Improved cognitive function in postmenopausal women after 12 weeks of consumption of a soya extract containing isoflavones

Abstract

We previously reported that a high soya diet improved memory and frontal lobe function in young volunteers, and since soya isoflavones are agonists at oestrogen receptors, they may improve these functions in postmenopausal women. Thirty-three postmenopausal women (50–65 years) not receiving conventional hormone replacement therapy (HRT) were randomly allocated in a double-blind parallel study to receive a soya supplement (60 mg total isoflavone equivalents/day) or placebo for 12 weeks. They received a battery of cognitive tests and completed analogue rating scales of mood and sleepiness, and a menopausal symptoms questionnaire before the start of treatment and then after 12 weeks of treatment. Those receiving the isoflavone supplement showed significantly greater improvements in recall of pictures and in a sustained attention task. The groups did not differ in their ability to learn rules, but the isoflavone supplement group showed significantly greater improvements in learning rule reversals. They also showed significantly greater improvement in a planning task. There was no effect of treatment on menopausal symptoms, self-ratings of mood, bodily symptoms or sleepiness. Thus, significant cognitive improvements in postmenopausal women can be gained from 12 weeks of consumption of a supplement containing soya isoflavones that are independent of any changes in menopausal symptoms, mood or sleepiness.

Introduction

A soya diet containing high levels of isoflavone phytoestrogens significantly improved memory and frontal lobe function in young healthy male and female volunteers compared with volunteers receiving a soya-free diet for 10 weeks (File et al., 2001a). Isoflavones are nonsteroidal oestrogens (for review, see Wiseman, 2000); daidzin and genistin and their glucoconjugates are the predominant isoflavone forms in soya foods and supplements (Wiseman et al., 2002). They are hydrolysed in the large intestine to daidzein and genistein and these act as weak agonists at oestrogen receptors (Pike et al., 1999). There are two types of oestrogen receptor (ERα and ERβ)  and both are expressed in the brain (Kuiper et al., 1998). The isoflavones have a greater affinity for ERβ (Kuiper et al., 1998), and it is possible that they can reach the brain in sufficient concentrations to activate these receptors, since high plasma concentrations are reached after daily consumption of a textured soya protein burger for 2 weeks (Rowland et al., 2000). ERβ mRNA is prevalent in the hippocampus, frontal cortex and thalamus Shughrue et al., 1997, Pau et al., 1998, Petersen et al., 1998, McEwen and Alves, 1999, Shughrue et al., 2000, Gundlah et al., 2000, Osterlund et al., 2000, and thus it is likely that the ERβ receptors will play an important role in cognition.

Soya phytoestrogens have been shown to act like oestrogen in the brain, which has a number of direct and indirect receptor-mediated genomic effects that could affect cognition, such as influencing cell survival, growth and neuroplasticity (McEwen, 2001). Phytoestrogens have been shown to increase choline acetyltransferase and mRNA levels of neurotrophins in the frontal cortex and hippocampus Pan et al., 1999a, Pan et al., 1999b. In addition, there are receptor-mediated nongenomic effects of oestrogen that could be of great importance to cognition. For example, at physiological levels of glutamate, oestrogen potentiates glutamate-induced calcium signalling by acting at the NMDA receptors (Nilsen and Brinton, 2002). Other rapid actions of oestrogens are protection of neurones from damage by excitotoxins and free radicals Nilsen and Brinton, 2002, Toran-Allerand et al., 1999, Kelly and Levin, 2001. Thus, although it is unlikely that phytoestrogens will mimic all the CNS effects of oestrogens, there are sufficient potential mechanisms that could mediate cognitive improvement. Furthermore, it is possible that phytoestrogens could have effects that are not seen with oestrogens since, for example, there is a splice variant of ERβ in the hippocampus, to which oestradiol does not bind (Price et al., 2000).

In several well-controlled experimental studies, short-term oestrogen replacement therapy has been found to significantly improve episodic memory in postmenopausal women (e.g., Phillips and Sherwin, 1992, Jacobs et al., 1998, Duka et al., 2000). However, improved memory has only been found in 50% of experimental studies in which women have been randomly assigned to the treatments (see Hogervorst et al., 2000). Most of the cross-sectional epidemiological studies have reported improved memory in users of hormone replacement therapy (HRT) compared with nonusers, but these studies always carry a risk that the women who chose HRT might be younger or have higher levels of IQ, education or socioeconomic class than the nonusers (see Yaffe et al., 1998, Le Blanc et al., 2001, Hogervorst et al., 2000). Improvements in semantic memory have also been found in postmenopausal women treated with tibolone, which is only a weak oestrogen agonist Albertazzi et al., 2000, Fluck et al., 2002.

There is considerably less evidence on the effects of HRT on frontal lobe function. In a very small cross-sectional study, Keenan et al. (2001) found that women on HRT performed better than those who had never used HRT. However, in a study in which treatment was randomly assigned, no improvement in frontal function was found after 3 weeks of oestradiol treatment in postmenopausal women (Duka et al., 2000). There is even evidence that very long-term treatment (10 years) with HRT can impair frontal functions Fluck et al., 2002, File et al., 2002. These impairments were found both after oestradiol implants, which give rise to very high circulating levels of oestrogen, and after treatment with tibolone, which has oestrogenic potency only 1/50 of that of oestradiol.

The purpose of the present study was to evaluate the effects of 12 weeks of treatment with a dietary supplement that contained an extract of soya isoflavones on the cognitive performance of postmenopausal women. Improvements in memory were shown in our previous study after 10 weeks with a higher concentration of isoflavones (100 mg total isoflavones equivalents/day) consumed as part of the dietary matrix (File et al., 2001a). The cognitive test battery was the same as that used in our previous study looking at the effect of a 10-week period of dietary intervention with high and low soya diets (File et al., 2001a). The dose used in this study (60 mg total isoflavone equivalents/day) was chosen since 56 mg total isoflavone equivalents/day in a dietary matrix was shown to be effective in reducing in vivo lipid peroxidation in a previous study (Wiseman et al., 2000). The treatment period used in this study was chosen since 12 weeks consumption of 60 mg/day isoflavones in the diet showed beneficial effects on risk factors for cardiovascular disease and osteoporosis in postmenopausal women (Scheiber et al., 2001). In addition, we examined the effects on mood and menopausal symptoms in order to determine whether the supplement would be of more general benefit to this group of women.