Black Cohosh for Prostate Cancer: It's Not Just for Women Anymore

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 2 of a Series on Black Cohosh

One of the most well-known herbs for women, black cohosh, may indeed have efficacy in a male condition: prostate cancer. In vitro data and clinical evidence for the use of black cohosh in alleviating hot flashes of menopause, including tamoxifen-induced post-breast cancer hot flashes, led researchers to postulate the use of black cohosh in a condition that also involves sex hormone receptors. Investigations along these lines have led to some interesting results as summarized below.

History and Traditional Use

As detailed in a prior article,1 black cohosh is also known as black snakeroot, baneberry, bugbane, rattleroot, squawroot, and rattlesnake root, and it had a long history of use by Native Americans for snakebite, myalgias, rheumatic conditions, and a variety of gynecological concerns, such as amenorrhea, ovarian pain, and menorrhagia.2 It is a popular herb in Europe, and more recently the United States has caught on; black cohosh sales in the United States were $42 million in 2002, probably due to concerns about hormone replacement in menopause and women looking for alternative treatments.3

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.4,5

The presence of many other compounds (polyphenols, cycloartane glycosides, cinnamic acid esters, and caffeic acid derivatives such as fukinolic acid and cimicifugic acids A, B, E, and F) in black cohosh has been documented in the scientific literature and 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

Most of the published literature addressing the effect of black cohosh for the prevention or treatment of prostate cancer is limited to in vitro and animal studies exploring its possible mechanisms of action. However, intriguing data are surfacing showing that black cohosh extracts may be useful in both the prevention and treatment of prostate cancer.

Black cohosh has the ability to bind to the aryl hydrocarbon receptor (AhR), a receptor that mediates a variety of anticancer effects in both prostate and breast cancer cells.6 One research group followed up this finding by testing a standardized black cohosh extract (BNO 1055) in an AhR ligand assay and on androgen-sensitive human prostate cancer cells (type LNCaP) in vitro.7 The results of this study showed a statistically significant decrease in binding of a known ligand to AhR, and inhibited proliferation of LNCaP in a dose-dependent manner.

Furthermore, in other tests, black cohosh blocked the prostate cancer cell proliferation that normally happens in the presence of added estrogen or dihydrotestosterone. Given some of the doubts surfacing about the ability of black cohosh to bind to the known estrogen receptors alpha and beta, the researchers in this study mention that the anticancer effects may be mediated through AhR or some other unknown estrogen receptor.

Another group tested an isopropanolic-aqueous extract of black cohosh on LNCaP and two androgen-insensitive cell lines, PC-3 and DU 145.8 The black cohosh caused dose-dependent growth inhibition in all three cell lines (P < 0.001), and this inhibition was consistent with apoptosis as determined by flow cytometry. LNCaP was most susceptible to apoptotic cell death, occurring at a lower concentration than what was required to inhibit DU 145 and PC-3. The researchers also noted that induction of caspase, an enzyme involved in some apoptosis mechanisms, occurred in all three cells lines at a medium concentration (40 µg/mL) of black cohosh. The researchers conclude that black cohosh acts to induce apoptotic cell death, perhaps through the caspase system, and it seems to do so independently of androgen receptor status. Should these results be corroborated, a possible future use of a therapy like black cohosh would be to "prime" prostate cancer cells via caspase for more easily induced apoptosis (i.e., lower doses of chemotherapeutic agents and, hence, fewer side effects).

Given that some prostate cancer cells, such as the LNCaP line, are androgen-dependent, presumably due to the fact that testosterone is converted within the prostate by 5-alpha reductase to a potent prostatic growth stimulator 5-alpha dihydrotestosterone (DHT),9 5-alpha reductase has been the target of potential prostate cancer treatments. One research group found inhibition of this enzyme by black cohosh.10 Twenty rats per group were fed testosterone for five days with a subcutaneous injection of either a standardized black cohosh extract (BNO 1055), finasteride (a known 5-alpha reductase inhibitor), or nothing, and prostate size and weights, as well as prostate and serum testosterone and DHT concentrations, were compared. In both the black cohosh and finasteride groups there were statistically significant (P < 0.05) lower serum testosterone and DHT levels, as well as smaller prostates and seminal vesicles. By this indirect methodology, black cohosh appears to have some 5-alpha reductase inhibition comparable to finasteride, and this is being explored as a possible avenue to prevent and/or treat prostate cancer.

A study involving 36 mice inoculated with LNCaP prostate cancer cells, half of which then received the black cohosh extract BNO 1055 orally, followed tumor presence, tumor size, and serum prostate-specific antigen (PSA) and testosterone.11 At the end of the 10-week experiment, only five of 18 mice in the black cohosh group had detectable tumor, compared to 12 of 18 in the control group, though no statistical analyses were done on this result. In the black cohosh group, the tumor size was smaller (P < 0.05), the serum PSA was lower (P < 0.05), and there was more connective tissue versus carcinomatous cells (P < 0.05), though there was no difference in serum testosterone when compared to the control mice. These results show some in vivo effects of black cohosh on a murine model of prostate cancer.

