Terra Sigillata

A proprietary extract of black cohosh (Actea racemosa) sold in the US and Europe as Remifemin has long been purported as an alternative to hormone replacement therapy in menopause and perimenopause. Several trials have questioned the efficacy of this herb (one discussed on this blog) and the NIH has been concerned about sporadic reports of liver toxicity associated with some preparations of the herb. In the literature, black cohosh has been described in various instances as a phytoestrogen, an antiestrogen, an estrogen-receptor modulator, or devoid of any estrogenic activity. So, even I am confused by a recent press release on two articles showing 1) lack of promotion of breast cancer risk factors and, more provocatively, 2) association with decreased breast cancer risk:

Many women are choosing dietary supplements for the management of menopausal symptoms — especially since serious health concerns have been raised about hormone replacement therapy (HRT). Remifemin(R) black cohosh extract, the most extensively researched, non-prescription menopausal therapy has been found to safely and effectively reduce hot flashes, night sweats and irritability. Now, a study published in the International Journal of Cancer: 120, 1523-1528 (2007), has shown that this proprietary herbal product lowers the risk of breast cancer by as much as 60%.

“The standardized Remifemin(R) black cohosh extract has antiestrogenic, antiproliferative and antioxidant properties,” said Dr. Eckehard Liske, Director of the International Medical Department, Schaper & Bruemmer GmbH & Co KG, Salzgitter, Germany. “Rebbeck’s research suggests that Remifemin(R) may help in reducing the risk of breast cancer.”

Something just doesn’t seem right about this work as a recent paper noted that a concentration of 77 micrograms/mL black cohosh extract was required to block breast cancer cell invasiveness by 51% in cell culture. Given that the recommended daily dose of this extract is 20 mg, there is no way that such concentrations could be achieved in patients. The press release also conveniently avoids recent trials showing no benefit of Remifemin brand of black cohosh extracts over placebo in alleviating the vasomotor symptoms of menopause.


But to claim that this extract can prevent primary risk or risk of recurrence of breast cancer seems like an even greater reach, although I am aware that similar findings were indeed published in a peer-reviewed journal (International Journal of Clinical Pharmacology and Therapeutics). In this other paper, breast cancer recurrence was reduced by 17%, not the 60% claimed in the new International Journal of Cancer paper (the abstractnotes an odds ratio of 0.39 for black cohosh but 0.47 for black cohosh or Remifemin, hence my confusion). I’ll have to consult with some of my clinical colleagues to look at the methodology used in both of these papers. The latter, however, comes from the University of Pennsylvania and was supported by an NCI program project grant.

But for now, these claims for black cohosh seem to be more of a public relations campaign intended to capitalize on fears surrounding hormone replacement therapy. I welcome comments on this article if you have access to this full report or the newest paper in the International Journal of Cancer.

Comments

  1. #1 Roy Hinkley
    April 25, 2007

    Does the Henneicke-von Zepelin et al. paper mention progesterone receptor status? (I don’t have online access.)

    Because the MDA-MB-231 cells from (In Vivo 2007 Mar-Apr;21(2):349-55.) http://mend.endojournals.org/cgi/content/abstract/14/3/348
    are PR- negative.

    And the effects seen in Rebbeck et al. were not significant against PR(-) breast cancers.

    In contrast, the effect of black cohosh and/or Remifemin
    varied by PR status: the effect was significant in PR positive tumors
    (OR 5 0.36, 95% CI: 0.17, 0.78) but not in PR negative tumors
    (OR 5 0.62, 95% CI: 0.30, 1.29). While very preliminary, these results
    suggest that the effect of black cohosh and/or Remifemin may
    be greater in the ER positive and PR positive groups than in ER
    negative or PR negative tumors, although these differences are not
    large. In addition, these data suggest that PR activity may be related
    to the breast cancer protective effects of black cohosh/Remifemin
    because the effect of black cohosh and/or Remifemin was greater
    in PR positive tumors than in PR negative tumors.”

  2. #2 Cheryl Myers
    April 30, 2007

    I am the vice president of health sciences for Enzymatic Therapy, Inc., the company that distributes Remifemin in the United States. While I understand the confusion you express, related to mixed messages we are all receiving on black cohosh, I would like to offer what clarity I can. I do not pretend to have all the answers, because there is much research yet to be done to fully elucidate all the potential health benefits and mechanisms of action for Remifemin, which is obtained from black cohosh with a unique extraction process. However, there are three areas to which I’d like to respond: 1) the uneven track record on black cohosh research for vasomotor symptoms of menopause 2) questions concerning the current study showing a statistically significant breast cancer prevention effect. and 3) liver concerns.

