Does scientific evidence support the use of non-prescription supplements for treatment of acute menopausal symptoms such as hot flushes?
The objective of the present review was to critically evaluate the scientific evidence for efficacy of non-prescription supplements (NPS) available for treatment of acute menopausal symptoms; and where available, to identify constituents, specify dosage, propose mechanisms and indicate safety concerns. A Medline search identified 24 clinical trials assessing efficacy of seven NPS for treatment of hot flushes in symptomatic menopausal women; 19 were randomised placebo-controlled trials. Articles were located on black cohosh, dong quai, evening primrose oil, ginseng, isoflavonoid phytoestrogens (from red clover or soy) and sage. Evidence for each NPS was tabulated according to study design and menopausal outcomes. Findings from 13 randomised placebo-controlled trials, using isoflavonoids from red clover or soy, demonstrated significant efficacy for six studies (46%) with reductions in moderate to severe flushes by 10-44% compared with placebo; seven studies (54%) reported no significant improvements. In vitro studies indicate that isoflavonoids have significant oestrogenic activity, providing a supporting mechanism. One controlled trial reported that an extract of sage and alfalfa significantly reduced severe hot flushes by 60% compared with placebo. Two controlled trials reported that black cohosh improved overall menopause symptom scores; however, no data were available specifically on hot flushes. In conclusion, evidence from a small number of placebo-controlled trials suggested that further research is warranted to test efficacy of red clover, soy, sage and black cohosh for treatment of hot flushes in menopausal women. To date, controlled trials do not support use of dong quai, evening primrose oil and ginseng for treatment of hot flushes.
Key words: complementary and alternative medicines, hot flush, isoflavonoids, menopause, soy protein, women's health
(Nutr Diet 2005;62:138-151)
Controversies surrounding the safety of hormone therapy (HT) have prompted increased interest in non-prescription supplements (NPS) available for treatment of menopausal symptoms. In contrast to HT, NPS are often perceived as natural and, therefore, may represent a safer and more appropriate alternative to HT. However, little is known about their efficacy and the scientific rationale for their use. In view of the increasing community interest and marketing of these supplements, and their traditional use in some cultures, assessment of the scientific evidence supporting NPS is warranted. In the present review, the term NPS includes all tablets, powders or tinctures purchased without a doctor's prescription that are taken to treat menopausal symptoms. Other terms frequently used include herbal remedies, HT alternatives and complementary and alternative medicines.
The present review focuses on evidence supporting the use of NPS for the treatment of acute symptoms of menopause, particularly hot flushes. Although assessed in some of the trials, efficacy for other symptoms less specifically associated with menopause, such as anxiety and muscle aches, is beyond the scope of the present review. Hot flushes are one of the most common symptoms reported by women undergoing the menopausal transition. The underlying pathophysiology of hot flushes is not well understood; however, a relationship with declining oestrogen levels is assumed; hot flushes peak in the perimenopausal period, when oestrogen levels are fluctuating, and usually subside with age, suggesting sensitivity to relative rather than absolute oestrogen concentration. (1) Many NPS are designed to provide an ingredient with purported oestrogenic activity.
Previous published reviews have assessed the evidence supporting use of NPS for treatment of both acute symptoms associated with menopause, such as hot flushes, and chronic conditions, such as cardiovascular disease and osteoporosis. (2-9) The present review expands upon previous work by focusing in greater depth on acute menopausal symptoms and assessing a range of NPS including black cohosh, dong quai, evening primrose oil, ginseng, sage and phytoestrogens. Investigation of alternatives to HT for treatment of symptomatic menopausal women is a rapidly evolving area. Five reviews were identified that focused on acute symptoms, of which four did not include studies published after 2002. (10-13) The most recently published study investigated phytoestrogens alone. (14) Authors concluded that there was insufficient evidence to support the use of phytoestrogens for treatment of hot flushes and other menopausal symptoms; however, one limitation was that conclusions were drawn from studies that included phytoestrogen-rich diets, for which it is not possible to blind subjects to placebo or intervention status.
The aim of the present review is to provide health professionals with a critical evaluation of the scientific evidence for efficacy of the NPS available for treatment of acute symptoms of menopause, particularly hot flushes; and where available, to identify constituents, specify dosage, propose mechanisms and indicate safety concerns.
Search strategy for identification of studies
The search strategy identified relevant studies published from 1940 up to March 2004. The following databases were searched: MEDLINE (ScienceDirect), PUBMED, PROQUEST and the Cochrane Controlled Trials Register. Keywords used were: black cohosh, dong quai, evening primrose oil, ginseng, liquorice, red clover, sage, soy, kudzu, hormone replacement therapy and alternatives, phytoestrogens, isoflavonoids, menopause, hot flush, menopause supplement and non-prescription supplement. The literature review identified intervention studies on the efficacy of seven types of NPS for treatment of acute symptoms of menopause: black cohosh, dong quai, evening primrose oil, ginseng, red clover and soy isoflavonoids, and sage.
