Maturitas 63 (2009) 297301

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Maturitas
journal homepage: www.elsevier.com/locate/maturitas

Review

The health benets of berry avonoids for menopausal women: Cardiovascular disease, cancer and cognition
A.L. Huntley

a r t i c l e

i n f o

a b s t r a c t
There is an increasing amount of research into the health benets of berry avonoids. Moreover, the consumption of avonoid-rich food is on the increase; with women in particular showing a interest in eating a diet which may benet their long-term health. The aim of this review was to examine the evidence for the benets of berry avonoids for cardiovascular health, cancer and cognition in the menopausal woman. Due to the limited amount of clinical data on this subject both in vitro and animal as well as human studies have been included. These data appear to support epidemiological studies that suggest cardiovascular benets, cancer prevention and cognitive improvement from berry avonoid consumption. However to date, it is not possible to be denitive about the specic berry type, preparation or regime which confers maximum benets, or to give specic advice to menopausal women. Limited data from a combination of pre-clinical and clinical studies suggest that the addition of berry avonoids to the diet has moderate effects on cardiovascular function in subjects at risk and potential preventative effects in oesophageal cancer. Evidence for cognitive benets is limited to animal data but shows promise. 2009 Elsevier Ireland Ltd. All rights reserved.

Article history: Received 11 May 2009 Accepted 11 May 2009 Keywords: Berry avonoids Polyphenolics Cardiovascular health Cancer Cognition Menopause

Contents 1. 2. 3. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bioavailability and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiovascular health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Healthy subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Patients with cardiovascular risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Healthy subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Precancerous conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 298 298 298 298 299 299 299 299 299 300 300 300

4.

5. 6.

1. Introduction The World Health Organisation states that a recommended daily intake of 400 g of fruit and vegetables may provide protection against disease including cardiovascular disease and cancer [1]. Data shows average consumption of fruit and vegetables (excluding potatoes) in the UK is increasing: 346 g in 2007 compared to 325 g

E-mail address: alysonhuntley@btinternet.com. 0378-5122/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2009.05.005

in 20042005 [2]. In general, fruit consumption is on the rise in the UK, with 2007 data showing a 9.7% increase in total fruit consumption (fresh, processed and fruit juice products) compared with 20042005 data. The health benets of berry fruits have had a high prole in the public domain in recent years. It was reported at the Global Berry Congress that the market value of berries was 76.5m in the UK (2008) and that sales have nearly doubled in the past 7 years [3]. UK data suggests for women who are high consumers of fruit and vegetables, the most motivating factors were the health and natural content of the food [4].

298 Table 1 The avanoid subclasses within the class of polyphenolics. Subclass Flavanols Flavonols Anthocyanins Examples of compound names

A.L. Huntley / Maturitas 63 (2009) 297301

teins (HDL) and increasing resistance of low density lipoproteins (LDL) to oxidation [5,15]. 3.1. Clinical studies 3.1.1. Healthy subjects One study was carried out in nine healthy females (mean age 31 2 range 2341 years) in Denmark. Subjects after an overnight fast were given 500 ml of blueberry juice (total phenolics 2589 g gallic acid equivalents (GAE)/ml), cranberry juice (total phenolics 893 GAE/ml) or a sucrose solution (control) 1 week apart [16]. In this study, plasma antioxidant status was measured using in vitro assays to assess an ability of the plasma to reduce potassium nitrosodisulphonate and Fe (III)-2,4,6-tri(2-pyridyl)-s-triazine up to 4 h post-consumption and shown a maximum antioxidant capacity of cranberry juice at 60120 min. The authors attributed this positive effect of the cranberry juice predominantly to the vitamin C content (the product was fortied with vitamin C) which was increased by 30% in plasma samples compared to a very much smaller increase in total polyphenolics. The consumption of blueberry juice had no such effect and produced results similar to that of the controls; this product was organic and it was suggested that the bioavailability of the potential polyphenolic content was reduced by degradation. In a further study carried out in the UK, twenty healthy female subjects (1840 years) were randomised to consume either 750 ml of cranberry juice (total phenols 1136 3.5 mg/l, vitamin C 897 5.3 mg/l) or a placebo (coloured sweetened) drink in addition to their normal diet for 2 weeks [17]. Serum antioxidant potential was measured using glutathione peroxidise, catalase and superoxide dismutase activities in red blood cells and malondialdehyde and 8-oxo-de-oxyguanosine in urine samples. Serum plasma cholesterol (Total, LDL, HDL) and triglycerides were also measured. Plasma vitamin C increased signicantly in the cranberry group compared to the control group (p < 0.01) but there was no detectable increase in total phenols or anthocyanins or catechins (plasma or urine samples). The antioxidant potential of serum samples were the same in both groups as were the cholesterol, lipid and triglyceride levels. However, in a study in the USA, the diet of eight healthy elderly female subjects (66.9 0.6 years) was supplemented by strawberries (240 g), spinach (294 g), red wine (300 ml) or vitamin C (1250 mg) or no supplementation as part of a predetermined study diet; with each woman receiving all ve of the foods 2 weeks apart [18]. The main outcome measure was to determine the serum antioxidant capacity of each diet and the relationship with the vitamin C content. Using three antioxidant capacity assays, all ve diets increased serum antioxidant levels (725% in a 4 h period) but this increase in antioxidant capacity was only in part due to the vitamin C content with the relevant contribution from vitamin C, urate (purine metabolism from antioxidants) and other sources estimated at 7.28.7%, 36.539.1% and 50.554%, respectively across the strawberry, spinach and red wine groups. The effect of a wild blueberry supplement (Vaccinium angustifolium) on serum postprandial antioxidant status was examined in a single-blind crossover study of eight male participants (3854 years). The subjects consumed a high fat meal and a control supplement followed by 1 week later, the same meal supplemented with 100 g freeze dried wild blueberry supplement [19]. Serum antioxidant status was determined by oxygen radical and a total antioxidant laboratory assay. A signicant treatment effect was seen above that of controls from 1 h and at 4 h it was 15% greater than controls as shown by the oxygen radical absorbance capacity assay (p = 0.009). A further study investigated the effect of cranberry juice consumption in 21 healthy men (38 8 years) in which the men consumed 7 ml/kg of cranberry juice for 14 days as part of their

