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By Adriane Fugh-Berman, MD, and Dennis V.C. Awang, PhD, FCIC
Black cohosh [cimicifuga racemosa (l.) nutt., syn. actaea racemosa L.] has become a popular treatment for hot flashes and other menopausal symptoms. A member of the buttercup family (Rananculaceae), black cohosh is a perennial woodlands plant, native to North America, that produces 1-1.5 m racemes bearing numerous small (1 cm) white or cream flowers, with prominent protruding stamens. Other names include black snakeroot, bugbane, bugwort, rattleroot, rattletop, and rattleweed. Insects avoid it, which accounts for some of its common names.
The rhizomes (underground stems) of black cohosh are used medicinally; small amounts of root occasionally survive harvesting. Traditionally used by North American Indians for rheumatism, kidney disorders, and malaise, black cohosh became extremely popular among "Eclectic" practitioners (alternative practitioners of the 19th century), who called black cohosh "macrotys" and prescribed it primarily for gynecological problems, including amenorrhea, menorrhagia, dysmenorrhea, endometritis, infertility, threatened abortion, and labor pains.1
Neither the identity of the plant’s active constituents nor its precise mode of action is yet known. At least three classes of compounds have been proposed as active principles: triterpene glycosides; organic acids and esters; and flavonoids. Triterpene glycosides include principally the xylosides, actein, 27-deoxyactein,2 27-deoxyacetylacteol (these are actually 26-deoxyactein and 26-deoxyacetylacteol),3 cimicifugoside (cimigoside),2,4 cimicifugoside M,2 cimiaceroside A, and others.5 Eight cimiracemosides (A-H), triterpene arabinosides and xylosides, were isolated from a standardized extract of black cohosh;6 however, the cineracemoside A of Shao et al is different from that of Bedir and Khan, which appears identical to cineracemoside F.6 Recently, cimiracemosides I and J have been discovered (NR Farnsworth, personal communication).
The class of organic acids and esters includes the recently identified constituent, fukinolic acid (2E-caffeoylfukiic acid), which has showed estrogenic activity in vitro in a breast cancer cell line and in vivo (increased uterine weight in rats). Hydroxycinnamic acid esters of fukiic and piscidic acids, cimicifugic acids A, B, E, and F, as well as ferulic, isoferulic, and caffeic acids, also were identified.7 Salicylic acid also has been reported.8 Flavonoids also are found in black cohosh. Formononetin, known to be a phytoestrogen, was reported in a methanol extract of the dried rhizome of C. racemosa,9 but a more recent analysis of commercial ethanolic solutions and two extracts prepared from the dried rhizome (a 60% ethanol extract and a 40% isopropanol-water extract) failed to detect the isoflavone, although other flavonoids (unidentified) were claimed to be present.10 Small amounts of the isoflavone biochanin A also have been identified in C. racemosa alcohol preparations.11 Other black cohosh constituents reported include tannins and 15-20% cimicifugin (macrotin), an amorphous resinous substance, and a bitter principle, racemosin.12
Preparations and Dosages
Most clinical studies have been done with a commercial standardized black cohosh preparation, Remi-femin®. Each tablet contains 20 mg of black cohosh extract, containing 1 mg triterpenes (calculated as 27-deoxyactein). The current recommended dose is 20 mg twice daily. However, both the formulation and dosage of Remifemin have changed during the past 40 years, so studies done with earlier versions of the product may not be applicable to the current version. Originally sold as a liquid ethanolic extract, the preparation form subsequently was changed to tablets containing an isopropanolic extract. The tablet dosage also has changed from 2 to 20 mg/tablet. Remifemin currently is distributed by GlaxoSmithKline.
Other preparation forms include teas or capsules of dried root/rhizome (commonly 40-200 mg dried root/rhizome/d, but some recommend dosages are as high as 1 g tid); liquid extract (1:2) 1.5-3.0 ml/d, or tincture (1:10, 60% ethyl alcohol) 0.4-2 ml/d; or alcohol extract equivalent to 40 mg root/rhizome/d.13 A six-month dosing study of black cohosh extract (40 or 127 mg/d) found no difference between the two dosages in improving Kupperman index scores.14 (The Kupperman index, used in many black cohosh studies, is an older scale of menopausal symptoms that does not include vaginal dryness but does include formication, the sensation of insects crawling under the skin.)
Few controlled trials of black cohosh exist, and placebo-controlled trials are especially scarce.
A recent randomized, double-blind, placebo-controlled trial in breast cancer survivors age 18 years and older who were experiencing daily hot flashes found no effect of black cohosh on hot flashes but found a significant effect on excessive sweating.15 Eighty-five women with breast cancer (59 on tamoxifen) took one tablet twice daily of placebo or black cohosh (the preparation is not identified further in the paper) for two months; outcome measures included hot flash frequency and intensity by diary, a menopausal symptom index (including excessive sweating, palpitations, headaches, poor sleep, depression, and irritability), and a visual analog scale of overall health and well-being. Sixty-nine subjects completed the study. The frequency and intensity of hot flashes decreased in both groups, with no significant difference between the groups. Other symptoms assessed improved in both groups; only excessive sweating decreased significantly more in the treatment group than in the placebo group. There was no difference between groups in other symptoms and scores on the global health and well-being scale were not affected in either group.
