Phytoestrogens in menopause.
Abstract: In the context of research into phytotherapeutic agents for the treatment of menopausal symptoms, the phytoestrogen containing plants have received the most attention in the scientific arena. This review examines the evidence for benefits of these plants for menopause related complaints, including findings from clinical studies and postulated mechanisms of action. Research relating to safety concerns, particularly regarding long term use by women with, or at risk of estrogen dependent cancers, is also discussed. Evidence for the non phytoestrogen phytotherapeutic treatments of menopausal symptoms is reviewed in a subsequent article.
Article Type: Clinical report
Subject: Menopause (Development and progression)
Menopause (Physiological aspects)
Menopause (Care and treatment)
Isoflavones (Health aspects)
Isoflavones (Physiological aspects)
Women (Health aspects)
Women (Management)
Author: van Die, M. Diana
Pub Date: 03/22/2011
Publication: Name: Australian Journal of Medical Herbalism Publisher: National Herbalists Association of Australia Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2011 National Herbalists Association of Australia ISSN: 1033-8330
Issue: Date: Spring, 2011 Source Volume: 23 Source Issue: 1
Topic: Event Code: 200 Management dynamics Computer Subject: Company business management
Geographic: Geographic Scope: Australia Geographic Code: 8AUST Australia
Accession Number: 254971767
Full Text: Introduction

The phytoestrogen containing plants have received the most attention in the scientific arena with relatively little research conducted on other phytotherapeutic agents for menopause (Nedrow 2006). However concerns have now been raised over the safety of long term use of some phytoestrogens and phytoSERMs (defined below) specifically on breast and endometrial tissue proliferation (Bodinet 2004, Unfer 2004).

Phytoestrogens have been defined as plant derived diphenolic substances with a chemical structure similar to estrogen that enables them to bind to both alpha (ER[alpha]) and beta (ERP) estrogen receptors (Kuiper 1998). Phytestrogens might act as anti-estrogens (estrogen antagonists) or estrogen agonists, depending on the levels of endogenous estrogens or other competitive receptor ligands (Setchell 1999). Thus their estrogen like effects could predominate in the estrogen depleted environment of postmenopause.

Classes of phytoestrogens

The main classes of phytoestrogens are isoflavones, coumestrol and lignans. Isoflavones such as daidzein and genistein are found in highest concentrations in soybeans and soy products. In soybean itself and most soy products, genistein and its beta glycoside, genistin, constitute around 50-55% of total isoflavone content compared with 40-45% for daidzein/daidzin and 5-10% for glycitein/ glycitin (Messina 2006). Isoflavones are also found in Trifolium pratense (red clover) along with coumestrol. Coumestrol also occurs in alfalfa sprouts (Medicago spp), clover sprouts (Trifolium spp), soy sprouts (Glycine max) and split peas (Pisum spp) (Murkies 1998, USDA 1998). Lignans such as secoisolariciresinol diglucosides are found in linseeds/flaxseed (Linum usitatissimum) and whole grains (Murkies 1998, USDA 1998).

Mechanisms of action

There are several possible mechanisms by which phytoestrogens may exert their effects including interaction with estrogen receptors (Collins-Burrow 2000, Pearce 2003), displacement of estrogens from sex hormone binding globulin (Aldercreutz 1992, Hillerns 2005, Hodgert 2000), regulation of estrogen metabolism (Dai 2002, 2003) and inhibition of aromatase (estrogen synthetase) (Kao 1998). While the condition for phytoestrogen activity in the case of lignans is completely dependent on colonic bacteria that convert the precursor, secoisolariciresinol diglucoside into enterodiol and enterolactone (Aldercreutz 1998), isoflavones are inherently estrogenic and may become further activated by conversion to equol, a bacterial metabolite of daidzein in the gastrointestinal tract (Setchell 2002).

Estrogenic potency of phytoestrogens

The estrogenic potency of all the xenobiotic estrogens however is very low compared with that of endogenous estrogens (Cassidy 1998, Jefferson 2000, Muthyala 2004). Genistein transactivates ER[alpha] and induces estrogenic effects with approximately 103-104 fold less potency than estradiol (Jefferson 2000, Muthyala 2004). Similarly for daidzein and two of its metabolites, equol and O-desmethylangolensin, binding affinity to ER[alpha] was found to be 103-104 fold lower than for the endogenous estrogen estradiol (Schmitt 2001). [S-equol has an affinity for ER[beta] nearly as high as that of genistein] (Muthyala 2004). Nonetheless the estrogenic potency of phytoestrogens is believed to be significant enough, especially for ER[beta], that they may trigger many of the biological responses that are evoked by the physiological estrogens (Kuiper 1998). After a high soy meal, serum isoflavone concentrations can reach low micromolar levels (Mathey 2006, Takshima 2003) exceeding postmenopausal total estrogen concentrations by approximately 103 fold, although free serum genistein levels return to baseline after twenty four hours (Lapcik 1998).