In line with what consumers might be purchasing, five combination herbal products containing 2-7 different plants were tested on two cancer cell lines (PC-3 and 22Rv1) and in 30 mice (six groups, five mice per group including a control group).12 Two of the supplements appeared to be particularly effective (P < 0.05) in preventing the development of tumor as well as treating the tumor once present. Though the names of the products were not given, the authors did mention one of the particularly effective supplements contained the highest concentration of both black cohosh and licorice, and soy, dong quai, and vitex berry were also present. This is an interesting initial screen, but one that needs to be followed up with mechanistic studies and specifics about which plant or plants may actually be causing the effects observed.

Other mechanisms have been explored by breast cancer researchers. For example, there is some thought that black cohosh has selective estrogen receptor modifier activity, either via ER-alpha or ER-beta,13 or that it binds a third type of estrogen receptor or acts via a dopamine receptor system.6 These explorations are relevant given that estrogens interact with prostate cancer cells in a variety of ways that could contribute to growth or proliferation.14,15

Clinical Trials

Currently, there are no published clinical trials in Medline or PubMed on the use of black cohosh either in the treatment or the prevention of prostate cancer in humans. The above-mentioned mechanistic studies are intriguing and certainly deserve consideration when developing hypotheses about future prostate cancer therapies.

Dosage and Formulation

It is difficult to discuss appropriate dosages of black cohosh for prostate cancer treatment or prevention, given that the state of research is still in the in vitro and animal model stage. That said, human clinical trials in menopause 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 Klimadynon® (BNO 1055, a 58% aqueous ethanolic extract).3 Black cohosh tinctures are available; there is a wide variety of published recommended 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).2,4

Adverse Effects, Contraindications, and Drug Interactions

It is slightly premature to talk about adverse effects and contraindications until clinical trials determine the relevance of black cohosh therapy in prostate cancer. Nonetheless, clinical trials of black cohosh in menopause and case reports have demonstrated mild gastrointestinal upset, possible hepatotoxicity, and one case of toxic myopathy.16-19

Conclusion

There are in vitro and animal studies showing effects of black cohosh on both prostate cancer cells and some receptors involved in prostate cancer cell proliferation. Black cohosh binds to AhR (a receptor that inhibits prostate cancer cells), induces the apoptosis-causing enzyme caspase, hinders 5-alpha reductase, and inhibits the growth of both androgen-sensitive and androgren-insensitive prostate cancer lines. These effects translated into one mouse model showing the efficacy of a standardized black cohosh extract BNO 1055 on prostate tumor size and differentiation. There are still no human clinical trials taking these initial results to the next level.

Recommendation

Black cohosh has promise in prostate cancer prevention and treatment, acting at many different relevant physiological steps, as demonstrated by in vitro and animal models. However, it is too early to make a formal recommendation for its use in humans, given the complete lack of clinical data. It is not completely free from adverse effects, otherwise it could be a useful daily preventive until further data surface. At this point, the health care provider and patient can either wait for further guidance from the medical literature, or have a risk-benefit discussion about using black cohosh in the specific prostate cancer case. In the latter case, it must be emphasized that both risks and benefits to men have yet to be defined.

References

1. Kiefer D. Black cohosh for menopause: Is it still hot? Altern Med Alert 2006;9:133-137.

2. Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.

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

6. Jarry H, et al. In vitro effects of the Cimicifuga racemosa extract BNO 1055. Maturitas 2003;44(Suppl 1):S31-S38.

7. Jarry H, et al. Cimicifuga racemosa extract BNO 1055 inhibits proliferation of the human prostate cancer cell line LNCaP. Phytomedicine 2005;12:178-182.

8. Hostanska K, et al. Apoptosis of human prostate androgen-dependent and -independent carcinoma cells induced by an isopropanolic extract of black cohosh involves degradation of cytokeratin (CK) 18. Anticancer Res 2005;25(1A):139-147.

9. Negri-Cesi P, et al. Presence of 5alpha-reductase isozymes and aromatase in human prostate cancer cells and in benign prostate hyperplastic tissue. Prostate 1998;34:283-291.

10. Seidlova-Wuttke D, et al. Inhibition of 5alpha-reductase in the rat prostate by Cimicifuga racemosa. Maturitas 2006;55(Suppl 1):S75-S82. Epub 2006 Aug 22.

11. Seidlova-Wuttke D, et al. Inhibitory effects of a black cohosh (Cimicifuga racemosa) extract on prostate cancer. Planta Med 2006;72:521-526.

12. Ng SS, Figg WD. Antitumor activity of herbal supplements in human prostate cancer xenografts implanted in immunodeficient mice. Anticancer Res 2003;23:3585-3590.

13. 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.

14. Risbridger GP, et al. Oestrogens and prostate cancer. Endocr Relat Cancer 2003;10:187-191.

15. International Prostate Health Council Study Group. Estrogens and prostatic disease. Prostate 2000;45:87-100.

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

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

18. 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.

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