Research article

Short-term changes in endogenous estrogen

levels and consumption of soy isoflavones
affect working and verbal memory in young
adult females
Fariha Islam1, Cassandra Sparkes2,3, Steven Roodenrys1, Lee Astheimer2,3
Schools of 1Psychology and 2Health Sciences, University of Wollongong, New South Wales, Australia
3
Smart Foods Centre, University of Wollongong, New South Wales Australia

Estrogen is known to modulate certain cognitive functions, most notably improving working
memory and verbal memory. Soy foods contain isoflavones, phytoestrogens structurally similar to
estrogen that weakly bind to estrogen receptors. We investigated the effects of natural variations in
estrogen levels and short-term dietary supplementation with soy isoflavones on cognitive function
in 28 young women. Performance was examined across a range of cognitive tasks on three
occasions during separate menstrual cycles: during a menses phase (low estrogen), during a
luteal phase (highest estrogen), and once during a menses phase after a 3-day phytoestrogen-rich
dietary intervention. Soy supplementation during menses led to an improvement in working
memory and verbal memory. The menstrual cycle effects were mixed, with high estrogen improving
performance on a verbal memory task but not on working memory. Our results suggest that soy
phytoestrogens may improve working memory through estrogen-independent mechanisms.
Keywords: cognition, verbal memory, working memory, estrogen, soy isoflavones, menstrual cycle

Introduction prefrontal cortex, hippocampus and basal forebrain,3

Estrogen has profound cellular, molecular, and
morphological effects on the central nervous system
through all life stages, including effects on synaptic
plasticity, neurotrophism, and specific neurotrans-
mitter systems.1 These effects are thought to be
mediated through estrogen receptors: ‘classical’
estrogen receptor (ER)-α located predominantly in the
hypothalamus and regions associated with
reproductive physiology and behaviour2 and the more
recently elucidated ER-β found in frontal and
Correspondence to: Steven Roodenrys, School of Psychology, University
of Wollongong, Northfields Avenue, Wollongong, 2522 NSW, Australia.
Tel: +61 2 4221 4072; Fax: +61 2 4221 4163; E-mail:
steven_roodenrys@uow.edu.au
Received 24 February 2008, manuscript accepted 20 June 2008
areas of significance for cognitive functions such as
learning and memory.4,5 Variations in circulating
estrogen levels occur naturally in humans and other
animals over both short (e.g. estrus and menstrual
cycles) and long (puberty, seasonal reproduction,
pregnancy and menopause) time-frames, as well as
with exogenous therapeutic treatment (birth control
pills, hormone replacement therapy). Experimental
short-term manipulations of estrogen levels have
demonstrated an effect on plasticity of hippocampal
neuron structure,4,6,7 important for cognitive processes
such as learning and memory,8 and may be a
contributing mechanism underlying the observed
effects of estrogens on cognitive function.
Sex differences in cognitive functions show that
women generally perform better on verbal and fine

© 2008 W. S. Maney and Son Ltd Nutritional Neuroscience 2008 Vol 11 No 6 251
DOI 10.1179/147683008X301612
Islam et al. Effects of soy on cognition across the menstrual cycle
motor tasks and some memory tasks, while males
perform better on spatial tasks, particularly 3-
dimensional tasks like mental rotation of objects.9–11
There appears to be a trend for cognitive performance
in gender-specific tasks to be related to the natural
variation in estradiol levels during the menstrual
cycle.9,12–14 Specifically, women tend to perform better
on female-positive tasks during the mid-luteal phase
when levels of circulating estrogen are high, and
poorer on those tasks during the menses phase when
estrogen is low.12,13 Conversely, women tend to perform
worse on male-positive tasks during the mid-luteal
phase , and better on those tasks during the early
menses phase.12,13 Haussman et al.9 found that spatial
abilities, as tested by the Mental Rotation Test (MRT),
varied significantly with endogenous estrogens, with
high scores during the menses and low scores during
the luteal phases. Further, performance on memory
and semantic tasks fluctuate across the cycle, showing
improved performance during periods of high
estrogen.14–16
The observation that exogenous estradiol may
improve cognitive performance in postmenopausal
women, has stimulated interest in whether phyto-
estrogens, plant-derived estrogen analogs, can modulate
neural function in a similar manner. Though binding to
estrogen receptor with lower affinities, soy-derived
phytoestrogens (isoflavones) can occur at much higher
concentrations in plasma and tissue than endogenous
steroids, increasing the potential for their influence
through ligand-binding mechanisms.17 Rodent studies
using chronic dietary consumption of soy isoflavones
have demonstrated enhancements of key estrogenic
functions in the basal forebrain cholinergic system,
frontal cortex and hippocampus.18,19 Functionally,
phytoestrogens are associated with a reduction in age-
related neuron loss and cognitive decline in male rats19
and reversal of a sexually dimorphic pattern of visual-
spatial memory performance.20 In postmenopausal
women, chronic dietary supplementation with
isoflavones improved performance on certain memory
and frontal lobe functions,21,22 although Howes et al.23
did not observe significant effects. A range of
confounding experimental factors, including differences
in menopausal status, may cause this inconsistency. In
early menopause, estrogen receptor levels first undergo
up-regulation in response to estrogen withdrawal, but
later decline.2 In this peri-menopausal window, estrogen
therapies such as estrogen replacement therapy or
phytoestrogen supplementation would theoretically have
maximal effect24 and would have less effect with
increasing age and declining estrogen receptor
availability. Studies of older postmenopausal women
252 Nutritional Neuroscience 2008 Vol 11 No 6
confirm this, where cognitive performance shows no
improvement after isoflavone supplementation.2,23
Very few studies have investigated the impact of
dietary isoflavones on cognitive function in young
healthy adults. File et al.25 examined the effects of 10
weeks of high and low soy diets on attention, memory,
and frontal lobe function in healthy males and
females, finding significant improvements in short-
term and long-term memory and in mental flexibility
in both sexes. Improvements in tests of letter fluency
and planning were found only in the females, and no
effect on attention was identified.25 However, the
cognitive effects of isoflavones in relation to
endogenous estrogen fluctuations across the
menstrual cycle have not been examined.
We aimed first to investigate the relationships
between endogenous steroid hormone levels and
performance on specific cognitive tasks, comparing
individual young women tested under three
conditions: during the menses (low estrogen) and
luteal (high estrogen) phases of the menstrual cycle
and during a second menses phase following short-
term, high-phytoestrogen consumption. Based on
previous findings, we anticipated that on tasks where
cognitive performance is poorer when endogenous
estrogen is low, dietary isoflavone consumption may
ameliorate this effect.
Subjects and methods
Study design
Premenopausal women were tested on three separate
occasions (each during a different menstrual cycle) on
a range of cognitive tasks that have previously been
shown to be sensitive to endogenous estrogen or have
shown reliable sex differences in performance (see
below). One testing session occurred in the early luteal
phase of a cycle when endogenous estrogen levels
should be high; the second testing session occurred in
the menses phase of a cycle when endogenous estrogen
should be low; and the third session occurred during
the menses phase of another cycle following a 3-day
soy diet intervention. The order of testing sessions was
randomised across participants. The phase of the
menstrual cycle was determined by the stage of pill
cycle in women taking contraceptives or by measuring
daily basal body temperature (BBT) in women not
using contraceptive pills. In the latter, luteal phase
samples were taken only after a definitive rise in BBT.
Blood samples were taken in the morning prior to
each cognitive testing session to evaluate plasma levels