Proanthocyanines (condensed tannins), epicatechins Quercetin, myricetin Cyanidins, peonidin

There is a growing and impressive evidence base for the health benets of berry avonoids. The main focus of the berry polyphenolic research is cardiovascular health, cancer prevention and cognitive decline. The aim of this review is to examine the available evidence applicable to the menopausal women. Berry fruits contain many important dietary components: vitamins, minerals, folate and bre; but it is their polyphenolic content to which their biological action is most often attributed [5]. It is thought that these effects are synergistic as opposed to being due to one constituent alone. The prole of berry phenolics includes avonoids (avanols, avonols and anthocyanins), phenolic acids and tannins [Table 1]. Whilst the majority of the research has been carried out on avonoids and in particular the anthocyanins, there is increasing interest in the tannins as well. Berry avonoids are best known for their antioxidant and anti-inammatory action but research has shown that their action extends to impacting on cell signalling mechanisms [5]. Whilst these effects were initially conrmed with in vitro studies, there has been increasing amounts of animal and clinical research. 2. Bioavailability and metabolism Previously it has been assumed that berry consumption leads to low bioavailability of berry polyphenolics [6]. This was based on the measurement of circulating polyphenolics following consumption. Tracing the effects of these metabolites is made difcult by the technical limitations. However more recent research has shown that berry polyphenolics are readily metabolised in the gut and liver before they arrive in the body tissues [7]. Animal work on neural tissue has shown, albeit not consistently that these metabolites can cross the bloodbrain barrier and accumulate after long-term consumption [8,9]. Thus the accumulation of polyphenols in neural tissue suggests that they may act directly within brain areas responsible for modulating cognitive processes. Bioavailability and metabolism of berry avonoids is not only variable between individuals based on a persons genetic variability and nutrigenomic (interaction between dietary and genetic) factors but is also different between the different avonoids [10]. 3. Cardiovascular health Cardiovascular disease is the leading cause of death in women and more heart disease is present in older women than men. Risk factors for heart disease affect men and women differently, with a greater impact of diabetes, hyperlipidemia and smoking in women [11]. A combination of both animal and clinical studies has shown benet to cardiovascular health after the consumption of polyphenolic foods such as red wine, cocoa and tea [1214]. However such food contains ethanol, fat and caffeine-related substances which can to some extent counteract these effects. Berries have a high polyphenolic content without these less healthy components and in addition contain other bioactive components. There is evidence that the addition of berries to the diet can positively affect risk factors to cardiovascular health by inhibiting inammation, free radical scavenging, modulation of eicosanoid metabolism and improving endothelial function, reducing blood pressure, inhibiting platelet aggregation/activation, increasing circulatory high density lipopro-

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normal diet [20]. The focus was on plasma lipoprotein levels and LDL oxidation. These parameters were found to be related to waist circumference prior to the intervention. Following the invention oxidised LDL levels were signicantly reduced (9.9% 17.8, p = 0.0131) and antioxidant capacity increased (+6.5% 10.3, p = 0.014) from baseline levels but no there was no signicant change in plasma lipoprotein lipid or inammatory marker concentrations.