PhytoSERMS

Some phytoestrogens are believed to have selective estrogen receptor modulator activity and hence have been termed phytoSERM. Like the selective estrogen receptor modulator (SERM) drugs, they may have a selective pattern of estrogen agonist antagonist activity depending on the target tissue. The soy isoflavone genistein preferentially binds to ER[beta] with a 7-30 fold greater affinity for ER[beta] than for ER[alpha] (McCarty 2006).

Glycine max L, soybean, family Fabaceae

Research on soy for menopausal symptoms/ hot flushes

Evidence of benefit in hot flushes has been derived from clinical studies on soy in the form of soy isoflavones (Ferrari 2009, Han 2002), a standardised soy extract (Scambia 2000), soy protein (Albertazzi 1998, Basaria 2009, Faure 2002, Washburn 1999), soy foods (Dalais 1998), daidzein rich isoflavone aglycones (Khaodiar 2008) and genistein (Crisafulli 2004, D'Anna 2007). Genistein also significantly improved Kupperman Index (KI) scores in an open randomised controlled trial (RCT), compared with baseline and with placebo, p<0.05, after 12 months (Sammartino 2003). Another RCT with a soy isoflavone extract (total of 50 mg genistin and daidzin per day) showed a positive trend that did not reach statistical significance, p<=0.08 (Upmalis 2000). However findings from soy studies in this context have been conflicting, with other RCTs showing improvements for the control group as well as soy flour (Murkies 1995), isoflavone supplementation (Knight 2001, Secreto 2004), soy protein (Burke 2003, St Germain 2001) and soy beverage (Table 1) (Kotsopoulos 2000, Van Patten 2002).

Possible reasons for conflicting findings regarding hot flushes

It has been suggested that these contradictory findings may reflect the diverse supplement regimens studied (McCarty 2006), the range of exposure measures used (urinary or serum isoflavone levels versus intake of soy products/foods/isoflavones) and/or the differing amounts of products consumed or dosages administered (Messina 2006). In addition variations in the bioavailability of genistin may be at least partially responsible for conflicting findings. Processing has been shown to reduce the isoflavone content of some soy proteins by as much as 80% (Murphy 1999), thereby affecting the estrogenicity (Allred 2004) as well as circulating (and probably also target tissue) concentrations of genistein aglycone, the biologically active form (Allred 2005). It is therefore possible that some of the isoflavone regimens tested have failed to achieve adequate free genistein concentrations in some subjects (McCarty 2006).

There is also considerable inter individual variation in gut metabolism of genistein and daidzein (Setchell 2002), and it has been suggested that 'bacterio typing' individuals, according to their capacity to form equol, may hold the clue to the effectiveness of soy protein diets in the treatment or prevention of hormone dependent conditions (Setchell 2002). As suggested by the recent study on daidzein rich isoflavone aglycones (Khaodhiar 2008), the type of isoflavone may be the determining factor in the effectiveness of soy supplementation for alleviating hot flushes. High genistein containing isoflavone supplements (providing more than 15 mg genistein, calculated as aglycone equivalents per treatment) were also found to consistently report a statistically significant decrease in hot flush symptoms according to a review of 11 studies (Williamson-Hughes 2006). Additionally the failure of some studies to reach significance over placebo/control, may reflect the modest benefit of soy isoflavones that is expected in relation to hot flushes (McCarty 2006).

Other benefits of soy in postmenopause

In addition to potential benefits on menopausal symptoms, soy has been shown to favourably affect cardiovascular risk markers such as total cholesterol, low density lipoprotein (LDL) cholesterol (Washburn 1999, Anderson 1995, Taku 2007), diastolic blood pressure (Washburn 1999), high density lipoprotein (HDL) cholesterol and triglycerides (Zhan 2005) and vascular endothelium (Shah 2003). Studies have also shown benefits on bone metabolism (Ho 2003, Kritz-Silverstein 2002, Setchell 1999) and bone resorption (Weaver 2009) with some additional support from epidemiological studies from China and Japan for a positive relationship between bone density and soy intake (Ho 2003, Somekawa 2001). The preventive effects of isoflavones on bone loss in early postmenopausal women were shown in a one year RCT to depend on an individual's capacity to produce equol (Wu 2007). Thus dietary or supplemental soy may confer additional advantages for the postmenopausal woman at greater risk than her premenopausal counterpart of CVD and osteoporosis.