Criteria for selection of studies
Selection criteria for types of studies were non-restrictive because of the small number of randomised placebo-controlled trials for all supplements, apart from isoflavonoids. Consequently, non-randomised and uncontrolled intervention trials were included. Studies were included if subjects were otherwise-healthy women with menopausal symptoms; women with hormone-sensitive conditions such as breast cancer were not included. In total, 19 randomised controlled trials were identified. Interventions to test the efficacy of NPS for menopause have measured a range of outcomes such as indices of general or psychological health and markers of hormonal status. However, the present review focused only on outcomes specifically associated with menopause, including frequency and severity of hot flushes or night sweats, and scales designed to measure overall menopausal symptoms, such as the Kupperman Menopause Index and the Greene Menopause Score. These scales attempt to quantify symptoms of menopause and incorporate measures of vasomotor (hot flushes), somatic and psychological symptoms. (15,16)
Results and discussion
The review of the literature identified two lines of evidence pertaining to NPS for treatment of menopausal symptoms. The first approach included investigation of the mechanism of action to explain the use of the NPS, most commonly the ability to bind to oestrogen receptors and exert an oestrogenic response. The second line of inquiry was through clinical intervention studies involving symptomatic women, and examined the effects of NPS on hot flushes. As few clinical studies specifically addressed safety issues of NPS, additional information was located in the literature and included in a separate section. The strengths and limitations of the studies are discussed, enabling evaluation of the evidence regarding the efficacy of a particular NPS for treatment of hot flushes.
Black cohosh (Cimicifuga racemosa) was one of the more extensively studied menopausal NPS. Traditionally used in North America, Europe and China for gynaecological conditions, black cohosh has been used in Germany since the 1940s to treat disorders of menstruation and menopausal symptoms. Biological activity is attributed to the presence of triterpene glycosides, including actein, cimicifugoside, deoxyacetylacteol and 27-deoxyactein. (17) The mechanism proposed to explain the effect of black cohosh has been the possession of oestrogenic components, (18-20) although this has not been supported by in vitro studies investigating the ability of the triterpenes to bind to the oestrogen receptor and exert an oestrogenic response. (21-23) Authors have postulated that black cohosh may possess alternative mechanisms of action by activating receptors for pituitary hormones that regulate oestrogen synthesis, such as luteinising hormone or follicle stimulating hormone, or that black cohosh components influence enzymes required in the synthesis of endogenous oestrogen. (20,21,23) However, these possibilities have not been tested.
Seven clinical trials between 1982 and the present have investigated the efficacy of black cohosh for relief of symptoms in menopausal women (Table 1); two of these trials were placebo-controlled. (27,30) The majority used Remifemin, a standardised extract of Cimicifuga racemosa root containing 1 mg of the triterpene 27-deoxyacetein per tablet. (17) The current recommended dose of Remifemin is two tablets/day (40 mg black cohosh extract/day). This is lower than the dose of four tablets/day (or 80 drops of liquid extract/day) used in trials prior to 1996, because of an improvement in the extraction process; however, the quantity of active constituent was not altered. (17) Of the seven clinical trials, two were conducted after 1996, using the current recommended dose; (29,30) there was no observed difference in efficacy between studies conducted either before or after introduction of the new formulation.
In a placebo-controlled trial with 80 women, Stoll reported that Remifemin reduced mean overall symptom scores by 59% compared with baseline and responses were significantly greater than the reduction by 29% with placebo. (27) Similar results were obtained in a second placebo-controlled trial by Wuttke et al. (30) Both studies were conducted over 12-week periods among German women with moderately severe symptoms of at least three hot flushes/day. They featured a parallel design that compared the effect of black cohosh with conjugated oestrogen (0.625 mg/day) or placebo on a measure of overall menopausal symptom scores. Although both studies reported a decrease in overall menopausal symptom scores, the effect on the hot flush component was not described (27) or was not significant. (30) Remifemin compared with placebo also resulted in a significant increase in the degree of proliferation of vaginal epithelial cells, suggestive of an oestrogenic effect. (27)
Five uncontrolled trials have also reported consistently significant improvements in overall menopausal symptoms compared with baseline after 12-24 weeks of treatment with Remifemin. (24-26,28,29) None of the studies reported separately on the frequency of hot flushes. In one study the improvement in symptoms was accompanied by increased proliferation of vaginal epithelial cells, (26) although another study found no changes in vaginal epithelium. (29) However, in the absence of a placebo control, the results of these studies are not definitive.
Extracted from the root of Angelica sinesis, dong quai or tang-kuei has been used in Chinese herbal medicine to treat disorders of menstruation and menopausal symptoms. Dong quai contains various coumarins and a phenolic constituent, ferulic acid. The mechanism of action is uncertain, although it has been proposed that the ferulic acid could provide oestrogenic activity. (31) However, results of in vitro studies investigating the ability of dong quai extracts to activate the oestrogen receptor are inconsistent, with findings of no oestrogenic activity, (20,21) an antagonist effect, (22) or a weak oestrogenic effect. (23)
One randomised placebo-controlled trial has investigated the use of dong quai root in 71 symptomatic postmenopausal American women (Table 2). (31) Following a 24-week intervention, no significant differences between treatment and placebo groups were observed in frequency of hot flushes or overall menopausal symptom scores. A power-based estimate of sample size indicated that subject numbers were adequate to detect a difference of 11 hot flushes per week. Although dong quai root given alone did not demonstrate an effect in this group of women, practitioners of Chinese medicine who have reported positive outcomes typically use dong quai in combination with at least four other herbs, including Radix paeoniae lactiflorae, Rhizoma ligustici, Rhizoma atractylodes, Rhizoma alismatis, Sclerotium poriae. (31) These herbs could potentially affect hot flushes either alone or in combination with dong quai but these possibilities have not been tested in placebo-controlled studies.
Evening primrose oil
Evening primrose oil has been perceived by many women to be effective for the control of acute menopausal symptoms. (32) Gamma-linolenic acid, an omega-6 polyunsaturated fatty acid, is considered to be the active component. (35) Gamma-linolenic acid is the precursor of other omega-6 fatty acids including dihomogamma-linolenic acid and prostaglandins of the '1' series, which possess anti-inflammatory and antithrombotic properties. (36,37) Evening primrose oil also contains arachidonic acid, which gives rise to the '2' series of prostaglandins, which are pro-inflammatory. (38) On the basis of anti-inflammatory and antithrombotic properties, evening primrose oil has been promoted for treatment of a range of health problems including cardiovascular disease and arthritis, although there is no scientific rationale to support the use of evening primrose oil for treatment of hot flushes.
