Is Black Cohosh Estrogenic?

Source: Bodinet C, Freudenstein J. Influence of Cimicifuga racemosa on the proliferation of estrogen receptor-positive human breast cancer cells. Breast Cancer Res Treat 2002;76:1-10.

Abstract: Hormone replacement therapy is contraindicated in women with breast cancers due to concerns regarding the potential for breast cell proliferation. To determine the influence of black cohosh (Cimicifuga racemosa [CR]) on estrogen-dependent mammary cancers, these researchers conducted an in vitro investigation of the effect of an isopropanolic CR extract on the proliferation of estrogen receptor-positive breast cancer cells. The experiments were performed using the human breast adenocarcinoma (MCF-7) cell test system. The influence of CR extract on the proliferation of the MCF-7 cells was determined by measuring the incorporation of radioactively labeled thymidine. Under estrogen-deprived conditions, the CR extract significantly inhibited MCF-7 cell proliferation. Additionally, application of the CR extract inhibited estrogen-induced proliferation of MCF-7 cells. Moreover, the proliferation-inhibiting effect of tamoxifen was enhanced by the CR extract. Such data that suggest a non-estrogenic or estrogen-antagonistic effect of CR on human breast cancer cells lead to the conclusion that CR treatment may be a safe, natural remedy for menopausal symptoms in breast cancer.

Source: Kennelly EJ, et al. Analysis of thirteen populations of black cohosh for formononetin. Phytomedicine 2002;9:461-467.

Abstract: Black cohosh (Actaea racemosa L. syn. Cimicifuga racemosa L. Nutt.) is a promising natural alternative to hormone replacement therapy for treating menopausal symptoms, but the mechanism of action is not understood. The clinical actions of this plant have been attributed to the isoflavonone formononetin since 1985, when its presence was reported in a black cohosh extract. Others have since looked for formononetin, but have not detected it. These researchers looked for formononetin in extracts of black cohosh roots and rhizomes collected in 13 U.S. locations. The rhizome samples were extracted using 80% methanol, and the extracts were partially purified using solid-phase extraction to concentrate any isoflavonoids that might be present. The researchers tested for formononetin using thin-layer chromatography and high-performance liquid chromatography with a photodiode array detector and a mass spectrometer. Formononetin was not detected in any of the plant populations examined. Remifemin and CimiPure also were analyzed, and no formononetin or ononin (formononetin-7-glucoside) was found. Therefore, the clinically observed estrogen-like actions of black cohosh, such as reduction of hot flashes, likely are due to a compound, or combination of compounds, other than formononetin.

Comments by Mary L. Hardy, MD

Clinicians interested in using black cohosh want to know one thing: Is this herb estrogenic or not? The presence or absence of estrogenic activity has implications for both safety and efficacy, especially for patients who either do not want or are advised not to take estrogen. The confusion over the status of black cohosh began during its development as a modern phytomedicine in Germany. Because of the observed clinical effects on menopausal women, estrogenic activity was assumed. Since then, black cohosh routinely has been referred to as a phytoestrogen (a plant-based product that acts like an estrogen) and has even been called a SERM (selective estrogen receptor mediator). Earlier literature reported the presence of formononetin, a weak phytoestrogenic constituent, in the root of black cohosh. This was perplexing to botanists and other herbal experts who did not expect to find constituents common to the Fabaceae or bean family (the plant family of both soy and red clover) in such an unrelated species. Black cohosh belongs to the buttercup or Ranunculaceae family. So, in order to clarify this question we have to examine the evidence for three things: Does black cohosh contain a known phytoestrogen? Do black cohosh extracts (BCE) bind to estrogen receptors? Do BCEs demonstrate evidence of growth promotion generally associated with estrogen—especially in breast cancer cells? The abstracts selected for review this month address these issues.