Soy safety concerns

Because of the estrogen like effects exerted by isoflavones under some conditions, concerns have arisen that they may potentially promote breast and endometrial cancers (Bodinet 2004, Unfer 2004). This is discussed further below. Uterotrophic effects were shown in rats fed genistein at doses of 750 mg/kg (Rachon 2007, Santell 1997). In an RCT with 376 healthy postmenopausal women with an intact uterus, long term treatment (up to 5 years) with soy phytoestrogens (150 mg of isoflavones per day) was associated with a significantly higher occurrence of endometrial hyperplasia than with placebo (3.37% vs 0%), although no cases of malignancy were detected by endometrial histology from biopsies. No impact has been shown of soy isoflavones on endometrial proliferation in other clinical studies (Balk 2002, D'Anna 2007, Penotti 2003, Sammartino 2003). Of some concern is the potential antithyroid/goitrogenic effect of soy, especially in an iodine deficient environment (Ikeda 2000, Kimura 1976) and possible exacerbation of autoimmune thyroid disease with high soy intake (Doerge 2002). This appears unlikely at dietary levels.

Soy consumption/supplementation and breast cancer

Soy was initially investigated for its potential to reduce cancer risk, particularly breast cancer (Adlercreutz 2002). This is supported by epidemiological evidence showing that among Asian women, higher soy intake is associated with a lower breast cancer risk (Hirose 1995, Lee 1991, Wu 2008, Wu 1996, Yamamoto 2003) (nearly a one-third reduction) (Wu 2008). The findings that soy isoflavones exert anti estrogenic effects and may thereby be chemopreventative (Folman 1966) and a protective effect of soy against carcinogen induced breast cancer in rodent studies (Barnes 1990) further add weight to this consideration.

Concerns that subsequently arose regarding a potential adverse impact on breast cancer risk and the growth of existing estrogen dependent tumours were predominantly triggered by findings from in vitro research as well as rodent studies showing that isoflavones bind to and transactivate estrogen receptors (ERs) (Jefferson 2000, Muthyala 2004) and induce proliferation and estrogenic markers in MCF-7 cells (an ER positive breast cancer cell line) (Bodinet 2004, Ju 2001, Schmidt 2001). In ovariectomised athymic mice, dietary genistein and genistin enhance the growth of human MCF-7 cell tumour xenoplants (Hseih 1998) which appears to hinge on the activation of ERa (McCarty 2006). Effect of soy protein isolates and genistein in this context is dose dependent (Ju 20, Allred 2001). Dietary daidzein had only a slight but significant effect on tumour growth while equol did not stimulate the growth of estrogen dependent tumours in athymic mice, even though total daidzein or equol plasma levels in these mice were in the range that stimulated MCF-7 cell growth in vitro (Ju 2006). This may suggest that pharmacokinetic factors attenuate the estrogenic effects of daidzein and equol in vivo (Ju 2006).

A recent study in nude mice found that combined soy isoflavones did not affect primary tumour growth but increased metastasis to all organs tested, daidzein increased mammary tumour growth by 38% and increased lung and heart metastases, while genistein decreased mammary tumour growth by 33% and decreased bone and liver metastases (Martinez-Montemayor 2010). The ability of genistein to inhibit human cancer metastasis and modulate markers of metastatic potential in humans has been corroborated in animal studies and early phase human clinical trials (Pavese 2010). Fermented soy milk products have also shown growth inhibitory effects on various human breast carcinoma cell lines, especially on MCF-7 cells in severe immune deficient mice (Chang 2002) and on induced mammary carcinogenesis in the rat (Ohta 2000).

Relevance of in vitro studies and rodent models to humans

Findings from in vitro studies and rodent models are of questionable relevance to humans. It has been pointed out that the lack of immune function in athymic mice and the estrogen depleted environment do not accurately reflect the situation in either pre or post menopausal women (Messina 2008). Studies using parenteral doses of purified isoflavones are of limited interest, as are those using scaled oral doses 8 to 16 times higher than the typical intake from traditional Asian diets (Messina 2008). In humans at least 95% of isoflavones are conjugated and largely inactive (Rowland 2003). A higher percentage of genistein and daidzein appears in the free/aglycone form in rats (Gu 2006). In addition the metabolite, equol, is effectively formed by gut bacteria in rodents and predominates in the serum of rodents, whereas only 30-50% of humans are equol producers (Rowland 2000). Daidzein and genistein remain the predominant isoflavones in human serum after ingestion of soy or mixed isoflavones (Gu 2006, Rowland 2000, Setchell 2002).