of steroid hormones and isoflavones. Isolated plasma
was stored at –80°C for later analysis. A 24-h urine
sample was collected for the 24 h prior to attendance
at the clinic for blood sampling for the testing session
following the diet intervention. Total volume was
recorded and aliquots taken for isoflavone analysis
(stored at –80°C).
Subjects
Healthy females were recruited from the University of
Wollongong student population via sign-up sheets.
Follow-up interviews determined the inclusion of 31
women aged 18–34 years (mean, 21 ± 4.15 years); all
gave written, informed consent. Exclusion criteria
included regular and/or high consumption of soy-
based foods, use of antibiotics in the previous 3
months, irregular menstrual cycles, current illness or
use of psycho-active medication. Initial enquiries from
potential participants indicated a paucity of female
university students not using contraceptives, so
women who were using contraceptive pills were
included in the study as a separate cohort. Participants
were requested to abstain from consuming products
containing phytoestrogen-rich foods for a 1-month
‘wash-in’ period prior to commencement of the study
and throughout the study with the exception of the
soy-diet period; participants were provided a list of
soy-containing foods to avoid. Two of the final
participants required antibiotics during the soy-diet
part of the study and their data were subsequently
eliminated from analyses since antibiotics can disrupt
the intestinal bacteria required for phytoestrogen
metabolism.26 Another participant scored in the severe
range on the anxiety measure on all testing occasions
and had erratic performance from trial to trial within
tasks, so her data were also eliminated. For the
remaining 28 participants, body mass index ranged
from 18.5–28.1 kg/m2 (mean, 22.42 ± 2.49 kg/m2), and
none had suffered from a head injury within the last 7
years. All participants had normal, or corrected-to-
normal vision. Twelve of the participants reported
having ‘normal’ 26–30-day regular menstrual cycles
and the remaining 16 women were taking monophasic
oral contraceptive pills for at least 3 months prior to
the study. All participants received book or movie
vouchers and/or partial credit in a university
psychology subject (where applicable) for their
participation. Verbal IQ estimates ranged from 93 to
127 (mean, 108.76 ± 9.06) based on Australian
National Adult Reading Test (AUSNART) scores;
these did not differ consistently in relation to
contraceptive pill use, t(26) = 0.92.
Islam et al. Effects of soy on cognition across the menstrual cycle
Procedure
Participants attended an introductory meeting during
which those women not using contraceptive pills were
shown how to measure and record their BBT each
morning using BBT thermometers (provided by
Becton-Dickinson, Pty. Ltd). For these women, an
abrupt increase in BBT was defined as ovulation and
their luteal testing session was conducted as soon after
this rise as was feasible (within 1–4 days). For women
taking contraceptives, the luteal peak was defined as
days 13–16 of the 28-day pill cycle. The menses phase
testing sessions were conducted within 4–7 days after
the onset of menses (or after ‘active’ pill consumption
for females on the pill). Prior to the ‘menses + soy’
testing session, all participants carried out the 3-day
soy dietary intervention. Researchers were in contact
with participants often to assist in tracking and
scheduling testing sessions based on their menstrual
cycles.
On the scheduled testing day, participants came to
the clinic between 08:30–10:30 h for blood collection
by a registered nurse. Each participant came at the
same time on each of the three occasions. There was
no restriction on participants eating or smoking
before the testing session. Blood (10 ml) was taken
from the saphenous vein into Sarstadt tubes, spun for
10 min in a refrigerated centrifuge (Hettich Inc.).
Plasma was aliquoted into 1-ml Eppendorf tubes and
frozen at –80°C until assayed for steroids (estradiol,
ethinylestradiol for women taking contraceptives,
progesterone and testosterone), sex hormone binding
globulin (SHBG) and isoflavones (genistein, daidzein,
glycetein and equol).
Soy supplement
Dietary supplementation with soy-containing foods,
as opposed to isoflavone-containing capsules, was
selected based on improved bioavailability of
isoflavones through dietary sources and our past
experience in soy dietary trials.27,28 For 3 days prior to
one of the menses testing sessions, participants
consumed two servings daily (approximately a
teaspoon each) of soy germ flour (Soy Isolife, Acatris)
mixed with a drink, providing approximately 20 mg
isoflavones/gram. We used a moderate-to-high dose of
isoflavones (120 mg/day for a 70 kg person, or 1.655
mg/kg) based on a recent study that found significant
improvements in cognition in young adults after a 10-
week high-soy diet providing 100 mg isoflavones per
day.25 Soy germ was packaged as daily doses based on
subject body mass (8.28 mg/5 kg) adjusted in 5 kg
Nutritional Neuroscience 2008 Vol 11 No 6 253
Islam et al. Effects of soy on cognition across the menstrual cycle
increments. Due to the tendency of the soy germ to
adhere to packaging materials, an extra 0.1 mg of soy
germ flour was added to each serving. Participants
were instructed to consume the servings with their
usual morning and evening meals. An additional
serving was consumed in a breakfast meal before
arrival on the day of testing (day 4). Participants also
collected a 24-h urine sample during the last day of the
dietary intervention, submitting these on the morning
of blood collection and cognitive testing, so that levels
of urinary isoflavones could be assessed.
Cognitive testing
Testing sessions ran for approximately 1 h, and all
three sessions were conducted at the same time of day
for each subject (with one exception having a 3-h
delay). Almost all cognitive testing sessions occurred
immediately after having blood taken. For any
individual subject there were 4–6 weeks between
testing sessions. The researcher administering the
cognitive tests was blind to the testing condition of all
participants. Obviously, participants could not be
blind to cycle phase condition.
During each testing session, participants completed
the tasks in the order presented below. These tasks
were selected either because performance has
previously been shown to be sensitive to fluctuations
in estrogen, to differ between males and females, or to
rely on parts of the brain which are known to have
greater concentrations of estrogen receptors. Where
tasks involved the recall of verbal information
(Paragraph Recall, the Auditory Verbal Learning
Task, and Letter Fluency), alternative stimuli were
used in each session and, accordingly, three different
‘versions’ of the test battery were compiled, each of
which were distributed between the three sessions
across the participants.
Depression, Anxiety & Stress Scale (DASS-21)
Participants completed a questionnaire consisting of
21 items quantifying their feelings of depression,
anxiety and stress over the past week.29 This is a public
domain measure of affective state which has been
demonstrated to have acceptable internal consistency
and concurrent validity.30
Paragraph Recall – immediate and delayed
Participants heard a pre-recorded short story through
headphones, consisting of 24 units of information,
read at the rate of 1 unit per second. Two Wechsler
Memory Scale31 paragraphs were used in addition to
one taken from Stone et al.,32 which has been
254 Nutritional Neuroscience 2008 Vol 11 No 6
demonstrated to be of equivalent difficulty.33
Participants were told to remember as much
information as possible and, after hearing the
recording, were asked immediately to recall the story
as closely to the original as possible; the number of
correctly recalled units was scored. After an
approximately 30-min delay, during which time other
tasks were performed, the subject was asked to recall
the story and their performance was scored.
Mental Rotation Task
Participants were presented with two 3-dimensional
block-prisms simultaneously on a computer monitor
and asked to distinguish whether they were the ‘same’
(including rotated depictions) or ‘different’ (mirror-
image) objects in a forced-choice procedure. ‘Same’
trials showed one object at any two orientations, while
‘different’ trials showed two different objects at any
two orientations. Participants responded by pressing
the ‘S’ key for ‘same’ and the ‘D’ key for ‘different’
objects on a standard keyboard, and were asked to
respond as quickly and accurately as possible. Shapes
were adapted from the wire and block shapes used in
the Shepard and Metzler 3D Mental Rotation Task.
Objects were rotated 0°, 60°, 120° and 180° from the
test object in the ‘same’ trials. There were 24 trials of
each of the four rotation angles (presented randomly)
and six practice trials, for a total of 102 trials, half of
which were ‘same’ trials and half of which were
‘different’. After each trial, participants received
feedback on their performance and were allowed one
untimed break halfway through the trials. Reaction
times and correct responses for each angle were
recorded.
Object Array Memory Task
A computerised version of the Silverman and Eals34
paper and pencil test was used in which participants
were presented with an array of 36 objects in random
positions on a computer monitor. Participants were
asked to study the array closely over 1 min, after which
time a similar array was presented in which some of
the objects had changed positions with other objects,
and some had remained in the same position.
Participants were required to cross any objects that
changed (using the left mouse button) and circle any
objects that stayed the same (using the right mouse
button). Half of the objects changed position and half
remained the same. Stimuli were 126 pictures selected
from a set of 260 coloured and shaded images
commissioned by Bruno Rossion (Brown University
and University of Louvain, Belgium) and Gilles
Pourtois (Tilburg University, The Netherlands)