    1) While I am aware that there are conflicting studies on black cohosh efficacy for menopausal symptoms, I would like to offer one illustration. The science staff at our company strongly encouraged Dr. Pockaj of the Mayo Clinic to extend the length of her proposed black cohosh trial, as previous work with Remifemin showed significant effects after 12 weeks, not 6 weeks. We were very concerned that a shorter duration trial would not yield results. Dr. Pockaj chose to proceed with a short duration trial. We were pleasantly surprised when her study using Remifemin did yield significant results-her conclusion states: Black cohosh appeared to reduce hot flashes and had a low toxicity. The efficacy found in this trial seems to be more than would be expected by a placebo effect (20%-30% hot flash reduction in previous trials). These results suggest that further evaluation of this black cohosh preparation with a phase III randomized trial is indicated.

    Dr. Pockaj then used a different black cohosh preparation for her follow up study�also only 6 weeks in duration. This study failed to find significant impact on hot flash reduction [Pockaj BA, Gallagher JG, Loprinzi CL, 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 Jun 20;24(18):2836-41.]

    Would this trial have achieved significance if it had been of longer duration? Perhaps. However, this illustrates some of the unevenness we encounter when looking at studies on herbs: the extraction processes of the herb, the company supplying the test product, the length of the trial, the dose, the physical status of the participants, all can impact outcome. Often, all these parameters are not included in the published paper, and we are left to assume we are comparing apples to apples when in fact we may have a few oranges on our hands.

    2) The recent study indicating that Remifemin has an impact on breast cancer was not supported in any way by Enzymatic Therapy, Inc. and was published in a peer-reviewed journal. We had an idea that Remifemin might offer a protective effect based on an earlier study, a pharmaco-epidemiological retrospective cohort study on breast cancer occurrence and recurrence free survival that was first presented as a lecture and later published. [H.H. Henneicke-von Zepelin, H. Meden, K. Kostev, D. Schroder-Bernhardi, U. Stammwitz and H. Becher. Isopropanolic black cohosh extract and recurrence-free survival after breast cancer. International Journal of Clinical Pharmacology and Therapeutics. Vol. 45 No. 3/2007 (143-154).] This study showed that, not only did Remifemin NOT increase risk for breast cancer or recurrence, it showed a potential protective effect. The researchers found that, of the participants who developed breast cancer, 14% of the non-Remifemin group had a recurrence at the 2 year mark. However, it was not until 6.5 year mark that 14% of the Remifemin users with previous breast cancer developed a recurrence of their breast cancer. We found this significant, prolonged disease-free survival very intriguing.

    As for the “up to 60% reduction” claim: Of the 1582 women in this study, 43% (677 women) developed breast cancer. In the Remifemin/black cohosh group, only 18-25% developed breast cancer (depending upon group total or subgroup). Therefore, the difference between the overall breast cancer occurrence observation of the study and the Remifemin/black cohosh groups was between 42% and 60% less than that observed for the study cohort as a whole.

    3) Remifemin has been used in Germany for decades without significant adverse effects. In addition, one study specifically examined the effects of Remifemin on liver enzyme concentration and found no alterations following supplementation. The randomized, double-blind, placebo-controlled trial revealed that Remifemin does not elevate liver enzyme activity in peripheral blood [Osmers R, Friede M, Liske E, Schnitker J, Freudenstein J, Henneicke-von Zepelin H-H. Efficacy and Safety of Isopropanolic Black Cohosh Extract for Climacteric Symptoms. Obstet Gynecol 2005;105:1074-83]. When compared to placebo, there was no statistically significant difference in liver enzyme activity. The maximum increase in liver enzyme activity and the posttreatment ranges for aspartate amino transferase, alamine amino transferase, and gamma-glutamyl transferase were similar for both the placebo and Remifemin groups.

    We are not aware of any serious liver issues reported with Remifemin. The most well-publicized black cohosh case “Fulminant hepatic failure associated with the use of black cohosh: a case report” was not Remifemin. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=PubMed] The patient was taking 1000 mg daily of black cohosh. That is opposed to our recommended 20-40 mg twice daily.

    In the other well publicized black cohosh/liver case, a woman sued after needing a liver transplant. The case was dismissed for lack of scientific merit, and because it was found the woman in question was not truthful in her deposition. The black cohosh was not Remifemin. [http://www.nutraingredients-usa.com/news-by-health/news.asp?id=70681&idCat=133&k=black-cohosh-liver]

    There is additional information on black cohosh safety made available by the American Botanical Council (ABC), available at: http://www.herbalgram.org/herbclip/review.asp?i=44736
    The ABC is a leading independent, non-profit, organization providing education using science-based and traditional information to promote the responsible use of herbal medicine. The ABC also publishes HerbalGram, the journal of the ABC.

    I know this has been a long posting, and I thank those of you who took the time to read this response. It is our belief that a time-tested, safe product like Remifemin is the superior choice for many women who struggle with the menopausal transition. When used as directed, this product can yield excellent benefits for women without increasing their risk for breast or uterine cancer – or heart disease or deep vein thrombi – risks now associated with hormone replacement therapy (HRT). Many women have moved away from HRT because of new information on these risks, and I am proud to work for a company that can offer a safe and effective option.

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