Biphasic effects of dose have been observed both in vitro (Fioravanti 1998, Zava 1997) and in vivo (Messina 1991). In vitro genistein at higher concentrations (>10 [micro]M) inhibits growth of MCF-7 cells (probably by estrogen independent mechanisms such as modulating genes) (Chen 2003, Zava 1997) but stimulates growth at relatively low and physiologically relevant concentrations ([micro]M) via estrogen dependent mechanisms (Chen 2004, Power 2003). In standard rodent models, isolated soy protein or isoflavones were shown to suppress rather than stimulate growth of tumours in mice implanted with MCF-7 cells (Gotoh 1998) and even enhance the efficacy of tamoxifen (Mai 2007). Han and co workers (2001) found that both genistein and daidzein were able to inhibit the proliferation stimulating activity in MCF-7 cells in a high estrogen environment, suggesting that the hormonal milieu may be of relevance to the in vivo effects. In rodent models the timing of soy or isoflavone exposure relative to the implantation of cancer cells or the administration of carcinogens may be a critical factor in determining whether tumour development or growth is suppressed or enhanced (Messina 1991). Prepubertal administration of high dose genistein induced a premature differentiation of breast tissue that diminished susceptibility of adult rats to carcinogen induced breast cancer (Cabanes 2004).

An additional limitation with the observation of in vitro binding to ER[alpha] and ER[beta] is that ER binding alone is a poor predictor of in vivo activity (Pike 1999), ER ligands often have very different/opposite effects depending on dosage and the type of tissue studied (Pearce 2003).

Findings from clinical studies have generally but not exclusively been favourable in regard to breast cancer risk. In premenopausal women soy supplements resulted in stimulation of estrogen sensitive markers and increased breast epithelium proliferation (McMichael-Phillips 1998, Sathyamoorthy1994) consistent with reports that low concentrations of isoflavones (isoflavone supplement 40 mg per day equivalent) stimulate ER positive cells. Another study reported that after 6 months of soy protein isolate, hyperplastic epithelial cells were present in 7 of 24 completing subjects compared with 1 at baseline (Petrakis 1996).

However no increase in breast cell proliferation (a marker of potential tumour promotion) was observed following supplementation with isoflavone or isolated soy protein in four clinical studies; three with breast cancer patients (Hargreaves 1999, Sartippour 2004, Palomares 2004) and one with healthy women (Cheng 2007) in which breast biopsies were taken before and after. Two pilot studies on breast cancer survivors showed no significant effect of isoflavone supplementation on breast cell proliferation over 2 weeks (Sartippour 2004) and one year (Palomares 2004) respectively. Recently conducted one year and two year long studies indicated that isoflavone supplements do not affect breast density in premenopausal women (Maskarinec 2003, 2004) nor endometrial thickness in postmenopausal women (Steinberg 2010).

Case control studies have found an inverse association between soy intake and risk for premenopausal breast cancer in Asian populations; two such studies have found a similar association with postmenopausal breast cancer (Dai 2001, Hirose 1995, Lee 1992, Wu 2002, Wu 1996). In one of these, high soy intake among Asian Americans during adolescence was found to predict a lower risk for postmenopausal breast cancer, especially for those maintaining the high soy consumption into adult life (Wu 2002). Breast cancer survival is unrelated to soy food intake in epidemiological studies (Boyapati 2005, Fink 2007).

While current evidence suggests that isoflavone intake at dietary levels is unlikely to increase breast cancer risk or estrogen sensitive breast cancer recurrence, most studies have been relatively short term. Concerns exist regarding long term safety. The possibility has been raised that by promoting low level activation of ERa, nutritional intakes of genistein could modestly boost cancer growth (McCarty 2006). Additionally breast cancer patients taking SERMs are advised to limit their intake of soy foods and avoid isoflavone supplementation due to concerns these may interfere with SERMS such as tamoxifen (McCarty 2006, Messina 2008).

Linum usitatissimum L, linseed/flaxseed, family Linaceae

Lignans are nonsteroidal polyphenolic substances that have been shown to bind to estrogen receptors and exert partial agonist or antagonist action depending on the target tissue (Aldercreutz 1987, Kaldas 1989). They influence hepatic estrogen metabolism and increase the synthesis of SHBG involved in the binding and availability of sex steroids (Aldercreutz 1987). Data from a cross over study (Lemay 2002) with 25 hypercholesterolemic menopausal women indicates that after 2 months of treatment, 40 g of crushed linseed was as effective as 0.625 mg of conjugated estrogens in relieving mild menopausal symptoms measured on the KI, and in lowering serum levels of glucose and insulin, but produced no significant change in lipid profile.