The fact that berry polyphenolics properties extend beyond antioxidation and have also been shown to inuence cell signalling gives us the insight into their potential anti-cancer properties. Berry phenolics have also been shown in animal and in vitro studies to have anti-inammatory properties, induce the carcinogenic detoxication (phase II) enzymes and modulate cell signalling in cancer cell proliferation, apoptosis and tumour angiogenesis [24]. Clinical studies are less common. 4.1. Healthy subjects

3.1.2. Patients with cardiovascular risk In one study, 72 volunteers (46 women) with a mean age of 58 years and showing at least one of the following risk factors for cardiovascular disease: mild hypertension, elevated blood glucose or serum lipids were entered into a single-blind randomised placebocontrolled 8-week trial [21]. Participants were randomised either to receive 100150 g of berries daily (bilberries in lingonberries syrup, blackcurrant or strawberry pure or cold pressed chokeberry and raspberry juice). The control group were asked to eat their normal diet but to refrain from eating berries. The average daily intake of berry products in the active group was 837 mg and the plasma concentrations of berry polyphenolics in this group was increased signicantly from baseline compared to the control group (p = 0.006 for all). Berry consumption had modest effects on both systolic and diastolic blood pressure (SBP and DBP) with SBP decreasing slightly in the berry group (1.5 mm Hg) and increasing slightly in the control group (0.5 mm Hg). There was no change in DBP in the berry group and a small increase in the control group (0.9 mm Hg). In a subgroup of patients (numbers not recorded) with high baseline blood pressure, the mean decrease in SBP was 7.3 mm Hg compared to 0.2 mm Hg in the control group (p = 0.024). Total serum and triacylglycerol were unaffected by the intervention but there was a small increase in serum HDL-cholesterol in the berry group (5.2% (1.55 mmol/l (1.411.68) to 1.63 mmol/l (1.471.79)) compared to the control group (0.6%). A further study investigated the effect of cranberry juice consumption on 30 men (51 10 years) who were abdominally obese [22]. The men consumed increasing doses of low calorie cranberry juice during three successive periods of 4 weeks (125, 250, 500 ml/day) and the outcome measures were both metabolic and physical. Body weight, height and waist and hip measurements were made and nutritional habits were assessed. Total, very low density lipoproteins (VLDL), LDL and HDL levels, antioxidant status and oxidative stress were measured by laboratory assay. There was some improvement in the physical measurements of the participants on completion of the trial but in terms of positive metabolic effects, only HDL cholesterol was increased. This effect on HDL was seen after 250 ml supplementation (+8.6 SD 14% p < 0.05 versus control group) and then plateaued at 250 ml supplementation (+8.1% SD 10% p < 0.001 versus control group): HDL levels increased from on average (graph data) from 1.18 to 1.27 mmol/l during the study.

In a small study, 20 healthy female volunteers consumed 750 ml of cranberry juice or a placebo equivalent (coloured, avoured water) for 2 weeks and fasting blood and urine samples were taken over 4 weeks [17]. Supplementation with cranberry juice did not affect 8-oxo-deoxyguanosine in urine or endogenous or H2 O2 induced DNA damage in lymphocytes. 4.2. Precancerous conditions Following encouraging results from experimental studies [2527] with lyophilised black raspberry berry (LRB) (Rubus occidentalis), a 6-month chemopreventive pilot study looked at the effect of a daily 32 g of LRB in 10 patients (three female) (age 59 1.91 range 4868 years) with Barretts oesophagus (a premalignant condition) [28]. At baseline, the average length of the Barretts tongue was 2.9 cm with a range of 2.08.0 cm and the length of the Barretts lesion was unchanged during the 26 weeks intervention. Assays for two biomarkers of oxidative damage were used (8-OHdG and 8-Iso-PGF2). Levels of urinary 8-Iso-PGF2 were signicantly reduced following 26 weeks of daily LBR administration (data in graph form p < 0.05 from baseline). However, there was no overall changes in the mean levels of urinary 8-OHdG following treatment with LBR although ve individuals did exhibit signicant decline (p < 0.05). 5. Cognition For women the decline in oestrogen levels during and after the menopause is associated with memory problems and other cognitive impairment. As cognitive function declines with age and the onset of dementia is generally later in life, this suggests that the cognitive decline is at least as likely to be due to environmental factors such as diet in addition to genetic factors. There is strong evidence from animal studies that berry phenolics are benecial for age-related motor and cognitive decline. It is suggested that with increasing age there is an increase of oxidative stress in addition to a decrease in anti-oxidant defence mechanisms. A series of animal experiments from one research group has given us the most information on this topic [8]. In one long-term study, Fischer 344 rats followed from middle age (6 months) to old age (15 months) were supplemented with one of four diets: vitamin E (500 IU/kg), strawberries or spinach (providing the same amount of vitamin E) or a control diet. Cognitive function in terms of spatial learning and memory was positively affected in all of the intervention diet groups with a similar magnitude in the strawberry and vitamin E groups. Further studies on older rats (19 months) in which their diet was supplemented with either strawberries, blueberries, spinach compared to an unsupplemented diet for 8 weeks shown a reversal of age decit effects in terms of cognitive function with the blueberry diet being the most efcacious. Other studies have shown that a blueberry diet also has a positive effect on object recognition, balance and co-ordination and spatial reversal learning. Importantly, all the fruit diets were of equal antioxidant potential but oxidative stress markers were shown to be only moderately affected by the diets suggesting that the mechanism is probably not