One placebo-controlled trial has investigated the effect of evening primrose oil on hot flushes in 56 English women (Table 2) and reported no significant differences between treatment and placebo groups. (32) The sample size was adequate to detect a 13% treatment difference in hot flush frequency; however, one limitation was the high withdrawal rate, with only 63% of women completing the trial, attributed to a lack of efficacy of the treatment. Based on the lack of observed efficacy and a plausible rationale, authors of the study concluded that evening primrose oil should not be promoted for treatment of hot flushes.
Ginseng (Panex ginseng), a traditional herbal medicine used in China, Japan and Korea, is widely valued as a stimulant. (39) The biologically active ingredients are considered to be a series of saponin glycosides known as ginsenosides or panoxosides. (40) Oestrogenic activity of the ginseng saponins has been suggested as a mechanism of action to support the use of ginseng in treatment of menopausal symptoms. (39) In one study, which used a methanolic extract of ginseng, significant binding to oestrogen receptors in a human myometrial tissue assay was observed; (39) however, two assays reported no significant oestrogen receptor binding affinity. (22,23)
One randomised placebo-controlled trial has been conducted to test the efficacy of ginseng in 384 postmenopausal Swedish women (Table 2). (33) After 16 weeks, ginseng, compared with the placebo, had no significant effect on the frequency of hot flushes, with similar reductions in frequency observed in both treatment (30%) and placebo (24%) groups. The placebo response of 24% was typical for studies of hot flush frequency. The sample size was calculated to detect a change in five units of the Patient Generated Wellbeing Index, rather than the frequency of hot flushes. However, the large sample, with approximately 190 women per group, and high completion rate of 98%. suggest that the numbers would have been sufficient to detect possible changes in hot flush frequency. Results of that study indicate that ginseng is not useful for the treatment of hot flushes.
Sage (Salvia officinalis) contains the phenolic constituent ferulic acid, which has the potential to bind to the oestrogen receptor, (41) although the specific binding affinity of sage has not been tested. De Leo et al. undertook a study to test the efficacy of a product based on an extract of sage and alfalfa in a group of 30 Italian women with an average of 14 hot flushes/day (Table 2). (34) Following 12 weeks of therapy the occurrence of hot flushes ceased in 20 women (67%); was reduced in frequency to between one and three flushes/day in four women (13%), and to between four and six flushes/day in six women (20%). The mean reduction by 85% in the frequency of hot flushes in the treatment group was significantly greater than the reduction by 25% in the placebo group, and comparable in magnitude to the effect of HT. (42) De Leo et al. concluded that the product was an effective agent for treatment of hot flushes and without side-effects. (34) However, the mechanism is not clear and it cannot be assumed that sage alone was the effective component because alfalfa (Medicago sativa) is a significant source of the isoflavonoid, coumestrol, which could have contributed to the observed efficacy. (43) Further studies using sage and/or alfalfa in treatment of menopausal symptoms are required to confirm findings of that study and to clarify a mechanism.
Phytoestrogens were the most extensively studied NPS for the treatment of acute menopausal symptoms. The main supplemental sources of phytoestrogens used in the clinical trials were isoflavonoids derived from either red clover or soy. These are discussed separately as their isoflavonoid profiles differ. Red clover (Trifolium pratense), a forage legume, contains genistein, daidzein and their methylated precursors, biochanin A and formononetin, respectively. Soybean (Glycine max) contains predominantly genistein and daidzein, with smaller quantities of glycitein. (44,45)
The primary mechanism proposed to explain the effect of isoflavonoids in the treatment of hot flushes pertains to weak oestrogen agonist effects. Isoflavonoids are structurally similar to the mammalian oestrogen, 17-[beta] oestradiol, and in vitro studies using tissue assays have demonstrated their capacity to bind to oestrogen receptors (ER). (22,23,43,46-48) Although molar binding affinities for isoflavonoids to the classic ER-[alpha] are 100- to 1000-fold weaker than that of oestradiol, certain isoflavonoids, notably genistein and coumestrol, have a relatively high binding affinity for the ER-[beta] subtype. For example, the binding affinity of genistein compared with oestradiol is 4% for ER-[alpha] and 87% for ER-[beta]. (48) Isoflavonoids can also stimulate transcriptional activity in both ER-[alpha] and ER-[beta] subtypes at physiological concentrations, suggesting they have the potential to exert an oestrogenic response. (48,49) These data support a potential mechanism for the possible efficacy of phytoestrogens in the treatment of hot flushes.
