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Evid Based Nurs 13:29-33 doi:10.1136/dtb.2008.12.0031
  • Reprinted from DTB

Herbal medicines for menopausal symptoms

Reprinted from: [Abstract/FREE Full text]

Abstract

Many women are now using herbal medicines to try to relieve menopausal symptoms such as hot flushes and night sweats, in light of recent evidence suggesting that hormone replacement therapy (HRT) may increase the likelihood of breast cancer, ovarian cancer, venous thromboembolism, heart attacks and stroke.1,,6 For example, one survey has suggested that around 40% of women in the UK have used complementary and alternative treatments for their menopausal symptoms.7 Here we review the efficacy and safety of herbal medicines for the relief of such symptoms.

Menopausal symptoms

The menopause occurs at a median age of 53 years.8 The change in hormone levels during the perimenopause and menopause, particularly the decline in levels of oestrogen, can cause acute menopausal symptoms; for example, about 30–70% of women in Western countries will experience vasomotor symptoms, such as hot flushes and night sweats.9,10 Some women also report vaginal dryness and psychological symptoms, including tiredness, sleep disturbances, mood swings, forgetfulness and loss of libido.10 The median duration of menopausal vasomotor symptoms is about 4 years but, in around 10% of women, they last longer than 12 years.11

About herbal medicines

Herbal products can be obtained from a variety of retail outlets, as well as via the internet, at a wide range of prices. Such products are often assumed to be ‘safe’ on the grounds that they are ‘natural’, and many patients do not tell their doctors that they are taking herbs.12,13 In reality, however, herbal medicines have pharmacological actions, and so can cause unwanted effects and have potentially dangerous interactions with other medicines (both herbal and conventional).14,,16 Also, because most herbal medicinal products available in the UK are unlicensed, they do not have to comply with quality and good manufacturing practice regulations. This has resulted in cases of poor-quality unlicensed herbal remedies on the market (e.g. in some Ayurvedic and Chinese herbal products) with substitution of herbs with alternative, sometimes toxic, ingredients; contamination or adulteration, for example, with undeclared prescription-only pharmaceutical ingredients or heavy metals; and mislabelling.17

To improve the safety of herbal medicines, the UK Medicines and Healthcare products Regulatory Agency (MHRA) is implementing the Traditional Herbal Medicinal Products Directive.18,19 This will become fully operational after April 2011, at which time, all over-the-counter herbal medicines will have to conform with the Traditional Herbal Medicines Registration Scheme (except those already licensed as a medicine, which have a Product Licence [PL] number). The scheme has established a simplified registration procedure for manufactured traditional herbal medicinal products for human use that fulfil all of the following criteria: the traditional use is shown to be plausible and not to be harmful; there is evidence of traditional medicinal use for 30 years or more (15 years of which must have occurred within the European Union [EU]); the indications and composition are suitable for use without supervision of a medical practitioner; the product has a specified strength and posology; and it is available for oral, external and/or inhalation use.18 The registered herbal products are required to meet specific standards of safety and quality, and have patient information on their safe use. However, the scheme allows for the product to be registered based on a long tradition of use and without the need for clinical trials. The scheme does not cover products bought outside the EU. Under the scheme, there are already over 20 products with a Traditional Herbal Registration (THR) number on the UK market. Few herbal products are available as licensed medicines.

When buying herbal products, patients should be advised to buy, wherever possible, those with a PL number or a THR number on the product label.

Herbs for menopausal symptoms

Herbal medicines commonly used for menopausal symptoms include black cohosh (Actaea racemosa, formerly known as Cimicifuga racemosa); red clover (Trifolium pratense); Dong quai/Dang gui (Angelica sinensis); evening primrose (Oenothera biennis); and ginseng (Panax ginseng).12

Problems with the evidence

There has been a lack of studies of herbal medicines for menopausal symptoms. Also, many of the studies conducted have had limitations, such as design faults, small sample sizes (i.e. being underpowered) and short duration.20 As there is a wide range of different herbal preparations, trials may have used different preparations of the same herb, which are not chemically consistent, so making comparisons of the study results difficult. Several traditional herbal systems (e.g. Traditional Chinese Medicine) use mixtures, rather than single herbs, and there is little published research into use of such combinations as treatment for menopausal symptoms.

Black cohosh

Black cohosh is an indigenous North American plant, of which the root and rhizome are used medicinally. It has received considerable attention for its possible effects on menopausal symptoms.21,,28 No clear mechanism of action on such symptoms has been defined.