available online at <www.cog.brown.edu/~tarr/>. In
each session, two trials of this task were performed,
each with a unique randomisation of objects. The first
trial was subsequently treated as a practice trial, so
that only the accuracy and completion times for the
second trials are reported.
Counting Span
In a test of working memory capacity, participants
were required to view a series of displays that included
dark-blue circles, light-blue circles and dark-blue
squares in random positions on a computer screen.
They were told to count the number of dark-blue
circles in a display, and memorise this number. The
circles were counted aloud, one circle at a time, and
the final total was repeated aloud, at which stage the
next display would appear. After a number of displays,
the word ‘recall’ appeared in the centre of the screen,
which was the subject’s cue to say all the final totals
aloud, in the same order that they were presented.
Trials were 2, 3, 4, 5 or 6 counts long (3 of each) for a
total of 15 trials as well as 3 practice trials, and a single
random order of trial lengths was used. Participants
were instructed not to pause on any one count to avoid
rehearsal strategies. Only the counts that were recalled
in the correct position were recorded as correct. Three
versions of this task were created using the same pool
of displays but jumbled pseudo-randomly so that no
single trial included the same number twice.
Rey’s Auditory Verbal Learning Task (RAVLT) – immediate
and delayed
Participants heard a list of 15 words through
headphones, which had been pre-recorded onto tape at
a rate of one word per second. Immediately after this,
participants recalled any words they could remember,
in any order. The experimenter wrote down the order
in which the words were recalled. This process was
repeated three more times, and participants were told
to recall any words they could remember, even if they
had previously recalled them in earlier trials. A final
trial was carried out approximately 30 min later.
Alternative versions were drawn from Taylor35 and
Crawford et al.,36 which are of equivalent difficulty.37,38
The number of words recalled correctly out of fifteen
was taken as the performance measure on each trial.
Delayed Matching to Sample Task (DMST)
In this task, participants were presented with an object
in the centre of the computer monitor for 1000 ms and
requested to remember that object. After a delay of
either 4 s or 10 s, four similar objects were presented
and participants had to choose which of the four
Islam et al. Effects of soy on cognition across the menstrual cycle
matched the original by pressing the corresponding
arrow key. The task consisted of 5 practice trials and
30 test trials (15 of each delay). The 30 trials were
presented randomly, and the correct answer appeared
evenly across the four positions on the screen.
The stimuli consisted of objects composed of 4
quadrants of varying colours and patterns. Eight
patterns and seven colours were used to create a pool
of 56 quadrants. These quadrants were collated to
create 30 objects, in which no one object had the same
colour or pattern twice. For each object that was
created, 3 distractors were also used: in each instance,
one distractor was the same as the original with a
colour change in one quadrant, one distracter had a
pattern changed, and the third distractor had both a
colour and a pattern changed. The number of correct
trials and the mean reaction time for correct trials was
recorded.
Digit Span – forward and backwards
Participants were told that they would hear lists of
numbers, immediately after which they should repeat
the numbers aloud, in the same order that they heard
them. A Macintosh computer was used to present the
numbers auditorially in random order at a rate of one
digit per second. Only lists where all the digits were
recalled in the same order they were presented were
recorded as correct. The initial list was three digits
long and correct responses resulted in an increase in
list length by one digit, whereas incorrect responses
resulted in a reduction by one digit. The average span
of digits correctly recalled across 13 trials was
recorded as the subject’s digit span. This process was
repeated for the backwards span measure but
participants were asked to recall the numbers in
reverse order to that of presentation in each trial.
Letter fluency
Participants were asked to write down as many words
as they could think of beginning with a designated
letter in 1 min, excluding slang words, proper nouns
and plurals. Three equivalent forms of this task (using
the letters FAS, PRW and CFL) were drawn from
Lezak.38
Control measures
Participants had to confirm whether they had
continued to be in the same contraceptive status from
their initial interview at each session and report major
changes in sleeping patterns and alcohol, tobacco and
caffeine consumption. At their final session,
participants completed the Edinburgh Handedness
Questionnaire,39 because handedness is known to
Nutritional Neuroscience 2008 Vol 11 No 6 255
Islam et al. Effects of soy on cognition across the menstrual cycle