Isoflavonoids from red clover
Four randomised placebo-controlled trials have been conducted to assess the efficacy of red clover isoflavonoids in the treatment of hot flushes (Table 3). (50-53) Following adjustment for the placebo, the effect of isoflavonoids remained significant in one study, which reported a 44% decrease in the frequency of hot flushes. (52)
The report of a significant 44% reduction compared with the placebo in the frequency of hot flushes in the study by van de Weijer and Barentsen supports a role for red clover in the treatment of hot flushes. (52) However, this conclusion is disputed by the results of the three other trials, (50,51,53) including a study by Tice et al. with a larger sample size (252 women with 84 per group), high response rate (98%), equally stringent selection criteria in terms of symptom severity (>five flushes/day), and the same duration, dose and form of supplement (80 mg isoflavonoids/day for 12 weeks). (53) Notably, both studies showed a similar reduction in the frequency of symptoms, by 41% (53) or 44% (52) compared with baseline. However, a major difference was the magnitude of the placebo response compared with baseline, with a 36% decrease in the Tice study (53) compared with a 0% decrease in the van de Weijer and Barentsen study, (52) which allowed a significant treatment effect to emerge in the latter but not the former study. In a power-based estimate of the sample size, Tice et al. designed their study to detect at least a 15% greater reduction in hot flush frequency in the treatment compared with the placebo arms, and assumed a placebo response of 25% compared with the baseline. Therefore, the higher than expected placebo response (36%) would have contributed to the lack of overall treatment effect. (53) Interestingly, although these investigators reported no effect of isoflavonoids in the treatment group as a whole, they did observe a greater reduction of hot flushes in women above the median body mass index (BMI) (>25.1 kg/[m.sup.2]) compared with those below the median BMI (<25.1 kg/[m.sup.2]); the BMI trends were seen within the two isoflavonoid treatment groups but not within the placebo group (Table 3). Further studies are required to investigate the effect of BMI and adiposity on individual responsiveness to isoflavonoid treatment.
Isoflavonoids in the soy protein matrix or purified soy isoflavonoids
Nine randomised placebo-controlled trials have been conducted to investigate isoflavonoids within a soy protein matrix (54,55,60,61) or in purified form (56-59,62) (Table 3). Taken together, the reduction in the number or severity of hot flushes ranged from 28% to 61% (median 45%) in treatment groups compared with baseline and 18-77% (median 30%) in the placebo groups. After accounting for the placebo, the effect of isoflavonoids was significant in five of the nine studies. (54,55,57-59)
Power-based estimates of the sample size in two of the studies indicated that 30-35 subjects per group were required to detect a treatment difference of three hot flushes per day. (54,58) The majority of studies had a sample sizes between 27 and 89 women per group, although two studies had smaller numbers of 17 (55) or 20 per group, (59) which could limit the interpretation of their findings. Inclusion criteria for the frequency of hot flushes varied from low, more than one or two hot flushes/day (55,60,61) to moderate, more than five hot flushes/day (57) or high, more than seven to 10 hot flushes/day. (54,58,62) With the exception of one study, (62) significant improvements compared with the placebo were demonstrated only in studies that selected women with at least moderate to high flushing frequency; (54,57,58) no significant effects were observed in women with milder symptoms of one to two flushes/day; (56-59,60-62) one study did not specify the frequency of hot flushes in the inclusion criteria. (59)
There were no apparent dose-dependent effects, although in one study, a split dose designed to provide more consistent blood levels during the day was more effective than a single daily dose. (55) Efficacy was reported at isoflavonoid doses between 34 and 76 mg/day, (54,55,57-59) whereas in studies with no significant improvements, doses ranged from 42 to 118 mg/day. (56,60-62) The effective doses were within the physiological range of intakes achievable by regular consumption of phytoestrogen-rich foods, for example, mean isoflavonoid intakes obtained in communities with traditional consumption of soy foods have ranged from 15 to 54 mg isoflavonoids/day. (63-65)
Another possible source of variation relates to the reproducibility of the isoflavonoid content of supplements. An analysis of the isoflavonoid content of commercially available supplements, reported that Promensil (Novogen, Sydney, NSW, Australia), the supplement used in all studies with red clover isoflavonoids, provides a reproducible dose of isoflavonoids. (66) However, the accuracy of the isoflavonoid content of soy supplements cannot be confirmed from the data provided.
There was no clear preference between the provision of isoflavonoids in a soy protein matrix and as a purified supplement, with significant effects reported in two of four studies using soy protein (54,55) and three of five studies using purified soy isoflavonoids. (57-59) Efficacy was not consistently related to the duration of the study, with improvements noted in trials ranging from 6 to 16 weeks (54,55,57-59) and no improvements in studies from 12 to 104 weeks. (56,60-62)
A striking source of variation in the studies with either red clover or soy isoflavonoids was the placebo response, which ranged in magnitude from 0 to 70% compared with the baseline. The larger placebo responses in some studies could reflect the high motivation of the participants and belief in the benefits of isoflavonoids or inadvertent consumption of isoflavonoid-containing foods, such as soy and other legumes, during the study, as confirmed by increased isoflavonoid excretion in the placebo groups in two of the clinical trials. (50,51) This highlights the challenge of conducting such studies alongside growing community awareness of the possible benefits of soy and isoflavonoids and ready availability of products in pharmacies and supermarkets. The study that showed the greatest reduction in hot flushes, by 44% with treatment compared with placebo, implemented procedures to minimise the placebo effect by using a four-week observation period prior to intervention to identify susceptible individuals. (52) That study also involved Dutch participants whose diets are traditionally low in isoflavonoids, and participants were further instructed not to increase their intake of isoflavonoid-rich foods during the study.
Responsiveness to treatment could also depend on the individual's capacity to convert the isoflavonoid daidzein to equol, a secondary metabolite, which has greater oestrogenic potency than the original isoflavonoid. Not all individuals have the capacity to produce equol, with observed prevalence rates from 20% to 36% in different studies. (67) This factor could contribute to some of the unexplained variation in responses to the same supplement, with greater efficacy in equol producers. Differences in dietary macronutrient intake could also influence the absorption and hence efficacy of isoflavonoids. (68) None of the studies reviewed specifically addressed these issues.
Isoflavonoids from Kudzu
Kudzu (Pueraria lobata), or Japanese arrowroot, is used as a herb in traditional Chinese medicine. It has a unique profile of isoflavonoids with high concentrations of daidzein, exceeding those found in the soybean, and small quantities of genistein, formononetin, biochanin A and coumestrol. (44) No clinical trials were located on the efficacy of this herb in treatment of menopausal hot flushes.
