Black Cohosh Use in Menopause
By Monica J. Stokes, MD, FACOG, ABHM
Black cohosh (actaea racemosa l., syn. cimicifuga racemosa L. Nutt.; Family: Ranunculaceae) has long been used by indigenous North American cultures to treat a wide variety of maladies including rheumatism, menstrual complaints, and a range of menopausal symptoms.
In the mid 1800s, the Eclectic Physicians reported black cohosh use to reduce the discomfort of the first stage of labor, apparently by increasing contractile rhythmicity while it softened cervical tissues.1 In the late 19th and early 20th centuries, black cohosh composed the major herbal portion of the famous Lydia Pinkham’s Vegetable Compound (which also contained 18% alcohol),2 a remedy sold for "female complaints," a reformulation of which remains available even today.
In 1989, based partially on 33 years of use in Germany, the German Commission E approved black cohosh as a treatment for dysmenorrhea, premenstrual discomfort, and menopausal symptoms including palpitations, hot flashes, irritability, nervousness, sleep disturbances, vertigo, sweating, tinnitus, and depression. The Commission E limited the recommended duration of treatment to six months because no clinical studies had verified safety beyond this time period, making close clinical follow-up after that period prudent.3 In 2001, the American College of Obstetricians and Gynecologists added black cohosh to its published clinical practice guidelines for the treatment of menopausal symptomatology with the same six-month disclaimer.4
Constituents and Mechanism of Action
Currently, more than 135 over-the-counter supplements contain black cohosh, most containing small amounts in combination with several other herbs, minerals, and/or vitamins.5 Present-day black cohosh supplements are extracts of the dried rhizomes (underground stems) and roots.
Although the active constituents of black cohosh have not been determined conclusively, it is thought that the triterpene glycosides, the organic acids, or esters (or a complex interaction of these) may contribute to its observed clinical effects. The isoflavone formononetin, originally thought to be present in methanolic extracts,6 has not been found in more recently available commercial products,7 although small amounts of flavonoids have been detected.8 Different components are minimized or lost with different extraction processes. The exact mechanism of action of black cohosh is yet to be determined.
Clinical Studies
Estrogenicity of Black Cohosh. Reports regarding the actual estrogenicity of black cohosh are mixed. Early studies reported the observation of selective suppres-sion of luteinizing hormone (LH) (or a modulation of its pulsatile release), assumed to be via an estrogen-like mechanism.6,9
In 1987, Stoll et al performed the first randomized, double-blinded, placebo-controlled study with 80 menopausal women comparing the symptom-ameliorating effects of Remifemin (80 mg/d equivalent dose), placebo, and 0.625 mg of conjugated estrogens over a 12-week period.10 Use of Remifemin was associated with significant improvements in somatic and psychological measures of effectiveness including an increase in proliferation status of the vaginal epithelium. The authors concluded that black cohosh was an effective alternative to hormone therapy for symptom relief with no adverse estrogenic side effects (safe and tolerable), but a probable estrogen-like mechanism of action.
Warnecke et al found similar vaginal epithelial stimulatory effects.11 Further indirect evidence for potential estrogen-receptor binding of black cohosh constituents came when ovariectomized rats, given a one-third human dose equivalent for three weeks, were noted to have an increase in uterine weight.12
More recent investigations, however, reveal that it is much less likely that there is an estrogen-identical mechanism of action. The LH suppression noted in the Duker et al study9 was not validated in later clinical trials. Remifemin dose-comparison studies by Liske et al showed no effect on vaginal cytology, follicle-stimulating hormone (FSH), LH, sex hormone-binding globulin, prolactin, or estradiol levels, indicating no estrogen-like mechanism of action from isopropanolic extracts.13,14 In fact, no apparent estrogen-identical mechanism of action has yet been identified. Despite this, black cohosh has been found to be quite effective in the alleviation of several menopausal symptoms.
