By Adriane Fugh-Berman, MD, and Fredi Kronenberg, PhD
The recent definitive finding from the women’s health initiative that hormone replacement therapy (HRT) is associated with increased risk of cardiovascular events, stroke, and breast cancer has caused shock waves in both the medical and consumer community. Although it is very clear that HRT imparts no cardiovascular benefit in any population of women, HRT does help hot flashes and vaginal dryness. Even symptomatic women, however, may think twice before choosing the recently delineated risks of HRT. Alternative treatments for symptoms may well become more popular. This article will review the evidence for herbs and menopausal symptoms.
Herbs that have been used for menopause include black cohosh (Actaea racemosa, syn. Cimicifuga racemosa), chaste tree berry (Vitex agnus-castus), dong quai (Angelica sinensis), ginseng (Panax species), evening primrose oil (Oenothera biennis), wild yam (Diascorea villosa), motherwort (Leonurus cardiaca), red clover (Trifolium pratense), linden flower (Tilia platyphylla), yarrow (Achillea millefolium), licorice (Glycyrrhiza glabra), and mixtures of Chinese herbs.
Black Cohosh
Limited evidence supports the use of black cohosh for menopausal symptoms. Virtually all clinical studies of black cohosh have used the standardized product Remifemin® (however, over time the formulation has changed from liquid to tablets, and the dose has changed, so different products with the same name were tested).
Only two of five randomized, controlled trials (RCTs) of black cohosh for hot flashes were placebo-controlled (a third placebo- controlled trial examined only hormone levels).1 Of the two randomized, double-blind, placebo-controlled trials, one study in 85 breast cancer survivors, 59 of whom were on tamoxifen, found no benefit of Remifemin (40 mg/d ´ two months) for hot flashes.2 In an older study of 80 "climacteric" women, Remifemin (4 mg bid ´ three months) was more effective than conjugated estrogens (0.625 mg/d) or placebo in affecting the Kupperman menopausal symptom index and vaginal epithelium3 (the finding that estrogen did not affect vaginal epithelium nor menopausal symptom score may render other findings untrustworthy).
Two other trials (lacking a placebo control) have compared Remifemin to estrogens. A randomized, open, three-month trial in 60 women ages 45-60 with menopausal symptoms compared Remifemin (40 drops bid) to conjugated estrogens (0.25 mg/d) or diazepam (2 mg/d); all treatments reportedly reduced scores on the Kupperman index.4 Another randomized treatment- controlled trial in 60 symptomatic women (post-hysterectomy, but retaining at least one ovary) compared Remifemin tablets (4 mg bid) to estriol (Ovestin® 1 mg/d), conjugated estrogens (Presomen® 1.25 mg/d), or an estrogen/progesterone combination (Trisequens®) for six months; all groups improved.5
A placebo-controlled study in 110 menopausal women tested the effect of Remifemin 4 mg bid for two months on follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. There was no effect on FSH levels; LH levels were reported to be lower in the treatment group at two months. However, baseline values were not reported, rendering the results difficult to interpret.1
The mechanism of action of black cohosh is unknown, but is probably not due to phytoestrogens. Although formononetin, an estrogenic isoflavone, was previously reported to have been isolated from black cohosh extract,6 a recent examination of 13 populations of black cohosh, and samples of Remifemin, found no formononetin.7 Small amounts of biochanin, another isoflavone,8 and fukinolic acid9 have been isolated from C. racemosa roots.
No clinical trials of black cohosh have been longer than six months in duration, and most are only two or three months long. Even three months is too brief to show efficacy, because hot flashes are notoriously placebo-responsive, an effect that wanes after three months. Six months is adequate to assess efficacy, but is still too short to assess long-term safety.
The effects of long-term use of black cohosh are unknown. Two of the five RCTs examined estrogenic effects of black cohosh on vaginal epithelium; both reported a stimulatory effect.3,4 In vitro and in vivo studies are not yet consistent or sufficient. One of us (Dr. Kronenberg) is conducting a one-year study on the effects of black cohosh that will include endometrial thickness (the primary outcome is hot flashes; secondary outcomes include markers of bone metabolism and cognitive effects).