4. Cancer Cancer is the second main cause of death after cardiovascular disease in women aged 3564 years. Breast and colorectal cancer are the two most prevalent malignancies but lung cancer is on the increase in women. Although it is generally accepted that berry polyphenolics have anticarcinogenic properties, the evidence from epidemiological studies is mixed and generally describe the impact of dietary fruit and vegetable on cancer prevention as opposed to berry or any other specic avonoids; with the suggestion that increased fruit and vegetable consumption has been associated with a decreased risk of a number of cancers of epithelial origin, including oesophageal cancer [23].

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entirely through an antioxidant pathway. In addition it has been noted that the berries studied to date tend to have more cognitive neuronal effects as opposed to motor behavioural effects although blueberries, cranberries, grape juice and strawberries have been shown to affect motor behaviour. The research suggests that different polyphenols in different fruits have regionally specic effects on the brain acting directly in neurons and glia in the aging brain. Cohort and longitudinal studies suggest that increased fruit and vegetable intake is associated with a reduced risk of dementia [29,30]. One 10-year study investigating cognitive decline showed that a high intake of avonoids via a wide range of food type by people over the age of 65 (58% female) was associated with better cognitive function as measured by Mini-Mental State Examination, Bentons visual retention Test and Issac Set Test [30]. Although the data from this longitudinal study was adjusted for age, sex and educational level, it is important to note that such studies have many limitations which include not only estimating dietary content; in the above study this was only performed once at the 3-year stage, but also confounding factors of which there are many, and some impossible to correct or allow for e.g. changes in diet, personal circumstances. 6. Discussion In spite of a growing amount of research into the role of berry avonoids in health, it is difcult to be denitive as to how much of any single or combination of berry preparations is likely to help in the prevention of such conditions as cardiovascular disease, cancer and cognition. There are many factors to consider. Firstly, bioavailability, the research to date indicates this is different for each individual, between avonoids and between different products e.g. blueberry juice or supplement. We also aware that berry products can degrade and may not contain its original polyphenolic content. Some of the studies have been carried out on healthy young people and therefore do not show any clinical effects but do provide some information as to the amount of polyphenolics and vitamin C reaching the blood stream. Studies have mostly involved a small number of participants, not always women, with a variety of outcome measures over a very short time period. Thus, we are still far from determining which components of berries singly, or in synergy, are producing the clinical effect described in epidemiological studies and shown to a limited extent in clinical studies. Whilst cell and animal studies have shown anti-carcinogenic effects of berry polyphenolics, clinical studies into the cancer preventative effects are limited to oesophageal neoplasms; supported on the main by epidemiological studies of fruit and vegetable intake and cancer incidence. Evidence from longitudinal studies suggests that fruit and vegetable intake and more specically avonoid intake is associated with a reduction in the incidence of dementia. Evidence from more rigorous clinical studies is not available and is difcult to design and interpret. Although clinical studies of berry polyphenolics have been carried out with women of a range of ages, it is impossible to make any age- or gender-specic recommendations. It is difcult to be denitive about the amount of berry fruits or products that will improve cardiovascular health, prevent cancer or boost cognitive abilities but it is likely that future research will focus on avonoid supplements which will allow clinical studies to be conducted in a more rigorous manner and for specic clinical outcomes. In conclusion, berry avonoid research appears to support the recommendation of a daily intake of fruit and vegetables for disease prevention. Whilst any claims of freedom from disease with berry

consumption is unwise, research to date supports its importance as part of a healthy balanced diet for the menopausal woman. Conict of interest No interests to declare and no funding for this article References
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