Oral doses traditionally used are 40–200mg daily of dried root and rhizome or ethanolic extracts equivalent to 40mg of dried root and rhizome.29 In the UK, Menoherb Film-coated Tablets, which contain 6.5mg of a dry 60% ethanolic extract of black cohosh (equivalent to 29.25mg to 55.25mg of dried root), have been given a THR for the following therapeutic indication based on traditional use only: “the relief of symptoms of the menopause, such as hot flushes, night sweats, and temporary changes in mood” (such as nervous irritability and restlessness).30 The dose of Menoherb is one tablet daily.

Clinical trials

Several published double-blind randomised controlled trials have assessed the effects of black cohosh for the relief of menopausal symptoms.21,,28

A 1-year placebo-controlled trial involving 351 women with two or more vasomotor symptoms per day found that black cohosh (160mg daily of an ethanol extract given alone or 200mg daily as part of a multi botanical regimen) had no significant beneficial effects on vasomotor symptoms23 or vaginal dryness.21 Two other placebo-controlled trials involving 132 women with 14 or more hot flushes weekly24 and 122 menopausal women with three or more hot flushes daily,25 respectively, also found no significant benefit on this symptom with black cohosh (one capsule twice daily of 20mg rhizome extract24, and one capsule daily of 6.5mg dried rhizome extract25). A fourth trial involving 62 postmenopausal women compared black cohosh (two capsules daily of aqueous/ethanolic extract corresponding to a daily dose of 40mg of herb), conjugated oestrogens and placebo; it found no significant difference between treatments in effects on menopausal symptoms, as measured by change from baseline to end point in the Menopause Rating Scale* (MRS) (the primary outcome measure).28

*The Menopause Rating Scale comprises 10 items (hot flushes/sweating, heart complaints, sleep disorders, depressive mood, nervousness/ irritability, fatigue/memory problems, sexual disorders, urinary symptoms, vaginal dryness, and joint and muscle symptoms). The total score ranges from 0 (asymptomatic) to 44 (most complaints).

By contrast, the results of three other trials have suggested benefit from black cohosh.22,26,27 One of these, a double-blind trial, compared black cohosh (liquid extract corresponding to 20mg of the herb) with tibolone in 244 menopausal women with a Kupperman index** of 15 or more.22 The primary outcome measure, which was the benefit-risk balance at 3 months (defined from the total score of the Kupperman index and the frequency of adverse events), was similar with black cohosh and tibolone. At 12 weeks, the Kupperman index had decreased from 24.7 to 7.7 with black cohosh and to 7.5 with tibolone.

**The Kupperman index rates symptom severity (i.e. severe = 3; moderate = 2; mild = 1; not present = 0). Symptoms assessed are hot flushes, numbness/tingling, insomnia, nervousness, depression, vertigo, weakness, arthralgia/myalgia, headache, palpitations and formication. The maximum score is 51.

A double-blind placebo-controlled trial, which involved 304 women with menopausal symptoms, found that the change from baseline in the MRS mean score (the primary outcome measure) was greater with black cohosh (2.5mg isopropanolic extract twice daily vs. placebo, p=0.027).27 The third trial (blinding status not reported) compared black cohosh (40mg daily of isopropanolic aqueous extract) with low-dose transdermal estradiol in 64 postmenopausal women with menopausal symptoms.26 At 3 months, both black cohosh and estradiol had similarly reduced the number of hot flushes per day from baseline (p<0.001). Two further randomised placebocontrolled trials have assessed a combination of black cohosh and St John’s wort for menopausal symptoms.31,32 In one, involving 89 women with menopausal symptoms, the herbal combination reduced the Kupperman index (the primary outcome measure) more than placebo, at 12 weeks (p<0.001).31 In the other study, which lasted 16 weeks and involved 301 women with menopausal symptoms with a pronounced psychological component, the combination produced greater falls than occurred with placebo in both the overall MRS score (the primary outcome measure; mean difference 30.4%, p<0.001) and the Hamilton Depression Rating Scale total score (decrease in score of 7.9 points vs. 2.4 points, p<0.01).32

Cautions with black cohosh

The limited safety data available on black cohosh suggest that it is well tolerated, with similar rates of unwanted effects in randomised controlled trials to those of placebo.29 In short-term postmarketing surveillance studies of black cohosh, mild, transient unwanted effects such as headache, dizziness and gastrointestinal complaints have been reported.29 Evidence suggests a possible association between black cohosh and liver toxicity,33,34 and the MHRA’s Commission on Human Medicines has advised that it is important to inform users of black cohosh about this.35 The summary of product characteristics (SPC) for Menoherb states that patients should be told to stop using the product and consult their doctor if they develop symptoms and signs suggestive of liver dysfunction (e.g. yellowing of the skin and eyes, severe upper stomach pain with nausea and vomiting, anorexia).30 There are conflicting data on whether black cohosh has oestrogenic activity.29,36,37 However, the SPC for Menoherb advises that it should only be used by women of childbearing potential if contraception is used, as there is evidence that black cohosh may have hormone-like actions.35,38