However a recent RCT with 38 postmenopausal women found that flaxseed (46 mg lignans/day in the form of bread produced with partially defatted ground flaxseed) was no more effective than placebo for reducing hot flushes and KI (Simbalista 2010). Both groups had significant but similar reductions in hot flushes and KI after 3 months. Endometrial thickness was not affected in either group.

In another study linseed supplementation (40 g/ day) for 3 months was shown to improve lipid profile in postmenopausal women compared with a wheat based regimen (Lucas 2002). Elsewhere it was found to favourably but not significantly affect blood cholesterol compared with wheat germ after 12 months (Dodin 2005).

Trifolium pratense L, red clover, family Fabaceae, subfamily Papilionaceae

Red clover extracts are quite popular for the treatment of menopausal symptoms (Fugh-Berman 2001) and have received attention for their phytoestrogen content. A preformulated extract of red clover was found to contain the coumestan, coumestrol; isoflavones, daidzein, genistein and their methylated precursors formononetin, biochanin A; as well as flavonoids including naringenin. Daidzein, genistein, formononetin, biochanin A and naringenin were estrogenic in the alkaline phosphatase assay, with all of these except formononetin bound to one or both ERs (Booth 2006). In addition to SERM activity of the phyotestrogen components, biochemical analysis shows they act as selective estrogen enzyme modulators (SEEMs), have antioxidant activity and interact with transcription factors such as NF-kappa-[beta] (Beck 2005).

Clinical trials of red clover in hot flushes

Several RCTs have been conducted on Promensil[R], an extract of red clover leaf and flower standardised for isoflavone content, administered in a 500 mg tablet containing 40 mg per tablet of total isoflavones. Results have largely been disappointing with only one showing superiority over placebo to date. In a 12 week RCT with 30 symptomatic women aged 49-65 (26 completed), Van der Weijer and Barentsen (2002) found Promensil[R] (80 mg/day) to be superior to placebo for alleviating hot flushes (p=0.015) although no significant effect was observed for overall menopausal symptoms rated on the Greene Climacteric scale.

In a study by Baber and colleagues (Baber 1999), no significant difference was observed in flushing scores or Greene Climacteric scale scores (p=0.158) in a cross over trial with Promensil[R] 40 mg/day and placebo for 3 months each. Fifty one women aged 45-64 with a minimum of 3 flushes per day were recruited; 43 completed both arms. Lack of superiority was similarly found in another 12 week RCT that randomised 37 women with 3+ hot flushes per day to either 40 mg or 160 mg/day Promensil[R] or placebo although flushing frequency decreased in all arms over the 12 week period (Knight 1999). No between group differences were observed in these studies in vaginal cytology, endometrial thickness as measured by ultrasonography, or serum hormone levels.

While these studies may have been subject to lack of power due to the low numbers recruited, or lack of adequate symptom severity at baseline, a larger RCT by Tice and co workers (2003) similarly failed to support the superiority of Promensil[R] (82 mg total isoflavones/day) or of Rimostil[R] (57 mg isoflavones/day) over placebo. This RCT recruited 252 participants aged 45-60 years with at least 35 hot flushes per week and followed them up for 12 weeks.

Neither red clover (120 mg) nor black cohosh (128 mg) was superior to placebo (57%, 34% and 63% respectively) in reducing the number of vasomotor symptoms in 89 menopausal women over 12 months (Geller 2009), nor had any impact on cognitive function in 66 of these women (Maki 2009).

Other potential effects of extracts of red clover

Some evidence supports the role of red clover isoflavones in reducing bone loss induced by ovariectomy in rats, probably by reducing bone turnover via inhibition of bone resorption (Occhiuto 2007). In an uncontrolled study involving 46 postmenopausal women, the BMD of the proximal radius and ulna rose significantly over 6 months with two doses of isoflavones extracted from red clover (Trifolium pratense) (Rimostil[R]), namely by 4.1% over 6 months with 57 mg/day (p = 0.002) and by 3.0% with 85.5 mg/day (p = 0.023) of isoflavones) (Clifton-Bligh 2001). The effect was not dose related. In another RCT of 205 women aged 49-65, all women lost BMD but the group assigned to red clover derived isoflavone supplement (providing a daily dose of 26 mg biochanin A, 16 mg formononetin, 1 mg genistein, and 0.5 mg daidzein for 1 year) lost significantly less (Atkinson 2004).

