a systematic review of herbal medicinal products for the menopausal

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A systematic review of herbal medicinal products for thetreatment of menopausal symptoms

Alyson L. Huntley, PhD, and Edzard Ernst, MD

ABSTRACTObjective: Many women have turned to complementary and alternative medicines for relief from

their menopausal symptoms. The prevalence of herbal medicinal product use among menopausalwomen highlights the need for investigation into these interventions. The aim of this study was to

evaluate the benefit of herbal medicinal products for the treatment of menopausal symptoms byperforming a systematic review of randomized clinical trials.

Design: Literature searches of four computerized databases were done to identify randomizedclinical trials of herbal medicinal products for the treatment of menopausal symptoms. Manufac-

turers of herbal products were contacted, and our own files were also searched. There were norestrictions on the language of publication. Trials were considered if the outcome measures relatedto the physical or psychological impact of menopause, whether by compendium scores, question-naires, or womens symptom diaries, excluding studies describing artificially induced menopause.

This review was not concerned with biochemical or pathological data.Results: Eighteen randomized clinical trials that fit our criteria were identified. These studies

investigated black cohosh (n = 4), red clover (n = 4), kava (n = 3), dong quai (n = 1), eveningprimrose oil (n = 1), ginseng (n = 1), and combination products (n = 4). Trial quality was generally

good, with 16 of 18 studies scoring 3 or more (maximum 5) on the Jadad Scale.Conclusions: There is no convincing evidence for any herbal medical product in the treatment of

menopausal symptoms. However, the evidence for black cohosh is promising, albeit limited by thepoor methodology of the trials. The studies involving red clover suggest it may be of benefit for

more severemenopausal symptoms. There is some evidence for the use of kava, but safetyconcerns

mean this herbal product is not a therapeutic option at present. The evidence is inconclusive for theother herbal medicinal products reviewed.

Key words: Herbal medicine Menopause Black cohosh Red clover Kava.

The most common conventional medical treat-ment for menopausal symptoms is hormonereplacement therapy (HRT). The primary rea-

son women use HRT is for the relief of vaso-motor symptoms attributed to menopause, althoughthere is evidence for other benefits, such as protectionagainst bone loss and ischemic heart disease.1 How-

ever, there is also recent evidence to suggest that HRTmay increase breast cancer, heart attacks, coronary at-tacks, and strokes.2

It seems that because of a fear and dislike of adverseeffects as well as these possible long-term risks ofHRT, many women have turned to complementary andalternative medicines, hoping that these might relieve

menopausal symptoms.3,4,5

In a study of 500 women by theWomens NutritionalAdvisory Service, the most common reason cited fornot taking HRT was concern over risks.5 In a survey of

100 menopausal women carried out in the US, 29%were taking HRT, 16% used HRT plus dietary supple-ments, 32% used dietary supplements alone, and 13%were on no medication.6

Received July 23, 2002; revised and accepted January 7, 2003.

From the Department of Complementary Medicine, Peninsula MedicalSchool, Universities of Exeter & Plymouth, Exeter, England.

Address correspondence to: Alyson L. Huntley, PhD, ComplementaryMedicine, Peninsula Medical School, Universities of Exeter & Plym-outh, 25 Victoria Park Road, Exeter EX2 4NT England. E-mail:[email protected].

Menopause: The Journal of The North American Menopause SocietyVol. 10, No. 5, pp. 465-476DOI: 10.1097/01.GME.0000058147.24036.B0 2003 The North American Menopause Society Text printed on acid-free paper.

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It has been estimated that over one third of NorthAmerican adults use herbal medicinal products(HMPs) at an annual cost of $13.7 billion.7 A Swedishstudy suggests that approximately 4% of women treattheir menopausal symptoms this way.8 HMPs have

been promoted for both the physical and psychologicalsymptoms of menopause. Some are thought to have es-trogenic effects, eg, red clover. In general, the actualmechanisms involved are still to be elucidated. Otherherbal medicines, such as kava, are used to relieve anxi-ety in menopause. In addition, it is well documentedthat there is a marked placebo and time effect on meno-

pausal symptoms during trials.9

The aim of this systematic review is to summarizeand critically analyze all relevant randomized clinicaltrials (RCTs) on this topic.

METHODS

Identification of clinical trials

Computerized literature searches were performed toidentify RCTs of HMPs for the treatment of meno-pausal symptoms. The databases used were Medline,Embase, Phytodoc and The Cochrane Library (all fromtheir inception to December 2002). The search termsused were menopaus*, climacteric, hot flushes/flashes,herb*, phyto*, plant, diet, supplement, isoflavones,coumestans, lignans, nutrition, naturopathy, black co-hosh, blue cohosh, burdock, dong quai, evening prim-rose oil, feverfew, ginseng, hops, kava, liquorice, lin-seed, motherwort, red clover, St John wort, traditionalChinese medicine, vitex agnus castus, valerian, wildyam, and wheat.