Red clover

Red clover contains isoflavones (e.g. genistein, daidzein, formononetin, biochanin), which are a class of phytoestrogens.29 Phytoestrogens have oestrogen-like activity, but it is not clear whether they stimulate or block the effects of endogenous oestrogen or both.39 Foods such as soybeans, chickpeas, and other legumes (beans and peas) also contain phytoestrogens, and it has been postulated that a high dietary intake of soy may explain, in part, the lower prevalence of hot flushes among Asian women.9 The dose of red clover used is usually 4g as an infusion of the dried flowerhead three times daily, or 40–160mg of red clover isoflavone daily.13,29

Pooled data

A systematic review of 30 randomised trials (lasting at least 12 weeks and involving a total of 2,730 participants) assessed the efficacy, safety and acceptability of foods and supplements including high levels of phytoestrogens (i.e. red clover extracts, dietary soy, soy extracts, other types of phytoestrogens) for reducing hot flushes and night sweats in peri- or postmenopausal women.40 Seven trials used a red clover extract (in doses ranging from 40–160mg daily); five of these (including a total of 400 participants) were combined in a meta-analysis. No other trials had data suitable for inclusion in a meta-analysis. The reviewers found no difference overall in the frequency of hot flushes between red clover extract and placebo (weighted mean difference –0.57, 95% CI –1.76 to +0.62). Of the remaining trials, two found a reduction in hot flushes with dietary soy (one vs. placebo, one vs. regular diet); five with soy extracts (vs. placebo); and one with the isoflavone genistein (vs. placebo). The other trials found no difference between phytoestrogen therapy and placebo or control intervention. Many of the trials were underpowered, and the two positive trials of dietary soy had very high dropout rates (21% and 24%). Unwanted effects were not increased with phytoestrogens. The reviewers concluded that there was no evidence that phytoestrogen treatments helped to relieve menopausal symptoms.

The findings of this systematic review were broadly similar for red clover and isoflavones to previously published systematic reviews.20,41,,43 However, another review concluded that isoflavone extracts (from red clover and soy) reduced hot flushes in menopausal women (effect size –0.28, 95% CI –0.39 to –0.18, p<0.0001), particularly in those experiencing a high number.44 The effect was not significant in subgroup analysis of red clover products only (effect size –0.16, 95% CI –0.34 to +0.02, p=0.0435).

Cautions with red clover

Red clover appears to be well tolerated with few, if any, serious unwanted effects noted in clinical studies.40,45 There has been evidence of endometrial hyperplasia in a few studies of isoflavones,46,47 but not in most trials, where treatment lasted up to 2 years.40 Because red clover contains isoflavones, the question of safety in hormone-sensitive tissue (e.g. breast, uterus) is important but, at present, its safety in women with a history of hormonesensitive cancers or other hormone-sensitive conditions is unknown. There is some evidence that phytoestrogen supplements can interfere with selective oestrogen receptor modulators such as tamoxifen and may reduce the effects of aromatase inhibitors (e.g. letrozole).48,,50

Dong quai

Dong quai root (in combination with other herbs) has been used in Traditional Chinese Medicine for many centuries as treatment for a variety of disorders, including menopausal symptoms. Its mode of action in the treatment of women with menopausal symptoms is unknown.

Clinical trials

One 24-week double-blind randomised trial, involving 71 women with troublesome night sweats or vasomotor flushes (more than 14 combined events per week of any severity or more than five moderate to severe combined events per week), found no difference in Kupperman index scores and number of hot flushes (the primary outcome measures) between those on dong quai (4.5g of root daily) and those on placebo.51 However, at 24 weeks, Kupperman index scores improved in both groups from baseline (p<0.01). In another placebo-controlled randomised trial, involving 55 postmenopausal women with hot flushes, a combination of dong quai and chamomile (Matricaria chamomilla) was more effective than placebo in reducing the frequency of hot flushes from baseline (decrease of 90% in the day and 96% in the night vs. 15% and 20% with placebo, respectively, p<0.001), and the intensity of flushes (p<0.001).52

Cautions with dong quai

Photosensitivity has been reported as an unwanted effect of Angelica species related to dong quai.29,53 Dong quai potentiates the effect of warfarin, increasing the risk of bleeding;15,53 therefore, co-administration of these two drugs is contraindicated.