Although NPS are considered to represent a lower risk than pharmaceutical goods, a range of safety concerns have been identified in the literature. The studies detailed in Tables 1-3 focused on the efficacy rather than the safety of supplements. Although mild adverse events were reported in trials of black cohosh, dong quai, evening primrose oil, red clover, sage and soy, these did not differ significantly between placebo and intervention groups. (30-32,34,52,54,56-58) Of the studies that specified the nature of adverse events, the most common symptoms related to gastrointestinal effects, such as bloating, nausea and constipation. (54,56-58) However, as the duration of the clinical trials was 12-24 weeks in most studies, long-term safety cannot be assumed and interactions with pharmaceutical drugs may be possible.
Additional information on the safety of NPS was identified in the literature, although many reports of adverse events were isolated and the dose responsible was not specified. Other adverse effects included an association between dong quai and increased skin photosensitivity; (41) and between ginseng and increased hypertension, jitteriness, confusion, depression and insomnia, and risk of hypotension on withdrawal. (69) Dong quai contains coumarins and ferulic acid that can exert antithrombotic effects, which could potentiate the effect of anticoagulant drugs such as warfarin and increase the risk of bleeding in susceptible individuals; (70) increased prothrombin time was observed in a patient who had taken a 565 mg tablet of dong quai one to two times/day for 4 weeks. (71) Consequently, women with clotting disorders or on anticoagulant therapy should not use dong quai.
Results from two randomised placebo-controlled trials suggested that black cohosh compared with the placebo was beneficial for relief of overall symptoms of menopause; (27,30) however, further trials are required to specifically measure the frequency and severity of hot flushes. One preliminary placebo-controlled trial reported that an extract of sage and alfalfa significantly reduced the frequency of severe hot flushes by 60% compared with the placebo. (34) To date, placebo-controlled trials do not support the use of dong quai, (31) evening primrose oil (32) or ginseng (33) for treatment of hot flushes. There was no conclusive evidence for the presence of oestrogenic components in any of these supplements.
The findings from 13 randomised placebo-controlled trials using isoflavonoids from red clover or soy, demonstrated significant efficacy in six studies (46%), with reductions in moderate to severe hot flushes by 10-44% compared with placebo; (52,54,55,57-59) seven studies (54%) reported no significant improvements. (50,51,53,56,60-62) If there was no relationship between isoflavonoids and hot flushes, the chance of a statistically significant treatment effect would be less than one in 20, or 5% of studies. The fact that significant findings were reported by one in two studies (46%), conducted by 13 independent investigators, suggests that these findings may not have arisen by chance. Therefore, it is recommended that further studies are conducted with appropriate design, including an adequate sample size, attention given to minimise inadvertent consumption of isoflavonoids by the placebo group, and evaluation of possible differences in individual responsiveness to treatment, including equol-producer status, (67,68) background diet (67,68) and BMI. (53) In vitro studies have demonstrated that isoflavonoids can bind to oestrogen receptors and exert an oestrogenic response, (20,22,23,46) providing a mechanism to support their use.
The present review provides evidence for health professionals that can be used to inform their advice to women regarding the efficacy of NPS for treatment of acute menopausal symptoms. Studies on the use of dong quai, evening primrose oil and ginseng suggest that they are unlikely to be useful for treatment of hot flushes. Evidence from a small number of short-term, randomised control trials of 12- to 24-week duration indicates that further research is warranted on black cohosh, red clover, soy, sage and alfalfa, involving studies with appropriate design and outcome measures, to establish any evidence of efficacy and evaluate optimal dosage, elucidate precise mechanisms of action and identify any long-term adverse effects.
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School of Public Health, Queensland University of Technology, Brisbane
K. Hanna, BHealthSci (NutrDiet)
A. Day, BMedSci, MNutrDiet
C. Patterson, PhD, MSc, GradDipBusAdmin
P. Lyons-Wall, PhD, GradDipNutrDiet
Betty Byrne Henderson Centre, Royal Brisbane and Women's Hospital and The University of Queensland, Brisbane
S. O'Neill, MBBCh, BAO
Correspondence: P. Lyons-Wall, School of Public Health, Queensland University of Technology, Victoria Park Road, Kelvin Grove, Qld 4059, Australia. Email: email@example.com