interact with gender differences in spatial abilities.40
Only two participants were rated as left handed and
their exclusion did not change the pattern of results so
the results including these participants are reported
here.
Isoflavone and hormone analyses
Plasma isoflavone levels were analysed using high
performance liquid chromatography with electro-
chemical detection (HPLC-ECD), using standards for
the isoflavone metabolites daidzein, genistein,
glycetein and equol (Sigma).28 Extraction of
isoflavones from plasma was performed prior to
HPLC analysis. Briefly, thawed plasma samples were
centrifuged to remove fibrin, incubated with β-
glucuronidase from Helix pomatia (Sigma) to
deconjugate plasma isoflavones, extracted in ethanol,
dried under N2 gas, re-dissolved in methanol with
sonication and, after preconditioning Sep-Pak Light
C-18 cartridges, samples were finally eluted with
methanol, dried and reconstituted in 500 µl methanol.
Samples were then analysed by HPLC-ECD with 3–4
sets of external standards per run, using an injection
volume of 10–20 µl. Initially, the HPLC mobile phase
consisted of 45% H2O and 55% MeOH, though
during the course of the experiment it was found that
water:methanol (1:1, v/v) provided better peak
resolution. Each participant’s samples from each of
the 3 sessions were analysed within the same run, to
minimise inter-assay variability. Chromatograms were
analysed using Shimadzu HPLC software. The global
limit of detection was calculated to be 30 ng/ml.
We used standardised coated tube radioimmuno-
assay kits (DS Labs; Webster, TX, USA) to evaluate
plasma levels of estradiol (DSL 43100), progesterone
(DSL 3900) and testosterone (DSL 4000), a double-
antibody kit for ethinylestradiol (DSL 9500) and an
immunoradiometric assay kit for SHBG (DSL 6300).
Assays were conducted to manufacturer’s instructions
and results were analysed on GraphPad Prism v.IV.
All samples for each hormone were run in duplicate
and were included in a single assay to eliminate inter-
assay variations.
Statistical analysis
The behavioural data set was screened for outliers.
Only one participant scored more than 2.5 SD from
the mean in any task on a single occasion (the delayed
matching to sample task); because removal of their
scores from the data on that task did not change the
pattern of results, their data are included in the
analyses reported below.
A mixed ANOVA was conducted for each of the
cognitive tasks, comparing the scores across the three
conditions (luteal, menses, menses + soy) as a repeated
measures factor, with contraceptive pill status as a
between-participants factor. For presentation pur-
poses, the mean scores are collapsed across pill group
as this factor generally was not significant and did not
interact with testing session unless otherwise noted.
Comparisons of hormonal compounds and iso-
flavones in relation to condition were analysed by
means of repeated-measures ANOVA with testing
session as a within-participants factor and contra-
ceptive pill status as a between subject-factor.
Additional post-hoc comparisons were conducted
when required.
Results
Hormone relationships
The measures of estradiol, ethinylestradiol, and
progesterone were log transformed to normalise the
distribution of scores prior to statistical analysis. The
estradiol level did not vary significantly between
testing sessions (F(2,52) = 1.907; P = 0.159), but was
significantly higher in the group not taking the
contraceptive pill (F(1,26) = 46.88; P < 0.0001), and