A significant increase in HDL cholesterol has been observed with administration of red clover isoflavone 40 mg/day (Promensil[R]) over 3 months (Knight 1999) and Rimostil[R] at 28.5 mg, 57 mg, and 85.5 mg over a 6 month period (15.7-28.6%) (Clifton-Bligh 2001), although the magnitude of the response was independent of the dose used. The latter uncontrolled study also demonstrated a significant fall in serum apolipoprotein B (by 11.517.0%) after 6 months of treatment (Clifton-Bligh 2001). Also of relevance to atherosclerosis risk is the evidence from one study of improved systemic arterial compliance and elasticity with red clover supplementation in postmenopausal women (Nestel 1999).

Concerns have been raised regarding the safety of use of red clover isoflavone supplements in patients with breast or endometrial cancer (Booth 2006b) based on data suggesting a weak estrogenic action in the ovariectomised rat model (Burdette 2002). However a recent three year RCT of a once daily standardised 40 mg red clover isoflavone dietary supplement (Promensil[R], Novogen) in 401 women aged 35-70 years with a family history of breast cancer reported no adverse effect on breast density, skeletal strength or cardiovascular status (Powles 2008). No significant differences in endometrial thickness were detected between those taking red clover isoflavones and placebo, consistent with findings from a rodent model (Overk 2008).

Humulus lupulus L, hops, family Cannabinaceae

The strobiles of hops contain the potent phytoestrogen 8-prenylnaringenin (8-PN) (Overk 2005). The ability of 8-PN to exert systemic endocrine effects in healthy postmenopausal women was demonstrated in a dose escalation RCT using single oral doses of50, 250 or750 mg 8-PN (Rad 2006). Decreases in LH serum concentrations were found after the highest dose. Methanol extracts of hops showed significant competitive binding to ER alpha and ER beta, and exhibited estrogenic activity with cultured Ishikawa (endometrial) cells (Lui 2001). In rodent models H. lupulus extracts were not found to affect uterine weight gain, but 8-PN at equivalent doses to those used in human studies did show a dose related estrogenic effect on the uterus, raising concerns about a potential deleterious effect in women (Overk 2008).

Convincing evidence from robust clinical trials to support the efficacy of hops extracts for reduction of hot flushes is lacking. A RCT was conducted on a standardised (on 8-PN) hop extract administered to postmenopausal women at doses corresponding to 100 [micro]g 8-PN and 250 [micro]g 8-PN (Heyerick 2006). At the lower dose a significant reduction in the incidence of hot flushes and other menopausal symptoms (sweating, insomnia, heart palpitation, irritability) measured on the modified KI was found, compared with placebo, after 6 weeks p = 0.023, but not after 12 weeks p = 0.086. At the higher dose hop extract was superior to placebo for hot flushes at 6 weeks p <0.01. The effects of hop extract (standardised at 100 [micro]g 8-prenylnaringenin per day) were investigated in a double blind placebo controlled cross over study for 16 weeks with 36 menopausal women.

After 8 weeks both arms significantly improved on the KI, the Menopause Rating Scale (MRS) and a Visual Analogue Scale (VAS). After 16 weeks only the active treatment after placebo further reduced scores on KI (p = 0.02) and VAS (p = 0.03). However no significance was found over placebo (Erkkola 2010).

Hops was one component of the morning/evening formula found to reduce vasomotor, anxiety and depression scores on the Greene Climacteric Scale (GCS) by 50%, 56% and 32% respectively at the end of 8 weeks (Sun 2003). However the lack of a control group in this study is a serious limitation. The efficacy of hop extracts in reducing menopausal hot flushes has been reported by Goetz based on treatment of patients treated using different types of non standardised hops preparations (Goetz 2007).

The effects of a topical gel containing hyaluronic acid, liposomes, vitamin E and hop extract was assessed on vaginal dryness and associated atrophic vaginitis (itching, burning, dyspareunia, vaginal inflammation/oedema and rash) in 100 postmenopausal women in a multicentre open non controlled design (Morali 2006). Following application of 2.5 g of gel/day for 1 week, reduced to two applications/week for 11 weeks, symptoms were significantly reduced as assessed by a 4 point scale and presence of vaginal abrasions and disepithelialisation. An overall judgment on the acceptability of the treatment was made by the subjects as well as an overall judgment on the efficacy and safety of the device by the investigator.

Trigonella foenum-graecum L, fenugreek, family Fabaceae

Fenugreek has been the subject of one comparator trial with HRT that assessed the effects on vasomotor symptoms in 50 postmenopausal women (Hakimi 2006). Women were assigned to receive either 0.625 mg conjugated estrogen with 10 mg medroxy progesterone acetate or 6 g fenugreek seed powder daily for 8 weeks. Significant reductions were observed in both groups after four and eight weeks of treatment, although the HRT significantly outperformed the fenugreek.