Table 1. Clinical intervention studies with black cohosh for treatment of acute menopausal symptoms Study Subjects Intervention Daiber (24) 36 German women with Uncontrolled trial, climacteric symptoms, 45-62 parallel: Remifemin twice/ years day Vorberg (25) 50 German women with Uncontrolled trial, climacteric symptoms, 45-60 parallel: Remifemin 40 years drops twice/day (liquid extract). No control group Warnecke (26) 60 German women with Uncontrolled trial, climacteric symptoms, 45-60 parallel: years 1. Remifemin 40 drops twice/day (liquid extract) 2. Conjugated oestrogen 0.625 mg/day 3. Diazepam 2 mg/day Stoll (27) 80 German women with Placebo-controlled trial, [greater than or equal to]3 randomised double-blind, hot flushes/day and parallel: psychological symptoms (e.g. 1. Remifemin 8 mg/day (4 anxiety, vaginal symptoms), tablets/day) 46-58 years. Power estimate 2. Conjugated oestrogen of sample size not reported 0.625 mg/day 3. Placebo Lehmann- 60 German women, Uncontrolled trial, Willenbrock hysterectomised with at randomised, parallel: and least one intact ovary and 1. Oestriol 1 mg/day Riedel (28) climacteric symptoms, <40 2. Oestrogen 1.25 mg/day years 3. Oestrogen/gestagen 4. Remifemin 8 mg/day (4 tablets/day) Liske 150 Polish perimenopausal Uncontrolled trial, et al. (29) and postmenopausal women randomised double-blind, with KMI score parallel: [greater than or equal to]20 1. Remifemin standard dose (moderate severity), 42-60 39 mg extract/day (no. of years. Sample size tablets not stated) calculated to detect 2. Remifemin high dose 127 standardised difference of mg extract/day 0.5 units, [alpha] = 0.05. Power not stated Wuttke 62 German women with =3 hot Placebo-controlled trial, et al. (30) flushes/day, 40-60 years. randomised, double-blind, Power estimate of sample parallel: size not reported 1. Black cohosh ((a)) 40 mg extract/day (2 capsules/ day) 2. Conjugated oestrogen 0.6 mg/day 3. Placebo Duration Study (weeks) Results Daiber (24) 12 * [down arrow] KMI (P < 0.001) Vorberg (25) 12 Remifemin at 12 weeks compared with baseline: * [down arrow] KMI (P < 0.001) Warnecke (26) 12 Remifemin at 12 weeks compared with baseline: * [down arrow] KMI Stoll (27) 12 Remifemin at 4, 8 and 12 weeks compared with oestrogen or placebo: * [down arrow] KMI (P < 0.001) Lehmann- 24 All groups at 8, 12 and 24 weeks compared Willenbrock with baseline: and * [down arrow] KMI (P < 0.01) Riedel (28) Liske 12 Standard or high-dose Remifemin at 12 and 24 et al. (29) extended to weeks compared with baseline: 24 * [down arrow] KMI (change from moderate to normal range symptoms) in 70-72% of subjects Wuttke 12 Black cohosh compared with placebo at 12 et al. (30) weeks: * [down arrow] MRS (P = 0.05) * NS change in hot flush scale of MRS Study Comments Daiber (24) Mean KMI improved from moderate-severe to light-moderate symptoms at 12 weeks Vorberg (25) Mean KMI improved from moderate to light symptoms at 12 weeks Warnecke (26) P-values not cited Stoll (27) [down arrow] 48-59% in KMI scales with Remifemin, [down arrow] 24-29% with placebo and low-dose oestrogen, compared with baseline. Oestrogen dose was too low for efficacy. 86% completed trial Lehmann- [down arrow] 43% in KMI with Remifemin, [down arrow] Willenbrock 47-62% with oestrogen groups, compared with baseline and Riedel (28) Liske No difference between standard and high dose. NS et al. (29) side-effects at either dose of Remifemin. 82% completed 12-week trial. 77% completed 24-week trial Wuttke [down arrow] 1.8 MRS points with black cohosh versus et al. (30) [down arrow] 1.5 MRS points with placebo, compared with baseline. Specific values not presented. 97% completed trial (a) Cimicifuga racemosa preparation CR BNO 1055 (Klimadynon/Menofem). KMI = Kupperman Menopause Index; MRS = Menopause Rating Scale; NS = non-significant. Table 2. Clinical intervention studies with dong quai, evening primrose oil, ginseng and sage for treatment of acute menopausal symptoms Study Subjects Intervention Hirata 71 US postmenopausal women Placebo-controlled trial, et al. (31) with >14 hot flushes any randomised, double-blind, severity/week or >5 hot parallel: flushes moderate to 1. Dong quai root 1.5 g (3 severe/week, mean age; capsules/day) placebo group, 52.6 2. Placebo [+ or -] 6 years; treatment group, 52.2 [+ or -] 4 years. Sample size calculated to detect difference of 11 vasomotor episodes/week, 90% power, [alpha] = 0.05 Chenoy 56 UK menopausal women with Placebo-controlled trial, et al. (32) [greater than or equal to]3 randomised, double-blind, hot flushes/day, 45-67 parallel: years. Sample size to 1. Evening primrose oil 500 mg detect 13% difference in /day + Vit E (8 capsules/day) hot flush frequency, 90% 2. Placebo power, [alpha] = 0.05 Wiklund 384 Swedish postmenopausal Placebo-controlled trial, et al. (33) women with =6 hot flushes, randomised, double-blind: at least 3/7 days, 45-65 1. 100 mg ginseng extract (2 years. Sample size to capsules/day) detect difference of 5 2. Placebo units in Patient Generated Wellbeing Index, 80% power, [alpha] = 0.05 De Leo 30 Italian postmenopausal Placebo-controlled trial: et al. (34) women, with 1. 120 mg sage + 60 mg alfalfa [greater than or equal to] n = 30 (tablet no. not stated) 10 hot flushes/day, 46-52 2. Placebo, n = 12 years. Power estimate of sample size not reported Study Duration Results Comments Hirata 24 weeks Dong quai compared [down arrow] 35% in hot flush et al. (31) with placebo at 24 frequency with treatment, weeks: [down arrow] 19% in hot flush * NS change in hot frequency with placebo, flush frequency compared with baseline. 86% * NS change in completed trial Kupperman Menopausal Index Chenoy 24 weeks Evening primrose [down arrow] 11% in day et al. (32) oil compared with frequency and [down arrow] placebo at 24 19% in night frequency in weeks: treatment versus [down arrow] * NS change in hot 37% in day frequency and flush frequency [down arrow] 29% in night or intensity frequency in placebo, compared with baseline. 