Table 1 Mean plasma hormone levels by testing session and contraceptive pill group

Contraceptive pill group No-pill group

Hormone Menses + soy Menses Luteal Menses + soy Menses Luteal
abc
Estradiol 46.75 (15.34) 43.17 (14.86) 27.80 (8.61) 53.25 (16.00) 56.09 (16.74) 121.33 (50.83)
Ethinylestradiola 36.80 (28.69) 41.43 (47.10) 384.26 (210.97) – – –
Progesteroneabc 1.98 (0.65) 1.86 (0.44) 1.89 (0.49) 1.27 (0.65) 1.47 (0.46) 7.59 (4.88)
Testosterone 0.45 (0.21) 0.43 (0.19) 0.38 (0.17) 0.46 (0.17) 0.43 (0.21) 0.49 (0.16)
SHBGab 15.66 (15.41) 14.08 (15.00) 8.68 (9.68) 40.95 (14.84) 39.01 (17.97) 39.25 (17.69)

Values are expressed in ng/ml.

a
Effect of cycle phase significant; beffect of pill group significant; cinteraction between cycle phase and pill group significant.

256 Nutritional Neuroscience 2008 Vol 11 No 6


there was a significant interaction between these
factors (F(2,52) = 36.905; P < 0.0001; Table 1). As
expected, the group not taking contraceptives had
higher estradiol levels in the luteal phase than during
the two menses phases (F(1,11) = 24.721; P < 0.001),
which did not differ from each other (F(1,11) < 0.527;
P = 0.483). The group taking the contraceptive pill
had lower estradiol levels in the luteal phase than the
two menses phase occasions (F(1,15) = 24.364; P <
0.001), which did not differ from each other (F(1,15) =
0.798; P = 0.386). However, this group had higher
ethinylestradiol levels in the luteal phase than the two
menses occasions (F(1,15) = 112.498; P < 0.0001),
which did not differ from one another (F(1,15) =
0.270; P = 0.671. These results confirm our design
expectation that natural or contraceptively-derived
estrogen levels during the luteal phase were
significantly higher than during the menses phases for
this population.
Progesterone levels also varied significantly
between testing sessions (F(2,52) = 25.905; P < 0.0001;
Table 1), but not contraceptive pill usage groups
(F(1,26) = 2.664; P = 0.115); however, there was a
significant interaction between these factors (F(2,54)
= 26.582; P < 0.0001). Separate analyses showed that
the group taking the contraceptive pill did not differ in
progesterone level across the three testing sessions
(F(2,30) = 0.239; P = 0.789), while the group not
taking contraceptive pills showed higher levels of
progesterone in the luteal phase than the two menses
sessions (F(1,11) = 24.548; P < 0.001), which did not
differ from each other (F(1,11) = 1.092; P = 0.318).
Testosterone levels did not vary significantly across
testing sessions (F(2,52) = 0.355; P = 0.703) or
between pill groups (F(1,26) = 0.426; P = 0.52), and
the interaction between these factors was not
significant (F(2,52) = 1.581; P = 0.216).
The SHBG data were not normally distributed and
could not be normalised by transformation; there is no
Table 2 Isoflavone levels by testing session and contraceptive pill group
Contraceptive pill group
Is o f l av o n e M en s es + s o y M en s es L u t eal
Daidzein (plasma)a 286.1 (116.8) 15.9 (38.3) 1.5 (5.8)
Genistein (plasma)a 102.5 (56.2) 0.0 (–) 0.0 (–)
Glycetein (plasma)a 71.5 (38.3) 10.1 (19.0) 8.9 (20.7)
Urinary equol 704.4 (1516.9) – –
Urinary daidzein 11,788.1 (6953.0) – –
Urinary genistein 847.6 (512.0) – –
Urinary glycetein 3439.3 (2079.8) – –
Values are expressed in ng/ml.
a
Menses + soy significantly greater than other sessions.
Islam et al. Effects of soy on cognition across the menstrual cycle
non-parametric test for a mixed design. The Freidman
test was used to evaluate if SHBG levels varied
significantly across testing sessions for both groups
combined and separately. None of these tests reached
significance ( all P > 0.09). A Mann–Whitney U-test
indicated that the participants taking the
contraceptive pill (mean rank = 9.88; n = 16) had
significantly lower SHBG levels than those not taking
the contraceptive pill (mean rank = 20.67; n = 12) U =
22.0, z = –3.435; P = 0.001, two-tailed.
Isoflavone levels
As would be expected, after the soy consumption the
plasma isoflavone levels were significantly greater than
on the other two testing occasions, which did not
differ from each other for any of the isoflavones
(daidzein – F(1,26) = 118.726; P < 0.0001, and F(1,26)
< 0.001; P = 0.991: glycetein – F(1,26) = 69.185; P <
0.0001, and F(1,26) = 0.052; P = 0.821: genistein –
F(1,26) = 54.014; P < 0.0001, and F(1,26) = 1.002; P =
0.326: Table 2). Only seven of the participants (25%)
produced detectable levels of equol, an isoflavone
metabolite, in plasma or urine. This level of equol
production is typical of non-vegetarian Western
populations.41 Due to the small sample, further
statistical analyses relating specifically to equol were
not conducted; however, in those women producing
equol, this isoflavone was included when calculating
total isoflavone concentration.
Cognitive tests
The measures of mood from the DASS inventory were
not normally distributed so the Stress measure was log
transformed and the Depression measure was inverse
transformed prior to analysis. This analysis showed
that they did not differ significantly between the three
testing sessions (Depression F(2,52) = 1.201; P =
0.309: Stress F(2,52) = 1.981; P = 0.148), and did not
differ with contraceptive pill use (F(1,26) = 2.247; P =
No-pill group
M en s es + s o y M en s es L u t eal
288.4 (139.5) 4.8 (11.6) 19.4 (58.9)
95.2 (63.1) 2.4 (8.4) 19.8 (68.5)
43.5 (31.7) 0.0 (–) 0.0 (–)
185.2 (518.8) – –
8520.1 (4818.0) – –
668.4 (529.4) – –
2065.0 (1315.8) – –
Nutritional Neuroscience 2008 Vol 11 No 6 257
Islam et al. Effects of soy on cognition across the menstrual cycle