Pueraria montana var. lobata (formerly P. lobata) Lour, kudzu, family Fabaceae

Kudzu is a traditional Chinese herbal remedy for menopausal symptoms as well as an ingredient in preparations for conditions such as osteoporosis, CHD and some hormone dependent cancers (Woo 2003). Many different species of kudzu are used in Asia. In China P montana (also known as P. thunbergiana) and P. thomsonii are used interchangeably. P. mirifica and P. tuberosa are also used frequently (Abascal 2007). Kudzu root extract contains isoflavonoid phytoestrogen components such as daidzin, daidzein and genistein (Cherdshewasart 2008, Kang 2006) that may be responsible for its action.

No data from RCTs on vasomotor symptoms could be found for kudzu in the literature. From a non controlled trial of 6 months duration, data was obtained for two doses of Pueraria mirifica (50 mg/day and 100 mg/day) for 37 pre and postmenopausal women (Lamlertkittikul 2004). Significant reductions in scores of a similar magnitude on the modified Greene climacteric scale were seen for both groups (decreasing from 35.6 to 26.6, 17.2 and 15.1 with 50 mg/day, while 100 mg/day resulted in declines from 32.6 to 21.0, 14.8 and 13.6 at 1-, 3- and 6-months respectively).

A pilot study of isoflavones from kudzu and red clover with other nutrients on menopausal symptoms was conducted over 12 weeks on 25 menopausal women suffering from severe hot flushes and night sweats (Lukaczer 2005). A 46% decrease in hot flushes was observed, with an improvement in subjectively rated quality of life, p <0.001. Modest improvement was observed in cardiovascular risk markers, the ratio of total cholesterol to HDL cholesterol and homocysteine. A statistically significant improvement was found for a proposed marker of breast cancer risk, the ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone, p < 0.001.

A decocted root extract of Pueraria lobata, equivalent to 100 mg isoflavone, was compared with HT and no treatment in 127 postmenopausal women (n = 45, n = 43 and n = 39 respectively) for a 3 month period (Woo 2003). Kudzu had no significant effect on lipid profile, FSH or LH, but did improve flexible thinking and attention span compared with no treatment, p < 0.05.

A herbal supplement Avlimil[R] containing eleven herbal components including kudzu was observed to stimulate MCF-7 tumor growth in a dose dependent manner calling into question its safety for women with estrogen dependent breast cancer (Ju 2008). However no increase in uterine weight was observed in the animal model. Similarly in healthy postmenopausal women, no endometrial proliferation or hyperplasia was reported after 24 weeks of Pueraria mirifica at doses of 20, 30 and 50 mg/day (Manonai 2008). Beneficial effects on bone loss are suggested from studies in both human and rodent models (Manonai 2008).

Conclusion

Phytoestrogen containing plants are attracting increasing attention within the scientific arena for the treatment of menopausal symptoms, with some evidence supporting their benefits in vasomotor symptoms and reduction of risk factors for postmenopausal complaints. Existing data from human studies suggest that isoflavone consumption at normal dietary levels does not adversely impact on the risk/progression of estrogen-dependent cancers. However, research continues to further elucidate modifying factors such as type, quantity, duration and timing of exposure, as well as equol producer status, presence or absence of specific gut microflora, and hormonal profile of individuals.

References

The full reference list is available on request from ajmh@nhaa. org.au or download from www.nhaa.org.au under Publications & Products, AJMH, Journal supplements.

Dr Diana van Die is a Melbourne based medical herbalist, lecturer and researcher who completed her PhD on menopausal symptoms in 2008 at RMIT Melbourne Australia. Her scientific publications relate to menopausal symptoms, PMS like symptoms, Vitex agnus-castus and issues surrounding the placebo response. She has presented at international conferences and received the Australasian Menopause Society Scientific Award 2009 for the most meritorious contribution to the field of menopause by an Australian or New Zealand investigator.

M Diana van Die, PhD (1)

School of Health Sciences (Comp Med), RMIT University, PO Box 71, Bundoora, Victoria Australia 3083

email: diana.vandie@rmit.edu.au, phone 0403 011 151, fax 03 9925 6539

(1) Royal Melbourne Institute of Technology-University, Bundoora Victoria Australia; University of Melbourne, Department of general Practice, Carlton Victoria Australia
Table 1: Results of soy trial for menopausal symptoms

Authors            N    Intervention                 Comparator

Han 2002          80    100 mg soy isoflavones       placebo

Ferrari 2009      180   80 mg soy IF (genistein      placebo
                        60 mg/day)

Faure 2002        75    soy IF extract (genistein/   placebo
                        daidzein 70 mg/day)