Use to Transition from Hormone Replacement Therapy. In 1987, Petho et al tested the ability to switch patients from hormone replacement therapy to black cohosh. In this un-controlled, community-based practice study using the 80 mg/d dose, they reported good or better response (decrease in the Kupperman Menopause Index) in approximately 80% of patients, although more than half of the patients required some hormonal supplementation (one estrogen injection) during the six-month trial.15
In 1982, Stolze tested the efficacy of Remifemin in a mixed population of more than 700 gynecologic practice-based patients previously taking hormone replacement therapy, psychoactive drugs, both, or neither and found more than 90% effectiveness.16 Transient stomach upset, the only adverse effect noted, was reported in fewer than 7% of the patients.
High- vs. Low-Dose Black Cohosh. A six-month study by Liske and Wustenburg compared the 40 mg/d vs. a 127 mg/d dose of Remifemin in 152 women with menopausal symptomatology.9 There was a considerable positive clinical response, as defined by the considerable decrease in the Kupperman Menopause Index, in approximately 90% of the patients by six months, and there was no increase in responsiveness with the higher dosage. It should be noted that most of the studies prior to 1998 used average dose equivalents of 80 mg/d and were open-label and un-blinded.
Use in Women with Estrogen Receptor-Positive Breast Cancer. Concerns exist regarding the use of black cohosh for treatment of menopausal symptoms in women with estrogen receptor-positive breast cancers. This issue stemmed from sources, such as those noted above, that assumed an estrogen-identical mechanism of action, and one in vitro study in 1999 that found that fukinolic acid (one constituent of black cohosh extract) stimulated the growth of MCF-7 breast cancer cells at a rate similar to estradiol.17
In 2002, Bodinet and Freudenstein directly addressed the potential influence of black cohosh on human breast adenocarcinoma (MCF-7 cell test system) cell lines.18 Cimicifuga racemosa extract (not just the isolated constituent, fukinolic acid, used in 1999) was found to: inhibit MCF-7 cell proliferation significantly when used alone; inhibit estrogen-induced proliferation of the same cell line; and enhance the proliferation-inhibiting effect of tamoxifen. This cell-line inhibition effect has been confirmed by Amato in intact mice and in a gene-expression assay system and by others using different breast cancer cell lines.19-22
In 2001, Jacobson and colleagues published the results of an eight-week randomized, double-blind, placebo-controlled trial of Remifemin to determine its effectiveness in treating hot flashes in women with a history of breast cancer, many of whom currently were using tamoxifen.23 The only parameter that showed a greater response with Remifemin than with placebo was sweating; both groups reported declines in the number and intensity of hot flashes. The study did not reveal any obvious estrogenic effects in this group of patients. One criticism is that the trial was of short duration.
Based on all of these studies and the fact that no known estrogen receptor-binding mechanism has yet been found, black cohosh currently is not contraindicated for use in women with a history of breast cancer. However, a recent 12-month study utilizing a murine model of breast cancer found that black cohosh, in a dosage proportional to that used in humans (40 mg daily), increased the incidence of metastatic spread to the lung. Black cohosh did not, however, increase the overall incidence of initial breast cancer development (unpublished results presented at the American Association for Cancer Research annual meeting, July 2003).
The question of safety of black cohosh use in women with a prior history of breast cancer is not likely to be put to rest until longer-term trials with larger numbers of participants are performed to conclusively prove or refute the apparent historical safety of black cohosh use for the treatment of menopausal symptomatology.
Adverse Effects
Black cohosh has no demonstrated contraindications, mutagenicity, teratogenicity, toxicity, or known drug interactions, despite decades of use of extracted products. Transient stomach upset and headache (that is not dose-related and resolves with discontinuation) are the only two significant associated adverse effects. Very rarely nausea and dizziness may occur.24
Use during pregnancy and lactation is not typically encountered, except in the late third trimester, during labor, and in early postpartum by midwives familiar and experienced with its safe dosing and use in these circumstances. Since more controllable, modern obstetrical methods are now available to accomplish what black cohosh was once used for, there currently is little or no practical reason to use the herb in this setting. Any complication even loosely associated with its use would be extremely difficult to defend.