Evening primrose

Evening primrose oil is extracted from the seeds of the evening primrose plant, a wild flower native to North America. The seed oil is a rich source of linoleic acid and gamma linolenic acid.29 It is unclear why evening primrose oil might have any effect on menopausal symptoms.

Clinical trials

One randomised controlled trial involving 56 menopausal women found that night time flushes were reduced from baseline with evening primrose oil (four 500mg capsules twice daily; p<0.05), but not more than with placebo; no other benefits were seen.54

Cautions with evening primrose oil

When given with drugs that can cause seizures (e.g. phenothiazines), evening primrose oil may further increase the risk of such events.15,29

Ginseng

Ginseng root has occupied an important place in Asian medicine for millennia. The common name, ginseng, is used to describe a number of chemically different species of Panax (e.g. P. ginseng, P. qinquefolium), so caution is essential when interpreting data between species. Studies have focused on its effects on quality of life issues in menopausal women.55,56

Clinical trials

One 16-week double-blind randomised controlled trial involving 384 postmenopausal women compared ginseng (two capsules daily of Ginsana, containing 100mg of standardised ginseng extract G115) with placebo and found that the Psychological General Well-Being Index scores (the primary outcome measure) did not differ between the treatment groups (p<0.1).55 Another double-blind randomised controlled trial investigated daily treatment with a combination of 200mg P. ginseng plus 120mg ginkgo (Ginkgo biloba) on mood and cognition after 6 and 12 weeks of treatment in 70 postmenopausal women; it found no beneficial effects on any menopausal symptoms with the combination compared to placebo.56

Cautions with ginseng

Ginseng appears to be well tolerated, but has been associated with unwanted effects such as headache, sleep problems and gastrointestinal disorders.16 Interactions have been reported between ginseng and warfarin (leading to a reduced INR), but the data are inconclusive and there may be differences between species.29 (On the other hand, gingko is thought to potentiate the action of anticoagulants.15)

Other herbs

Extracts of wild yam (Dioscorea villosa) are sometimes applied topically in a cream for the relief of menopausal symptoms. One double-blind randomised controlled trial involving 50 women with menopausal symptoms found that, compared to placebo, topical wild yam extract used for 3 months had no effect on symptom scores for diurnal flushing and night sweats (the primary outcome measures), as recorded daily in diaries.57 Both groups experienced improvement in these symptoms compared to baseline symptoms (p<0.05).

Chaste tree (Vitex agnus-castus) is a commonly used herb for menstrual problems. There are few data on its use for menopausal symptoms. One 3-month randomised placebo-controlled trial involving 50 healthy pre- and postmenopausal women has assessed the effect of a combination herbal product that included chaste tree as one of the ingredients, along with black cohosh, dong quai, red clover and American ginseng.58 At the end of the study, the number of hot flushes had reduced more with the combined herbal product (by a mean of 73% vs. 38% with placebo, p=0.026), as had the number of night sweats (69% and 29%, respectively, p=0.027).

Hops (Humulus lupulus) are also used for menopausal symptoms but there are few data on their use. One randomised controlled trial involving 67 women who had menopausal symptoms found no difference between an extract of hops (100–250mg) and placebo in alleviating “menopausal discomforts” after 12 weeks of treatment (p=0.086).59

Sage leaf (Salvia officinalis) is sometimes used to treat sweating associated with the menopause, but evidence for this use is lacking. In a nonblinded uncontrolled 3-month study, sage plus alfalfa (Medicago sativa) was given to 30 women with menopausal hot flushes and night sweats, and symptoms disappeared in 20 of the women.60

Kava kava (Piper methysticum), which was previously widely used for anxiety, including that associated with the menopause, has been banned in the UK because of reports of liver damage with the herb.61

Conclusion

The use of herbal medicinal products for the relief of menopausal symptoms is widespread. However, there is a lack of licensed herbal medicinal products on the market for menopausal symptoms. Also, the efficacy and safety of such products is generally under-researched, and information on potentially significant herb-drug interactions is limited. Healthcare professionals should ask women routinely if they are taking any such products.

The results from clinical trials of black cohosh are equivocal, some suggesting benefit while others suggesting none. The UK Medicines and Healthcare products Regulatory Agency has given a Traditional Herbal Registration to a herbal medicinal product (Menoherb) containing black cohosh for menopausal symptoms. It has also said that women taking black cohosh should be warned of the potential risk of liver toxicity, and told to stop using the product and consult their doctor if they develop signs and symptoms suggestive of liver dysfunction. There is no convincing evidence that red clover extracts have a beneficial effect. There is little evidence for or against benefit with other herbs commonly used for menopausal symptoms, such as dong quai, evening primrose oil, ginseng, wild yam, chaste tree, hops and sage.

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