleviating menopause symptoms. Numerous clinical trials and review articles seem to indicate that 40-80 mg daily of a standardized extract of black cohosh improves menopausal symptoms such as hot flashes. Negative trials may be the result of inadequate dose and duration of treatment. Subsets of patients, such as those early in menopause or with moderately severe symptoms, may benefit more from black cohosh. Black cohosh is generally well-tolerated; however, there have been a few reports of hepatotoxicity.

Recommendation

With concerns about hormone replacement in menopause and a lack of other tested therapies, black cohosh is one consideration for women suffering from hot flashes. In line with published clinical trials, use a standardized extract, such as Remifemin or BNO 1055, and begin at 20 mg twice daily. Consider testing liver function tests at baseline and occasionally during therapy, and use cautiously, if at all, in women with pre-existing liver disease, a history of breast cancer, or a strong family history of breast cancer, until more data surface to further guide use.

References

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2. Richardson MK. Black cohosh: Will there ever be an answer or answers? Menopause 2006;13:164-165.

3. Low Dog T. Menopause: A review of botanical dietary supplements. Am J Med 2005;118(Suppl 12B):98-108.

4. Kligler B. Black cohosh. Am Fam Physician 2003;68:114-116.

5. Carroll DG. Nonhormonal therapies for hot flashes in menopause. Am Fam Physician 2006;73:457-464.

6. Seidlova-Wuttke D, et al. Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: Comparison with estradiol-17beta. Eur J Endocrinol 2003;149:351-362.

7. Wuttke W, et al. Effects of black cohosh (Cimicifuga racemosa) on bone turnover, vaginal mucosa, and various blood parameters in postmenopausal women: A double-blind placebo-controlled, and conjugated estrogens-controlled study. Menopause 2006;13:185-196.

8. 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 Womens Health Gend Based Med 2002;11:163-174.

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11. Wuttke W, et al. Efficacy and tolerability of the Black cohosh (Actaea racemosa) ethanolic extract BNO 1055 on climacteric complaints: A double-blind, placebo- and conjugated estrogens-controlled study. Maturitas 2006 Aug 21; [Epub ahead of print].

12. Pockaj BA, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol 2006;24:2836-2841.

13. Nappi RE, et al. Efficacy of Cimicifuga racemosa on climacteric complaints: A randomized study versus low-dose transdermal estradiol. Gynecol Endocrinol 2005;20:30-35.

14. Osmers R, et al. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol 2005;105(5 Pt 1):1074-1083. Erratum in: Obstet Gynecol 2005;106:644.

15. Frei-Kleiner S, et al. Cimicifuga racemosa dried ethanolic extract in menopausal disorders: A double-blind placebo-controlled clinical trial. Maturitas 2005;51:397-404. Epub 2004 Dec 10.

16. Jacobsen JS, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001;19:2739-2745.

17. Hernandez Munoz G, Pluchina S. Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas 2003;44(suppl 1):S59-S65.

18. Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58-64.

19. Lynch CR, et al. Fulminant hepatic failure associated with the use of black cohosh: A case report. Liver Transpl 2006;12:989-992.

20. National Center for Complementary and Alternative Medicine and the NIH Office of Dietary Supplements, Hepatotoxicity: Workshop on the Safety of Black Cohosh in Clinical Studies. Available at: http://nccam.nih.gov/news/pastmeetings/blackcohosh_mtngsumm.htm. Accessed Oct. 9, 2006.

21. Raus K, et al. First-time proof of endometrial safety of the special black cohosh extract (Actaea or Cimicifuga racemosa extract) CR BNO 1055. Menopause 2006;13:678-691.

22. Minciullo PL, et al. Muscle damage induced by black cohosh (Cimicifuga racemosa). Phytomedicine 2006;13:115-118. Epub 2005 Jun 24.