A query of the Food and Drug Administration’s MedWatch web site, where reports of adverse effects of drugs and supplements are posted, revealed no entries for Cimicifuga or Actaea racemosa, black cohosh, or any of the other common names used.
Case reports of serious adverse effects (hypotension, acute hepatitis25) have been noted; however, causality cannot be conclusively assigned due to lack of exclusion of other causes for the observed effect or the use of a multi-herb combination.26,27 In other cases, contaminants and/or adulterants were not reliably excluded, or positive identification of the apparent offending agent was not made (potential misidentification).
Formulation and Dosage
Currently available commercial products (dedicated black cohosh) are primarily isopropyl/ethanolic extracts. The best studied of these products is Remifemin, which is made by the German company Schaper & Brummer GmbH & Co. and distributed by GlaxoSmithKline in the United States.
Studies conducted prior to 1996 are difficult to compare with those completed thereafter due to a change in the formulation and dosage of Remifemin. The formulation was changed from a liquid tincture to tablets and the dosage was changed from an average of 80 mg/d to 40 mg/d.
Today, each Remifemin tablet contains 20 mg of black cohosh extract containing 1 mg of triterpenes (measured as marker compound 27-deoxyactein). The recommended dosage is one tablet in the morning and one in the evening (40 mg per day). Up to 12 weeks of continuous use may be necessary to achieve full therapeutic response.28
Other preparations include dried root and rhizome, 0.5-1 g taken 3-4 times per day; liquid extract (1:2) 1.5-3 mL per day; and tincture (1:10) 6-12 mL per day.3
Remifemin should not be confused with Remifemin Plus, which contains St. John’s wort as an additional product component. It also is important to distinguish between black cohosh and blue cohosh. Blue cohosh is a completely different botanical (Caulophyllum thalictroides), used in the past for labor induction and augmentation, and has considerable adverse and toxic potential (abortifacient, teratogenicity, coronary artery constriction, etc).
Conclusion
The contraindications of hormone replacement therapy in certain subgroups of women will continue to be elucidated over time. The difficulty is that it is not yet known exactly which women are likely to benefit most from its use regarding potential disease prevention and which time frames of use are likely to yield the desired endpoints.
Extrapolations of adverse events in small numbers of women currently are being made to all menopausal women from large studies such as the Women’s Health Initiative. These events are being uncritically reported in the medical and lay literature, and many patients are suffering from symptoms that are seriously affecting their quality of life because they may be too fearful to initiate or continue low-dose hormone supplementation therapy. In large part because of this fear, more and more women are looking for safe, effective alternatives to hormone replacement therapy. While questions remain, black cohosh may be one of the more effective options available to those women.
Recommendation
Black cohosh extract has emerged as one of the safer therapeutic alternatives for the treatment of symptoms associated with menopause and can be used by patients prior to exposure to other non-hormonal pharmacologic agents for menopausal symptomatology. Black cohosh also can be used to help wean patients from or lower the dose of hormones used.
Practitioners should help patients choose a reputable product and underscore the need to use the recommended dosage for at least 12 weeks (in the absence of any persistent adverse effect) to determine individual effectiveness. Inform patients that the current recommendation is to limit continuous use of black cohosh to six months due to a lack of safety data beyond this time frame, but that this caution is not the result of strongly suspected adverse effects in humans.
Encourage patients to keep a record of their symptoms and responses, and ask them to return in three to six months with their record so you may re-evaluate symptoms and need for a change in treatment. Re-evaluation should closely parallel the follow-up of a patient on hormone supplementation, including evaluation for endometrial hyperplasia, until more data are accumulated on long-term safety of black cohosh.
Dr. Stokes has a consultative holistic, integrative medicine, and women’s health practice in San Francisco, CA.