In addition, 43 manufacturers of herbal productsmarketed for menopause were asked to contribute pub-lishedand unpublished material, and our own extensivefiles were searched. The bibliographies of the studiesthus retrieved were scanned for further trials. Therewere no restrictions on the language of publication.

Inclusion and exclusion criteria

RCTs of HMPs for menopausal symptoms were con-sidered if the outcome measures related to the physicalor psychological impact of menopause, whether bycompendium scores, questionnaires, or participantssymptom diaries. This review was not concerned with

outcome measures of blood hormonal level data, vagi-nal cytology, or other nonclinical endpoints. This re-view also did not include studies describing artificiallyinduced menopause. This reviewdid notinclude soy, asit was felt by the authors to be a topic in itself and thisreview would not be able to discuss the issues involvedin sufficient depth.

Data extraction and evaluation

The data were extracted according to predefined cri-teria by the first author. The trials were assessed formethodological quality using the Jadad score.10 It mea-sures the likelihood of bias based on description of ran-domization, blinding, and withdrawals on a scale of 0

(minimum) to 5 (maximum). Due to the diverse natureof the interventions and outcome measures, no quanti-tative analysis took place; thus, the information wasevaluated in a qualitative manner. Descriptions andsafety aspects of the HMPs included in this review aredetailed in Table 1 and in the discussion (excludingChinese medicine mixture).

RESULTS

Our systematic searches revealed 18 RCTs of HMPsfor the treatment of menopausal symptoms. TheseRCTs describe black cohosh (n = 4), red clover (n = 4),kava (n = 3), dong quai (n = 1), evening primrose oil

(n = 1), ginseng (n = 1), and combination products(n = 4). The quality of these trials was generallygood, with 16 of 18 scoring 3 points or more on theJadad score (Tables 2, 3, and 4). One trial was onlyavailable in abstract form so the Jadad score could not

be calculated.

Black cohosh: Actaea racemosa

(Cimicifuga racemosa)

Most of the information about black cohosh in theliterature (Table 2) relates to the product Remifemin(Schaper & Brummer, Salzgitter, Germany).

Warnecke randomized 60 menopausal women to re-ceive either 40 drops of Remifemin, conjugated estro-gen, or diazepam daily for 12 weeks.11 Outcome mea-sures were the Kupperman Index, Hamilton AnxietyScale (HAMA), Self-Assessment Depression Scale In-dex(SDS) and Clinical Global Impression (CGI) Scale.Although the authors stated that Remifemin resulted inthe greatest improvement in all outcome measures, nei-ther actual data nor statistical analysis was reported.

Stoll et al reported a 12-week study involving 80menopausal women who received Remifemin, low-dose estrogen, or placebo daily.12 Outcome measureswere the Kupperman Index and the HAMA Scale. All

groups improved, but the greatest improvement was inthe Remifemin group, with a statistically significant (P< 0.001) and clinically relevant reduction in Kupper-man Index compared with baseline.13 Similarly, theHAMA Scale was significantly reduced for Remifemincompared with baseline (P< 0.001). No intergroup dif-ferences were reported.

HUNTLEY AND ERNST

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In a 24-week study involving 60 hysterectomizedwomen with one intact ovary and climacteric symp-toms, participants were randomized to receive Remife-min, estriol, conjugated estrogens, or estrogen-

progesterone therapy.14 The outcome measure was amodified Kupperman Index. All groups improved sig-

nificantly (P = 0.01), and there was no differenceamong groups. None of the treatments resulted in a de-crease in the Kupperman Index to below 15 points.

The most recent study by Jacobson et al involved 85breast cancer patients experiencing menopausal symp-toms.15 Of this group, 42 women were assigned to

TABLE 1. Descriptions of the plant-based medicines reviewed

Herbal medicine Active ingredient & mode of action Possible adverse effects & interactions

Black cohosh (Actaearacemosa, also known asCimicifuga racemosa)

Putative active ingredient: triterpene glycosides(Remifemin standardized to 27-deoxyaceteincontent). Originally thought that action was througha direct estrogenic/endocrine effect. New researchsuggests otherwise.

Gastrointestinal complaints, hypotension, headache,dizziness, nausea, allergic reactions.31

May interact with antihypertensive agents.33

St. Johns wort (Hypericumperforatum)

Active ingredient may be hypericin and hyperforin.Use for mild to moderate depression, possibly actingthrough inhibiting the reuptake of serotonin,norepinephrine, and dopamine.