Red Clover
Red clover (Trifolium pratense) contains the phyto-estrogens formononetin, biochanin A, daidzein, and genistein,10 which are presumed beneficial for menopausal symptoms. Two three-month randomized, double-blind, placebo-controlled clinical trials of Promensil (containing 40 mg total isoflavones) conducted in Australia (one with 37 postmenopausal women, the other with 51) reported no significant benefit of red clover extract for hot flashes.11,12
Evening Primrose
Oil of evening primrose (Oenothera biennis) contains the prostaglandin E1 precursor gamma-linolenic acid.13 Evening primrose oil (EPO, 2,000 mg and 20 mg vitamin E twice daily ´ six months) was evaluated for hot flashes in a randomized, double-blind, placebo-controlled clinical trial of 56 menopausal women; no benefit of EPO was found. Evening primrose oil is a benign treatment. (Although the assertion that EPO causes seizures or decreases seizure threshold in phenothiazine-treated patients has been repeated in many publications, there have been no reliable published reports of such an effect. EPO was briefly used to differentiate electroencephalographic findings of temporal lobe epilepsy from schizophrenia,14 which may be the genesis of this claim.)
Yam Cream
A double-blind, placebo-controlled crossover trial found no benefit of wild yam cream over placebo in 23 symptomatic menopausal women treated for three months.15 There was no difference between groups in incidence of hot flashes or night sweats (both improved slightly in both groups). There were no changes from baseline in body weight, blood pressure, serum estradiol or salivary progesterone levels, blood lipids, or glucose.
Ginseng
One randomized, double-blind, placebo-controlled clinical trial in 384 menopausal women tested Ginsana® (containing 100 mg Panax ginseng standardized extract G115 ´ 14 weeks) for menopausal symptoms and quality-of-life measures.16 No effect was seen on hot flashes, endometrial thickness, vaginal maturation index, or FSH. Although no estrogenic effects were noted in this study, case reports have associated ginseng with postmenopausal bleeding;17,18 one case occurred after topical use of a ginseng-containing face cream19 (these products were not examined for adulterants).
Chinese Herbs
A randomized, double-blind, placebo-controlled clinical trial in 78 menopausal women found no benefit of a Chinese herb mixture for three months.20 The same combination of herbs was given to each woman.
Dong Quai
Dong quai (Angelica sinensis), a Chinese herb, was tested in a randomized, double-blind, placebo-controlled clinical trial in 71 women who received capsules containing 4.5 g placebo or dong quai root/d ´ six months; dong quai was not superior to placebo for hot flashes.21 Traditionally, however, dong quai is rarely used alone; it almost always is used as part of a mixture. Dong quai does not contain the typically reported phytoestrogens, and there is conflicting data on stimulation of estrogen receptor-positive breast cancer cells or binding to estrogen receptors.22,23 Dong quai contains coumarins and can cause bleeding when administered concurrently with warfarin;24 the furocoumarins it contains can cause photosensitization and photodermatitis.25
Other Herbs
No clinical trials of motherwort, linden flower, yarrow, or licorice for hot flashes have been performed. No serious adverse effects have been reported in the medical literature for linden, yarrow, or motherwort; there is very little information of any kind in the scientific literature on these herbs.
Glycyrrhizinic acid in licorice inhibits 11 b-hydroxysteroid dehydrogenase, and can cause a state of apparent mineralocorticoid excess; licorice has been associated with hypertension, hypokalemia, edema, and preterm birth.26 However, almost all adverse effects associated with licorice have been associated with consumption of licorice candies, gums, and liqueurs, and no cases of licorice toxicity have been associated with traditional Chinese medicine, although it is a common component of herbal mixtures.
Conclusion
In summary, among herbs tested for hot flashes, limited evidence supports a beneficial effect only for black cohosh (and long-term safety questions remain). Red clover has been shown ineffective in two trials; single trials show no effect of dong quai, wild yam, evening primrose oil, ginseng, and a Chinese herb mixture. Some of the trials of herbs were quite small and may have been underpowered, but it is clear that the herbs tested so far lack a dramatic effect.
References
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Fugh-Berman A, Kronenberg F. Herbs used for menopausal symptoms. Altern Ther Women's Health 2002;4(9):65-68.
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