Two months is a relatively short period of time for a trial of herbs for hot flashes, which are notoriously placebo-responsive. Additionally, hot flashes caused by tamoxifen may be more difficult to treat than normal menopausal hot flashes.
Another randomized, double-blind, placebo-controlled trial in 80 menopausal women compared 4 mg Remifemin bid to placebo or 0.625 mg/d conjugated estrogens.16 At 12 weeks, Kupperman index and Hamilton anxiety (HAM-A) scale scores were significantly lower in both treated groups compared to the placebo group. This is one of the few studies that assessed vaginal epithelium, and also one of the few that assessed hot flashes separately from other symptoms. Vaginal epithelium was significantly improved in the Remifemin group. Daily hot flashes decreased from 4.9 to 0.7 in the Remifemin group; from 5.2 to 3.2 in the estrogen group; and from 5.1 to 3.1 in the placebo group.
A six-month study in 60 women who had undergone hysterectomy but maintained at least one ovary found black cohosh extract (Remifemin 4 tablets/d) comparable to three estrogen regimens: estriol (1 mg/d), conjugated estrogens (1.25 mg/d), or sequential therapy (estradiol 2 mg and norethisterone acetate 1 mg) on Kupperman index scores at 1, 2, 3, and 6 months.17
An open, randomized, three-month-long trial in 60 symptomatic women (80% postmenopausal) compared Remifemin liquid (40 drops bid) to conjugated estrogens (0.625 mg/d) or diazepam (2 mg/d).18 All treatments improved the Kupperman index, a self-assessed depression scale, and the HAM-A scale.
Six months of treatment with 40 or 127 mg/d of Remifemin caused no changes in prolactin, estradiol, sex hormone-binding globulin, luteinizing hormone (LH), or follicle-stimulating hormone (FSH) in one study.14 Other studies also have found that black cohosh does not affect LH or FSH.15,17 One trial of 110 menopausal symptomatic women treated with 8 mg Remifemin/d for eight weeks found significantly lower mean LH (but not FSH) levels in the treated group compared with the control group.19 However, the report does not indicate that baseline levels of hormones were drawn, so it is not clear that groups were comparable at trial initiation.
One placebo-controlled, double-blind trial of black cohosh showed estrogenic changes in vaginal epithelium,16 but another study of two Remifemin doses (40 or 127 mg/d) found that six months of treatment caused no changes in vaginal epithelium.14
In vitro and in vivo estrogenicity studies have been mixed. Black cohosh increased uterine weights (an in vivo test of estrogenicity) in two studies of ovariectomized mice;20,21 a third showed no estrogenic effects in mice given oral doses or rats given subcutaneously injected doses.22
A recent test of black cohosh in several in vitro estrogenicity assays showed no estrogenic activity.23 Al-though four in vitro cell culture studies found that ex-tracts of black cohosh did not stimulate breast cancer cell growth,24-27 the most recent study found that black cohosh significantly increased breast cancer cell growth compared with control (the effect was equivalent to 17-beta-estradiol).20
A constituent of black cohosh, fukinolic acid, increased growth of MCF-7 breast cancer cells; again, the effect was similar to estradiol.7
Side effects of black cohosh include gastrointestinal discomfort or a frontal headache; nausea, dizziness, and bradycardia also have been attributed to black cohosh.13
The effects of black cohosh on endometrial or breast tissue stimulation have not been well delineated. No studies examining the uterine effects of black cohosh in humans have been completed. The recent Jacobson study of black cohosh in breast cancer survivors notes one case of endometrial hyperplasia, another of vaginal bleeding, a hysterectomy, and a D&C among black cohosh-treated women (all of whom also were taking tamoxifen). Certainly vaginal bleeding and endometrial hyperplasia have been associated with tamoxifen use, but no information is provided that would reassure the reader that black cohosh was not a contributor to the adverse event. Additionally, one case of arrhythmia (not otherwise defined, but classed as a "minor" adverse event) was reported in a black cohosh-treated patient who was not taking tamoxifen.
Adverse Birth Outcome
Black cohosh is used by midwives; it may be combined with the unrelated blue cohosh (Caulophyllum thalictroides) to prepare for labor or strengthen or restart contractions. There is a case report of neurological complications in a post-date baby after labor induction with a mixture of black cohosh and blue cohosh given during a home birth.28 After an apparently normal labor, a 3,840 g female was born with no spontaneous breathing; mechanical ventilation was necessary, and hypoxic injury of the basal ganglia and parasagittal area was demonstrated by CT scan. At age 3 months the baby had lower limb spasticity and required nasogastric feeds.
Blue cohosh contains the vasoconstrictive and oxytocic glycoside caulosaponin and is more likely to be associated with this adverse event than black cohosh.
Black cohosh traditionally has not been used for long periods of time, and no published studies have followed women for more than six months. Although short-term use for hot flashes or other menopausal symptoms may be useful, long-term use (more than six months) should be avoided until studies of estrogenic effects in humans are completed. Women with breast cancer should be advised to avoid black cohosh until its effects on breast tissue have been better established.
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