0.146 and F(1,26) = 1.724; P = 0.201, respectively: Object Array Task

Table 3). The measure for Anxiety could not be
corrected by transformation. The Freidman test was
used to evaluate if Anxiety scores varied significantly
across testing sessions for both groups combined and
separately. None of these tests approached
significance (all P > 0.18). A Mann–Whitney U-test
indicated that the participants taking the
contraceptive pill (mean rank = 16.28; n = 16) did not
differ on anxiety level from those not taking the
contraceptive pill (mean rank = 12.13; n = 12) U =
67.5, z = –1.337; P = 0.181, two-tailed.
Paragraph Recall
Performance in the immediate paragraph recall task
(Table 3) showed no effect of testing session (F(2,52) =
1.673; P = 0.198). There were no significant
differences among the testing sessions on the number
of items forgotten over the delay (F(2,52) = 0.222; P =
0.801). Neither measure was affected by contraceptive
pill use (F(1,26) = 0.269; P = 0.608, and F(1,26) =
0.506; P = 0.483, respectively).
Mental Rotation
Neither accuracy (F(2,52) = 1.536; P = 0.225) nor
reaction times (F(2,52) = 1.247 P = 0.296) on the
mental rotation task differed across testing sessions
(Table 3). Neither measure was affected by contra-
ceptive pill use (F(1,26) = 1.324; P = 0.260, and
F(1,26) = 0.434; P = 0.516, respectively).
Testing session did not influence the time taken to
complete the object array memory task (F(2,52) =
0.961; P = 0.389) or the number of correct responses
(F(2,52) = 1.001; P = 0.374: Table 3). Neither accuracy
or speed was affected by contraceptive pill use (F(1,26)
= 0.979; P = 0.332, and F(1,26) = 0.013; P = 0.910,
respectively).
Counting Span (Working Memory)
There was a significant effect of testing session on this
task (F(2,52) = 7.440; P = 0.001: Table 3). Soy
consumption significantly improved counting span
when compared to both the menses (M = 4.61; F(1,26)
= 9.605; P = 0.005) and luteal phases (M = 3.75;
F(1,26) = 14.854; P = 0.001), which did not differ
(F(1,26) = 0.268; P = 0.609). When estradiol level was
included as a co-variate in the analysis, the effect of
testing session remained significant. However, when
the combined isoflavone plasma level (i.e. excluding
equol) was included as a co-variate, the effect of
testing session was no longer significant (F(2,53) =
1.37; P = 0.262). There was no effect of contraceptive
pill group (F(1,26) = 0.095; P = 0.760) or interaction
between pill group and testing session (F(2,52) =
0.779; P = 0.464).
RAVLT
The number of words recalled on the first trial of the
RAVLT differed significantly between testing sessions

Table 3 Mean scores (± SD) for psychological measures by testing session

Menses + soy Menses Luteal

(Low E2) (Low E2) (High E2)
Mood measure
Depression 1.82 (2.32) 2.46 (2.56) 2.21 (2.27)
Anxiety 1.75 (2.46) 1.71 (1.96) 1.64 (2.09)
Stress 4.21 (3.82) 5.29 (4.16) 5.25 (3.49)

Cognitive measure
Immediate paragraph recall 14.14 (3.98) 13.18 (4.11) 12.68 (4.00)
Paragraph forgetting 1.11 (1.47) 1.36 (1.45) 1.36 (2.11)
Mental rotation accuracy 19.97 (2.80) 19.37 (3.16) 19.50 (2.96)
Mental rotation speed (s) 3.26 (1.95) 3.75 (1.36) 3.48 (1.69)
Object array task accuracy 28.50 (3.12) 29.57 (3.52) 28.21 (4.25)
Object array task speed (s) 88.50 (21.95) 93.93 (29.42) 87.86 (24.47)
Counting spana,b 46.79 (5.35) 42.18 (7.20) 43.04 (6.69)
Letter fluency 42.46 (7.34) 39.36 (7.73) 41.93 (7.50)
Delayed matching accuracy – 4 s 10.25 (2.35) 10.07 (2.62) 10.50 (2.24)
Delayed matching accuracy – 10 s 9.54 (2.90) 9.43 (2.78) 9.11 (2.36)
Delayed matching RT – 4 s 5.76 (1.66) 6.40 (1.93) 6.42 (2.07)
Delayed matching RT – 10 s 6.67 (1.65) 7.10 (1.78) 6.74 (1.94)
Digit span forwards 6.53 (0.82) 6.61 (0.83) 6.47 (1.01)
Digit span backwards 5.11 (0.62) 5.10 (0.87) 5.40 (0.95)
a
Significant effect of testing session; bmenses versus menses + soy significant.