Most common reports are of gastrointestinalsymptoms, allergic reactions, fatigue, and anxiety.Several cases of mania and one subacute toxicneuropathy have been reported. Photosensitivity is

possible, p articularly i n fair-skinned individuals.Interactions: serotonin reuptake inhibitors, oral

contraceptives, cyclosporins, warfarins,anticonvulsants, digoxin, theophylline, HIV proteaseinhibitors.36

Red clover (trifoliumpratense)

Putative active ingredient: isoflavones. It is postulatedthat substances with natural estrogenic-like activityalleviate climacteric symptoms.

Breast tenderness, menstruation changes, weight gain.Theoretically may interfere with anticoagulants and

hormonal therapies.36

Kava (Piper methysti cum) Follicle-stimulating hormone surges in menopausalwomen. Active ingredients: kavapyrones, actingthrough the -aminobutyric acid-A receptors in

nerve endings. Demonstrated anxiolytic effects.

Stomach complaints, restlessness, mydriasis, allergicskin reactions, dermatomyositis, hepatitis.

Potentiation of central nervous system drugs such as

alcohol, bezodiazepines, and barbiturates.

32

Dong quai (Angelicasinensis)

Reputed to have estrogenic properties. Bleeding, photosensitivity.Interaction with anticoagulants.36

Burdock (Arctium lappa ) Reputed to have estrogenic properties. Potential to interact with antidiabetic medications.36

Licorice (Glycyrrhizaglabra)

Contains isoflavones & glycyrrhetinic acid. sitosterolis reputed to influence estrogen activity.

Adverse effects consistent with adrenocorticotrophicactions.36

Motherwort (Leonoruscardiaca)

Contains alkaloid leonurine that is thought to stimulateuterine activity.

Potential to interact with cardiac glycosides,antihypertensives.36

Wild yam (Dioscoreabarbasco/Dioscoreavillosa)

Steroidal glycosides based on the sapogenin diosgenin.Mode of action has not been determined.

No adv erse reactions or know n drug interactionsexcept some cases of hormonal effects with onecommercial product.37

Evening primrose oil(Oenothera biennis)

Rich in gamma-linolenic acid (GLA). GLA productionmay be compromised in some conditions, includingaging. Part of the pathway to prostaglandin E1

production.

Gastrointestinal symptoms, headache.Theoretical interactions with antiinflammatory drugs,

corticoidsteroids, beta-blockers, antipsychotics,

anticoagulants, and epileptogenic agents.36

Ginseng (Panax g inseng) Ginsenosides (triterpene saponins) are thought to haveestrogenic properties.

Insomnia, diarrhea, vaginal bleeding, mastalgia,swollen tender breasts, increased libido, manicepisodes, a possible cause of Stevens-Johnsonsyndrome.

Interactions with monoamine oxidase (MAO)inhibitors such as phenelzine, increased effects ofhypoglycemics.36

Flax seed (Linumusitatissimum)

Reputed to have estrogenic, antiestrogenic, andsteroid-like activity.

No kn own side effects. The absorption of other drugsmay be negatively affected.37

Geranium (Pelargoniumgraveolens)

Reputed to have hormonal effects. No information found.

Sage (Salvia officinalis) Traditionally thought to have antihydrotic properties. Potential to interact with antihypertensives andantidiabetics.36

All citations correspond to the References list at the end of this article.

HERBAL TREATMENT OF MENOPAUSAL SYMPTOMS

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TABLE

2.

Randomized

clinical

trials

of

black

cohosh

and

red

clover

for

menopausalsymptoms

First

author

(yr)

Trial

sett

ing,

duratio

nofth

erapy

,

and

trial

des

ign

Stu

dy

part

icipants

(age

)

Exp

erimenta

l

treatment

(N)

Control

treatments

(N)

Outcome

measures

Results

Adverse

events

Jadad

score

Warnec

ke

(1985)

Not

des

cribed

,2w

,

open

60

women

with

noo

r

irregu

lar

menses

&cl

imacteric

comp

laints

(54

4y

)

40d

rops

ofR

emifem

in

twice

daily

(4m

gof

27-de

oxyacet

in)

(20)

0.6

mg

con

jugated

estrogen

daily

(20)

2m

gdi

azepam

daily

(20)

K

I

H

AMA

SDS

Index

C

GI

Index

Rem

ifem

inpr

oduce

d

greatest

improvement

inal

lm

easures,

but

no

actual

data

given

.

None

stated

2

Sto

ll(1

987)

Not

des

cribed

,12

w,

doub

le-b

lind

80

women

with3

hot

flus

hes

dai

ly

&1

more

symptom

(51.2

3

.1y

)

4ta

blets

dai

lyof

Rem

if

emin

(4m

g

of27-

deoxyacet

in)

(26)

Low-d

ose

estrogen

(0.6

25m

g)da

ily

(29)

Place

bo(2

0)

K

I

H

AMA

Rem

ifem

inpr

oduce

d

greatest

improvement

inK

I(

a systematic review of herbal medicinal products for the menopausal

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