63% completed trial Wiklund 2 weeks Ginseng group [down arrow] 30% in hot flush et al. (33) run in compared with frequency with treatment, 16 weeks placebo at 16 [down arrow] 24% in placebo, weeks: compared with baseline. * NS change in hot 99% completed trial flush frequency De Leo 3 months Sage and alfalfa [down arrow] 85% in hot flush et al. (34) compared with frequency with treatment, placebo at 3 [down arrow] 25% in placebo, months: compared with baseline * [down arrow] 60% in hot flush frequency (P < 0.01). Sage and alfalfa compared with baseline at 3 months NS = non-significant. Table 3. Clinical intervention studies with phytoestrogens for treatment of acute menopausal symptoms Study Subjects Intervention Red clover Baber 51 Australian Placebo-controlled trial, et al. (50) postmenopausal women, randomised, double-blind, [greater than or equal to] crossover: 3 hot flushes/day, 45-65 1. Promensil 40 mg years. Power estimate of isoflavonoids (1 tablet/ sample size not reported day) 2. Placebo Knight 37 Australian Placebo-controlled trial, et al. (51) postmenopausal women with randomised, double-blind, [greater than or equal to] parallel: 3 hot flushes/day, 40-65 1. Promensil 40 mg years. Power estimate of isoflavonoids/day (1 tablet sample size not reported /day) 2. Promensil 160 mg isoflavonoids/day (4 tablets/day) 3. Placebo Van de 30 Dutch postmenopausal Placebo-controlled trial, Weijer and women with >5 hot randomised, double-blind, Barentsen (52) flushes/day, mean age: parallel: 52.5 [+ or -] 5.2 years 1. Promensil isoflavonoids (placebo), 54.2 [+ or -] 80 mg/day (2 tablets/day) 7.4 years (treatment). 2. Placebo Power-based estimate of sample size not reported Tice 252 US menopausal women, Placebo-controlled trial, et al. (53) [greater than or equal to] randomised double-blind, 35 hot flushes/week, 45-60 parallel: years. Sample size to 1. Promensil ((a)) detect 15% decrease in hot isoflavonoids 82 mg/day (2 flush frequency, 90% power, tablets/day) [alpha] = 0.05 2. Rimostil ((a)) isoflavonoids 57 mg/day (2 tablets/day) 3. Placebo Soy isoflavonoids and soy protein Albertazzi 104 Italian Placebo-controlled trial, et al. (54) postmenopausal women, randomised, double-blind, [greater than or equal to] parallel: 7 hot flushes/day, 48-61 1. Soy protein ~76 mg years. Sample size to aglycone isoflavonoids detect difference of 3 hot (powder) flushes/day, 90% power, 2. Placebo [alpha] = 0.05 Washburn 51 US perimenopausal women, Placebo-controlled trial, et al. (55) [greater than or equal to] randomised, double-blind, 1 hot flush/night sweats/ crossover: day, 45-55 years. Power 1. Soy protein 34 mg estimate of sample size not isoflavonoids single dose reported (powder) 2. Soy protein 34 mg isoflavonoids, split dose 3. Placebo Kotsopoulos 94 Australian Placebo-controlled trial, et al. (56) postmenopausal women with randomised, double-blind, mild menopausal symptoms, parallel: hot flush number not 1. Soy isoflavonoids 118 mg specified, 50-75 years. /day (soy powder beverage) Power estimate of sample 2. Placebo size not reported Upmalis 177 US postmenopausal Placebo-controlled trial, et al. (57) women, randomised, double-blind, [greater than or equal to] parallel: 5 hot flushes/day, (mean 1. Soy isoflavonoid extract age 55 years). Power 50 mg isoflavonoids/day (2 estimate of sample size tablets/day) not reported 2. Placebo Scambia 39 Italian postmenopausal Placebo-controlled trial, et al. (59) women, hot flush number randomised, double-blind, not specified, 29-63 years. parallel: Power estimate of sample 1. Soy isoflavonoids 50 mg/ size not reported day (tablet no. not reported) 2. Placebo Conjugated equine oestrogens (CEE) give to all participants after week 6 St Germain 69 US perimenopausal women, Placebo-controlled trial, et al. (60) [greater than or equal to] randomised, double-blind, 10 hot flushes/night parallel: sweats/week. Power estimate 1. Soy protein of sample size not reported isoflavonoids 80.4 mg/day (aglycone) (powder + muffin) 2. Soy protein isoflavonoids 4.4 mg/day (powder + muffin) 3. Placebo Faure 75 French Placebo-controlled trial, et al. (58) postmenopausal women, randomised, double-blind, [greater than or equal to] parallel: 7 hot flushes/day, mean age 1. Soy isoflavonoids 70 mg 53 years. Sample size glycones (4 capsules/day) calculated to detect 2. Placebo difference of 3 hot flushes/day, 90% power, [alpha] = 0.05 Burke 241 US perimenopausal Placebo-controlled trial, et al. (61) women, mild symptoms randomised, double-blind, [greater than or equal to] parallel: 1 hot flush/day, 45-55 1. Soy protein 42 mg/day years. Power estimate of isoflavonoids (SP ((b)) sample size not reported beverage) 2. Soy protein 58 mg/day isoflavonoids (SP beverage) 3. Soy protein [greater than or equal to] 4 mg/day isoflavonoids Penotti 62 Italian Placebo-controlled trial, et al. (62) postmenopausal women, randomised, double-blind, [greater than or equal to] parallel: 7 hot flushes/day, 49-58 1. Soy isoflavonoids 72 mg/ years. Power estimate of day (2 tablets/day) sample size not reported 2. Placebo (2 tablets/day) Duration Study (weeks) Results Red clover Baber 2 X 12 4 Promensil compared with placebo at 12 weeks et al. (50) wash out (combined data): * NS change in Greene Menopause Score * NS change in hot flush frequency Knight 12 Promensil compared