Scambia 2000      39    standardised soy extract     placebo 6wks
                        (50 mg/day IF)               CEE added for
                                                     next 6wks

Albertazzi 1998   104   soy powder 60g (IF 76        casein powder
                        mg)

Washburn 1999     51    soy protein, 20 g (POs       placebo
                        34 mg/day)

Basaria 2009      93    soy protein powder, 20g      placebo
                        (160mg total IF)

Dalais 1998       52    soy or linseed diet          wheat diet

Khaodhiar 2008    190   daidzein-rich IF, 40 or 60   placebo
                        mg/ day

Crisafulli 2004   90    genistein (54 mg/day).       placebo and
                                                     estrogen/
                                                     progesterone
                                                     (HT)

D'Anna 2007       247   genistein (54 mg/d)          placebo

Sammartino        70    genistein 36 mg/day          placebo
2003

Upmalis 2000      177   soy extract (50 mg/          placebo
                        day IF)

Murkies 1995      58    soy flour, 45 g/day          wheat flour 45
                                                     g/day

Secreto 2004      262   80 mg of soy IF +/- 3 mg     placebo
                        of melatonin                 melatonin

Knight 2001       24    soy IF powder beverage       casein powder
                        60 g/day (IF 134 mg/
                        day)

Burke 2003        241   soy drink, IF, 42 mg/day     Soy drink with
                        or 58 mg/day                 IF removed

Van Patten        157   soy beverage, IF 90 mg/      placebo
2002                    day

St Germain        69    soy protein IF 80 mg/day     placebo (whey
2001                    or 44 mg/day                 powder)

Authors           Study                       Findings

Han 2002          4 months    K1 scores significantly decreased from
                              baseline p>0.01 and between groups
                              p<0.01

Ferrari 2009      12 weeks    Reduction In HFs greater (41.5%) with IF
                              than placebo (28.9%), p=0.016.
                              (mild-moderate 41.2% vs 29.3% p=0.023).

Faure 2002        16 weeks    61% reduction in HFs versus 21% placebo
                              Responders 65.8% vs 34.2%, p < 0.005

Scambia 2000      12 weeks    At 6 wks, soy decreased frequency of
                              HFs, p < 0.01 compared to placebo, and
                              severity on GCS, p < 0.001.

Albertazzi 1998   12 weeks    HF frequency improved with soy vs
                              casein, p < 0/01). 31% reduction with
                              soy vs 31% with casein.

Washburn 1999     6 weeks     Improved severity of HFs with soy vs
                              placebo, p < 0.001.

Basaria 2009      12 weeks    Significant improvements in all
                              subscales of MENQOL with IF but no
                              significance over placebo at any time
                              point reported.

Dalais 1998       24 weeks    Reduced rate of HFs with linseed diet
                              451%), wheat diet (51%), but not soy.

Khaodhiar 2008    12 weeks    At 12 weeks, HF frequency was reduced by
                              52% with 40 mg DRI, 51% with 60 mg DRI,
                              and 39% with placebo, p = 0.07 and p =
                              0.09 vs placebo.

Crisafulli 2004   12 months   HFs decreased with genistein vs placebo
                              at 3, 6 months and 12 months (p < 0.01).
                              Improvement with HT greater than
                              genistein at all times, p < 0.05.

D'Anna 2007       12 months   Genistein significantly outperformed
                              placebo on HFs at all intervals from the
                              first month, p < 0.001.

Sammartino        12 months   Improved KI score with genistein vs
2003                          placebo, p < 0.05.

Upmalis 2000      12 weeks    Between-group differences in HFs at week
                              6, p = 0.03, but not significant at week
                              12, p = 0.08. Significant reduction in
                              severity of HFs with soy, p = 0.01

Murkies 1995      14 weeks    No between group differences. Reduced
                              HFs and general symptoms in both groups,
                              p < 0.05.

Secreto 2004      12 weeks    No significant difference between
                              groups. Median percent reductions on GCS
                              of 39% for IF + MEL, 38% for IF alone,
                              26% for MEL and 38% for placebo.

Knight 2001       12 weeks    No between-group differences. Improved
                              flushing frequency in both groups.

Burke 2003        96 weeks    No between-group differences. Improved
                              HF frequency and severity in all groups.

Van Patten        12 weeks    No between-group differences. Improved
2002                          HF frequency in both groups.

St Germain        24 weeks    No between-group differences.
2001                          Significant decline in HF frequency (p =
                              0.0003) and night sweat (p = 0.0007) in
                              all groups.

IF = isoflavones

MEL = melatonin

DRI = Daidzein-rich isoflavones

GCS = Greene Climacteric Scale

HF = hot flushes

KI = Kupperman Index
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