258 Nutritional Neuroscience 2008 Vol 11 No 6

 Islam et al. Effects of soy on cognition across the menstrual cycle

1.967; P = 0.158), whereas it did for the non-pill group

(F(2,22) = 9.900; P = 0.001) in which the rate of
learning was greater during the menses condition than
in the luteal or menses + soy conditions (F(1,11) =
20.603; P = 0.001 and F(1,11) = 13.265; P = 0.004,
respectively). As can be seen from Figure 1, in the
menses condition the non-pill group perform more
poorly initially but this difference diminishes across
learning trials.
A measure of forgetting was calculated from the
RAVLT by subtracting the number of words recalled
on the delayed recall trial from the number recalled on
trial 4 (Fig. 2). Analysis of this measure showed no
effect of testing session (F(2,52) = 1.155; P = 0.323) or
contraceptive pill group (F(1,26) = 0.319; P = 0.577);
however, there was an interaction between these two
factors (F(2,52) = 4.018; P = 0.024). Separate
analyses of the two groups showed that the effect of
testing session failed to reach significance in either
Figure 1 Recall performance on the four learning trials of the
group (F(2,22) = 2.849; P = 0.079, and F(2,30) =
RAVLT as a function of testing session and 2.423; P = 0.112).
contraceptive pill group (bars indicate SE)
Letter Fluency
(F(2,52) = 4.513; P = 0.016), but not between The difference in performance on the letter fluency
contraceptive pill usage groups (F(1,26) = 3.282; P = task across testing sessions approached significance
0.082: Fig. 1). The interaction between these two (F(2,52) = 3.137; P = 0.052: Table 3), but did not
factors was significant (F(2,52) = 4.723; P = 0.013). differ between contraceptive pill groups (F(1,26) =
Separate analyses of the two groups showed no effect 0.620; P = 0.438). These results suggest a trend in the
of testing session in the group taking the contraceptive
pill (F(2,30) = 0.614; P = 0.548); however, the non-pill
group show an effect of testing session (F(2,22) =
5.265; P = 0.014), with recall worse in the menses
testing session than the luteal testing session (F(1,11)
= 7.187; P = 0.021) but not after Bonferroni
adjustment. However, recall was significantly better in
the soy condition than the menses condition (F(1,11)
= 10.385; P = 0.008).
Differences between conditions in the rate at which
words were learned across trials in the RAVLT can be
evaluated by a linear contrast on the four trials. A
score on the linear contrast was calculated for each
participant in each test session and subjected to
statistical analysis after transformation to correct for
normality. This showed that the rate of learning did
not differ significantly between groups (F(1,26) =
1.424; P = 0.244); however, it did differ between
testing sessions (F(2,52) = 3.910; P = 0.026) and there
was a significant interaction between these two factors
(F(2,52) = 10.018; P < 0.001). Separate analyses of the
Figure 2 Forgetting over the delay on the RAVLT (Trial 5 –
two contraceptive pill usage groups showed that the
learning rate did not differ between testing sessions for Trial 4) as a function of testing session and
the group taking the contraceptive pill (F(2,30) = contraceptive pill group (bars indicate SE)