with placebo at 12 weeks: et al. (51) * NS change Greene Menopause Score * NS change in hot flush frequency Van de 12 plus 4 Promensil compared with placebo at 12 weeks: Weijer and run in * [down arrow] 44% hot flush frequency Barentsen (52) (P = 0.02) * NS change in Greene Menopause Score Tice 12 At 12 weeks: et al. (53) Promensil/Rimostil compared with placebo: * NS change in Greene Menopause Score * NS change in hot flush frequency Subgroup with BMI > 25.1 versus subgroup with BMI <25 kg/[m.sup.2]; * [down arrow] 19% in hot flush frequency (Promensil) (P = 0.09) * [down arrow] 23% in hot flush frequency (Rimostil) (P < 0.02) Soy isoflavonoids and soy protein Albertazzi 12 Soy protein group compared with placebo at et al. (54) 12 weeks: * [down arrow] 15% in hot flush frequency (P = 0.01) Washburn 6 per Soy protein split-dose group compared with et al. (55) treatment, placebo: 18 total * [down arrow] 23% in hot flush severity (P < 0.05) * [down arrow] 11% in night sweat severity (NS) * [up arrow] 4% in hot flush frequency (NS) * [up arrow] 4% in night sweat frequency (NS) Kotsopoulos 12 Soy isoflavonoids compared with placebo at et al. (56) week 12: * NS change in menopause questionnaire * NS change in hot flush component of menopausal symptoms questionnaire Upmalis 12 Soy extract group compared with placebo at et al. (57) 12 weeks: * [down arrow] 10% in hot flush severity score (P = 0.01) * [down arrow] 9% in hot flush frequency (trend, P = 0.08) * [down arrow] 28% in night sweat frequency (P = 0.04 at 6 weeks, NS at 12 weeks) Scambia 12 Soy isoflavonoids compared with placebo at et al. (59) treatment week 6: and * [down arrow] 20% in hot flush frequency placebo (P < 0.01) Soy isoflavonoids compared with given to placebo at week 12 (both groups taking CEE): week 10 * NS change hot flush frequency only St Germain 24 High isoflavonoid soy compared with et al. (60) placebo at 24 weeks * NS change in hot flush frequency * NS change in night sweat frequency Faure 16 Soy isoflavonoids compared with placebo at et al. (58) 16 weeks: * [down arrow] 40% in hot flush frequency (P = 0.01) Burke 104 Soy isoflavonoids compared with placebo at et al. (61) 12 or 104 weeks: * NS change in hot flush frequency Penotti 24 Soy isoflavonoids compared with placebo at et al. (62) 12 or 24 weeks: * NS change in hot flush frequency Study Comments Red clover Baber [down arrow] 22% in hot flush frequency with Promensil, et al. (50) [down arrow] 32% with placebo, compared with baseline. 84% completed trial Knight [down arrow] 29% in hot flush frequency with 40 mg dose, et al. (51) [down arrow] 34% with 160 mg dose, [down arrow] 33% with placebo, compared with baseline. 95% completed trial Van de [down arrow] 44% in hot flush frequency with Promensil, Weijer and [down arrow] 0% with placebo, compared with baseline. Barentsen (52) 87% completed trial Tice Hot flush frequency compared with baseline: whole group: et al. (53) [down arrow] 41% with Promensil, [down arrow] 34% with Rimostil, [down arrow] 36% with placebo. Subgroup BMI > 25.1 versus BMI <25 kg/[m.sup.2]: Promensil: [down arrow] 49% versus [down arrow] 30%; Rimostil: [down arrow] 45% versus [down arrow] 22%; Placebo: [down arrow] 32% versus [down arrow] 40%. 98% completed trial Soy isoflavonoids and soy protein Albertazzi [down arrow] 45% in hot flush frequency with soy et al. (54) protein, [down arrow] 30% with placebo, compared with baseline. 76% completed trial Washburn Original scores compared with baseline not reported. No et al. (55) significant changes in soy protein single-dose group, compared with placebo. 82% completed trial Kotsopoulos Hot flush scores not reported. 80% completed trial et al. (56) Upmalis [down arrow] 28% in hot flush severity with soy versus et al. (57) [down arrow] 18% in placebo; [down arrow] 28% hot flush frequency with soy, [down arrow] 19% in placebo; [down arrow] 62% in night sweat frequency with soy, [down arrow] 34% in placebo, compared with baseline. 69% completed trial Scambia [down arrow] 45% hot flush frequency with isoflavonoids, et al. (59) [down arrow] 25% with placebo, compared with baseline. Withdrawal rate not specified St Germain [down arrow] 45% in hot flush frequency with 80.4 mg et al. (60) isoflavonoids, [up arrow] 3% with 4.4 mg isoflavonoids, [down arrow] 45% with placebo, compared with baseline. 99% completed trial Faure [down arrow] 61% in hot flush frequency with soy et al. (58) isoflavonoids, [down arrow] 21% with placebo, compared with baseline. 84% completed trial in soy group. 60% completed trial in placebo group Burke Hot flush frequency at 12 or 104 weeks compared with et al. (61) baseline, in whole group: 1. [down arrow] 19/42%, (42 mg isoflavonoids) 2. [down arrow] 50/59% (58 mg isoflavonoids) 3. [down arrow] 51/77% with placebo. 88% completed trial Penotti Hot flush frequency at 12 or 24 weeks, compared with et al. (62) baseline: 1. [down arrow] 44/53% with soy isoflavonoids 2. [down arrow] 53/53% with placebo. 79% completed study (a) Promensil contains a higher proportion of biochanin A and genistein; Rimostil contains a higher proportion of formononetin and daidzein. (b) Soy protein. BMI = body mass index; NS = non-significant.
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|Publication:||Nutrition & Dietetics: The Journal of the Dietitians Association of Australia|
|Date:||Dec 1, 2005|
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