References
1. Brinker F. Macrotys. The Eclectic Medical Journals 1996;2:2-4.
2. Foster S. Black cohosh, Cimicifuga racemosa—a literature review. HerbalGram 1999;46:35-50.
3. Blumenthal M, et al. Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications; 2000.
4. American College of Obstetricians and Gynecologists. Use of botanicals for management of menopausal symptoms. Practice bulletin #28. Washington, DC; 2001.
5. Natural Medicines Comprehensive Database. Available at: www.naturaldatabase.com.
6. Jarry H, Harnischfeger G. The endocrine effects of the contents of Cimicifuga racemosa. 1. Influence on the serum concentration of pituitary hormones in ovariectomized rats. Planta Med 1985;51;46-49.
7. Kennelly EJ, et al. Analysis of thirteen populations of black cohosh for formononetin. Phytomedicine 2002; 9:461-467.
8. Struck D, et al. Flavones in extracts of Cimicifuga racemosa. Plant Med 1997;63:289.
9. Duker EM, et al. Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med 1991;57: 420-424.
10. Stoll W. Phytopharmacon influences atrophic vaginal epithelium: Double-blind study—Cimicifuga vs. estrogenic substances [German]. Therapeutikon 1987;1:23-31. Cited in: Blumenthal M. The ABC Clinical Guide to Herbs. Austin, TX: American Botanical Council; 2003.
11. Warnecke G, et al. Influencing menopausal symptoms with phytotherapeutic agents: Successful therapy with Cimicifuga mono-extract [German]. Med Welt 1985; 36:871-874.
12. Eagon PK, et al. Estrogenicity of medicinal botanicals [abstract]. Proc Am Assoc Cancer Res 1998;39:Abstract 2624. Cited in: McKenna D, et al. Black cohosh: Efficacy, safety, and use in clinical and preclinical applications. Altern Ther Health Med 2001;7:93-100.
13. Liske E, Wustenberg P. Therapy of climacteric complaints with Cimicifuga racemosa: An herbal medicine with clinically proven evidence [abstract]. Menopause 1998;5:250.
14. Liske E, et al. Physiological investigation of a unique extract of black cohosh (Cimicifuga racemosae rhizoma): A 6-month clinical study demonstrates no systemic estrogenic effect. J Women’s Health Gend Based Med 2002;11:163-174.
15. Petho A. Menopausal complaints: Changeover of a hormone treatment to an herbal gynecological remedy practicable? Arztl Praxis 1987;47:1551-1553.
16. Stolze H. An alternative to treat menopausal complaints. [German] Gynekolog 1982;1:14-16.
17. Kruse SO, et al. Fukiic and piscidic acid esters from the rhizome of Cimicifuga racemosa and the in vitro estrogenic activity of fukinolic acid. Planta Med 1999;65: 763-764.
18. 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.
19. Amato P, et al. Estrogenic activity of herbs commonly used as remedies for menopausal symptoms. Menopause 2002;9:145-150.
20. Zierau O, et al. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol 2002; 80:125-130.
21. Dixon-Shanies D, Shaikh N. Growth inhibition of human breast cancer cells by herbs and phytoestrogens. Oncol Rep 1999;6:1383-1387.
22. Nesselhut T, et al. Unterschungen zur proliferativen potenz von phytopharmaka mit ostrogenahnlicher wirkung bie mammakarzinom-zellen. Arch Gynecol Obstet 1993;254:817-818.
23. 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.
24. Mills S, Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine. London: Churchill Livingstone; 2000.
25. Whiting PW, et al. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust 2002; 177:440-443.
26. Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58-56.
27. Thomsen M, Schmidt M. Hepatotoxicity from Cimicifuga racemosa? Recent Australian case report not sufficiently substantiated [letter]. J Altern Complement Med 2003;9:337-340.
28. GlaxoSmithKline. Available at: www.remifemin.com/professional.
Stokes MJ. Black cohosh use in menopause. Altern Med Alert 2003;6(9):97-101.
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