Kennelly and colleagues in New York have done a rigorous analysis of multiple samples of black cohosh collected from the wild in 13 U.S. locations. The chemical methods were extacting and the results are consistent. No formononetin was found in any of the wild samples or in two commercial extracts tested. This should put to rest the mistaken data reported in 1985. This work was performed by the botanical research unit headed by Fredi Kronenberg, PhD, and is independent of any commercial sponsorship. There is no known phytoestrogen in black cohosh.

Estrogen receptor binding of BCEs has not been reported, although several investigators have checked for such activity. This lack of binding has been demonstrated for both the alpha and beta estrogen receptors.

The theoretical concern still remains, however, that extracts could affect the growth of estrogen-dependent cells, such as breast cancer cells, despite the lack of demonstrated estrogen receptor binding or activation. The work presented by Bodinet and Freudenstein addresses this concern directly. A common breast cancer cell line (MCF-7) was exposed to BCE in the absence of estrogen, in the presence of estrogen, and in the presence of tamoxifen, a SERM used in the treatment of breast cancer. BCE given alone inhibited cell growth. When estrogen was added, BCE blunted the growth usually seen with estrogen stimulation. The normal inhibitory effect of tamoxifen on breast cancer cell growth was enhanced by the addition of BCE. Although this work was performed by the German manufacturer that produces the main commercially available extract of black cohosh, the observation that BCE impedes cell growth of breast cancer cells in vitro has been confirmed by other observers. For example, a study by Amato confirms the lack of stimulation of MCF-7 cell lines by BCE as well as the lack of effect on a gene expression assay system and in intact mice.1 Similar lack of response was seen by Liu and colleagues using an in vitro system with a different breast cancer cell line (S30) and in an endometrial cell line.2 Finally, two other research groups have shown similar results with MCF-7 cells as well as another breast cancer cell line (T-47D).3,4 The in vitro data are robust and have been duplicated in multiple labs. BCEs do not promote growth in human breast cancer cell lines.

Human clinical trials, although limited, have not demonstrated estrogenic activity with one exception. Early uncontrolled clinical studies reported some effects on vaginal epithelium. Two recent clinical trials do not support the presence of an estrogen effect in patients. A study of breast cancer survivors, the majority of whom were taking tamoxifen, was conducted by Jacobson et al.5 The BCE was not statistically more effective than placebo in controlling hot flashes in this very difficult population. Notably, there was no change in FSH or LH levels. The largest clinical trial of BCE by uncomplicated menopause patients was conducted by Liske, from the German manufacturer.6 However, the trial recently was published in a peer-reviewed journal and showed no estrogenic effects of their BCE, marketed as Remifemin. Vaginal cytology and a number of hormone levels were measured. A statistically significant decrease in hot flashes was shown. So, the limited clinical data follow the in vitro data and do not show an estrogenic effect for BCE.

In summary, a robust body of in vitro data supports the notion that BCE is not a classical phytoestrogen because it does not bind to estrogen receptors and does not promote growth in estrogen-sensitive assay systems. Clinically, although effect on menopausal symptoms has been reported, no estrogen effects can be demonstrated in human subjects either. So, although we don’t know the mechanism of action for black cohosh, it appears that BCE does not act through classic estrogen pathways. Clinicians can use this information to guide patients to effective therapy in the wake of the termination of the hormone replacement arm of the Women’s Health Initiative study. Because black cohosh does not appear to be estrogenic, it would be a reasonable option to consider in women who cannot or should not take conventional hormone replacement therapy.

Dr. Hardy is Medical Director at Cedars-Sinai Integrative Medicine Medical Group in Los Angeles, CA.

References

1. Amato P, et al. Estrogenic activity of herbs commonly used as remedies for menopausal symptoms. Menopause 2002;9:145-150.

2. Liu J, et al. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 2001;49:2472-2479.

3. Dixon-Shanies D, Shaikh N. Growth inhibition of human breast cancer cells by herbs and phytoestrogens. Oncol Rep 1999;6:1383-1387.

4. Zierau O, et al. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol 2002;80:125-130.

5. Jacobson 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.

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