Nutritional Neuroscience 2008 Vol 11 No 6 259

Islam et al. Effects of soy on cognition across the menstrual cycle
data such that performance was worse in the test
session at menses than the other two test sessions.
Delayed Matching-to-Sample Task
Accuracy on the delayed matching to sample task was
significantly poorer at the longer delay (F(1,26) =
7.786; P = 0.004), as was speed of reaction time
(F(1,26) = 12.531; P = 0.002), but neither differed
between testing sessions (F(2,52) = 0.152; P = 0.859
and F(2,52) = 1.279; P = 0.287, respectively: Table 3).
Neither accuracy or speed was affected by
contraceptive pill use (F(1,26) = 0.851; P = 0.365, and
F(1,26) = 1.021; P = 0.322, respectively).
Digit Span
Neither digit span forwards or backwards differed
across testing sessions (F(2,52) = 0.711; P = 0.496, and
F(2,52) = 2.165; P = 0.125, respectively: Table 3), or
between contraceptive pill groups (F(1,26) = 1.514; P
= 0.230, and F(1,26) = 0.934; P = 0.343, respectively).
Discussion
The primary aim of the study was to examine the
hypothesis that supplementation with dietary
phytoestrogens could ameliorate any effects on
cognition of reduced endogenous estrogen during the
menses phase of the cycle. This study differs markedly
in design from other studies attempting to
demonstrate effects of phytoestrogens on cognitive
functions in that the duration of phytoestrogen
supplementation was very short and provided when
estrogen levels were lowest. Several cognitive tasks
which have previously been shown to vary across the
menstrual cycle or shown reliable sex differences in
performance were tested to evaluate this possibility.
The results of this study suggest that phytoestrogens
may serve as an estrogenic analog in supporting
performance on some cognitive tasks at times when
endogenous estrogen levels are low. This is clearly
demonstrated in the verbal learning task for the group
not taking the contraceptive pill in which performance
on the first trial was significantly worse in the menses
phase, when estradiol was significantly lower than in
the luteal phase. With soy supplementation during
menses, performance was equivalent to the luteal
phase despite their low levels of estradiol. The number
of words forgotten during the delay between the final
learning trial and the delayed test showed the same
pattern for this group, though failing to reach
260 Nutritional Neuroscience 2008 Vol 11 No 6
significance, presumably due to the small number of
non-pill participants. That is, there was a tendency for
these participants to forget more words over the delay
during the menses phase, when estradiol was lower
compared to the luteal phase, than in the other two
testing sessions.
Paragraph recall has previously been found to show
an improvement following soy consumption in both
post-menopausal21 and young women.25 The results of
the present study showed a change in the same
direction, but failed to reach significance. However,
the dietary intervention in the present study was only 3
days whereas other studies tested participants after
chronic (10–12 weeks) soy supplementation; thus,
longer-term changes in neural function rather than
circulating levels of isoflavones alone may be required
to elicit this change.
Most surprising in our results is the absence of
change in performance on the working memory task
between the menses and luteal phases, yet working
memory was significantly improved in the soy
supplemented menses phase. Rosenberg and Park15
reported variation across the menstrual cycle in
performance on a verbal working memory task and
Duff and Hampson42 reported a significant benefit of
HRT on spatial and verbal working memory tasks in
post-menopausal women. The most likely explanation
for the lack of a menstrual cycle effect in our data is
the nature of the task used. The working memory
span task used in this study requires the encoding and
maintenance of information whilst processing other
information before a final recall phase. The working
memory tasks used in the studies of Duff and
Hampson42 and Rosenberg and Park15 require more
manipulation of the information than the counting
span task used here, and it may be these processes that
vary across the menstrual cycle. This evidence suggests
that the effect of soy on the working memory span
task may not be mediated directly by estrogen-
dependent mechanisms. One possibility is dopamine
function in prefrontal cortex as dopamine release has
recently been shown to be involved in a verbal working
memory task43 and dopamine release and re-uptake
varies with circulating estrogen levels.44 Further, it has
been suggested that serotonin interacts with dopamine
in working memory function and there is considerable
evidence of estrogenic influences on the serotonin
system.45
Previous research has found that performance on
mental rotation tasks varies across the menstrual
cycle, with better performance during the menses
phase (e.g. Hausmann et al.9); however, this effect was

not observed in our study. The male advantage on this
task has been linked to testosterone and Aleman et
al.46 found improved performance in females after
testosterone injection. Both Hausmann et al.9 and
Maki et al.14 found differences in performance across
the menstrual cycle, although they did not measure
testosterone. We did not observe a similar cycle effect
on mental rotation; however, this may reflect the fact
that testosterone did not vary significantly across the
menstrual cycle in either of our groups.
Traditionally, verbal tasks are thought of as
showing a female advantage which varies across the
menstrual cycle. Although some studies have found
that letter fluency does not differ across the menstrual
cycle,12 one study25 has shown an improvement on this
task in a sample of young women on a soy rich diet for
10 weeks. Our data show a nearly significant trend (P
= 0.052) for performance to be poorer in the menses
phase without soy than in either the luteal or menses +
soy tests, when estrogen or estrogen-like compounds
were more available. This suggests that there may be a
variation in performance associated with fluctuations
in endogenous estrogen and that this effect might be
ameliorated by soy consumption. The finding by File
et al.25 of an effect of soy on this task suggests that the
effect may be dependent on long-term effects of a soy-
rich diet, possibly through influences on receptor
density and/or distribution, and that the dietary
supplementation used here was too brief to produce a
strong effect.
The object array task has been demonstrated to
show a female advantage;34 however, again, perform-
ance in the present study did not differ significantly
across the menstrual cycle. This can be taken as
evidence that the female advantage on this task may
result from long-term organisational effects of
estradiol rather than short-term activational or
dynamic changes in hormone levels occurring during
the cycle.
Because of their small size and high lipophilicity,
steroid compounds can have important effects on the
brain. In a recent review of neuro-active steroids,
Birzniece et al.45 described the complex manner in
which estrogen, progesterone and other steroids may
influence mood, memory and other cognitive
processes. By virtue of their structural similarity to
steroid molecules, soy isoflavones may also exert
effects on these processes via estrogen receptors,
interactions with other steroids or neurotransmitter
pathways, such as serotonin and GABA systems. A
further mechanism of possible relevance to estrogenic
effects on cognition involves demonstrations that
Islam et al. Effects of soy on cognition across the menstrual cycle
hemispheric asymmetry of certain language related
tasks (left-brain dominance) varies across the
menstrual cycle. Hausmann and Gunturkun47 and
Fernandez et al.16 found that hemispheric asymmetry
in neural response is high during menses, but decreases
during the mid-luteal phase for semantic/lexical tasks.
These authors suggest that steroid hormones, through
as yet undetermined mechanisms, may facilitate cross-
hemisphere processing. Our study was not designed to
address the question of functional lateralisation;
however, soy isoflavones may contribute to
ameliorating such an effect during menses. Future
research may shed further light on the task specific
effects of these exogenous estrogens.
Conclusions
High levels of dietary phytoestrogens may have
multiple effects on cognitive function in females. There
appear to be effects linked to exposure to isoflavones
in which these exogenous estrogens effectively
substitute for reduced levels of endogenous estrogen.
Soy supplementation also appears to affect some
cognitive processes (working memory) in a manner
that is not directly related to estrogen levels. Finally,
there is a suggestion that there may be longer term
effects of dietary phytoestrogens which may be related
to the estrogenic milieu. Numerous aspects of these
results warrant closer examination in studies
measuring hormone levels and cognitive function.
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