Trough oestradiol
levels associated with cognitive impairment in
post-menopausal women after 10 years of oestradiol implants
Psychopharmacology
v.161, n1 21feb02
Sandra E. File • Joy E. Heard • Janice Rymer
Received: 30 October 2001 / Accepted: 17 January 2002 / Published online:
21 February 2002
Abstract Rationale: Oestrogen treatment has been found to improve
memory in healthy post-menopausal women, but the effects are small, especially
when socio-economic status is controlled. There is some evidence that with
long-term treatment the benefits decline, or reverse. Objective: To
examine the effects of 10 years of oestradiol implants on attention, memory
and frontal lobe function in healthy women (aged 51-72 years) who had
undergone a surgical menopause. Methods: In an open study, patients
were recruited from the Guy's Hospital menopause clinic and were tested just
before receiving a new implant. Exclusion criteria included any form of
psychoactive medication, IQ<90, English not the first language and anxiety
or depression scores in the clinical range. All patients had been receiving
HRT with an oestradiol implant for about 10 years. Each patient was
pair-matched to a woman who had never received HRT. Eighteen pairs were
matched for age, IQ, socio-economic status, years of secondary education, and
occupation. They completed questionnaires, mood rating scales and a battery of
cognitive tests. Results: The patients with oestradiol implants had
significantly greater psychological and somatic menopausal symptoms and
significantly worse mental flexibility (rule reversal) and long-term episodic
memory than did the control group who had never received HRT. Analysis of
covariance showed that the difference in menopausal symptoms did not account
for the cognitive differences. There were no differences in a test of
sustained attention or in a category generation task or in self-ratings of
mood after the stress of cognitive testing. Conclusions: Long-term
treatment with oestradiol implants does not convey cognitive benefits and may
lead to impaired function.
S.E. File, J.E. Heard
Psychopharmacology Research Unit, Centre for Neuroscience, Hodgkin Building,
King's College London, Guy's Campus, London SEI IUL, UK sandra.file@kcl.ac.uk
Tel.: +44-20-78486667, Fax: +44-20-78486660
J. Rymer
Department of Obstetrics and Gynaecology, Guy's, King's and St Thomas' School
of Medicine, Guy's Hospital Campus, London SEI 9RT, UK
Keywords Memory , Attention , Frontal lobe tasks Mood , Oestrogen ,
Menopause
Introduction
The menopause is associated with a dramatic decline in circulating oestrogen
concentrations and in well-controlled experimental studies short-term oestrogen
replacement therapy has been found significantly to improve episodic memory
(Phillips and Sherwin 1992; Jacobs et al. 1998; Duka et al. 2000). The effects
of hormone replacement therapy (HRT) have also been investigated in
epidemiological studies and in these studies there is always the concern that
women who have chosen to take HRT may be younger or have higher levels of
education and socioeconomic class than non-users (Barrett-Connor 1998). It has
been suggested (Hogervorst et al. 2000) that this may explain the higher
incidence of positive findings in epidemiological studies (17 out of 18) than in
experimental studies (7 out of 14).
However, a few cross-sectional studies have carefully matched HRT users and
non-users for age, IQ, education and socioeconomic class. In a small group of
elderly women (mean age 75 years), Verghese et al. (2000) found that present
(duration of use not specified) and past (use for 3 years) users of oestrogen
had better episodic and semantic memory than non-users, but did not differ on
tests of attention. In a study that also matched HRT users with non-users for
time since the menopause, Kampen and Sherwin (1994) found that users had better
episodic memory than non-users. Different forms of HRT had been used and the
duration of HRT was not specified in this study, but the average age of the
women was 64 years and their average age at menopause was 48. A recent study
(Flock et al. 2000, 2002) used a pair-matching technique to provide an even
tighter control between HRT users and non-users. Pairs of women were
matched on age, years since the menopause, IQ, years of secondary education,
occupation and anxiety and depression scores. The women who had taken tibolone
for 10 years had better semantic memory than the controls, but did not differ in
episodic memory and performed worse on a sustained attention task and a planning
task, tests that are associated with frontal lobe function. In a study that
matched groups for age and education, Barrett-Connor and Kritz-Silverstein
(1993) found that women who had used HRT for 20 years had better semantic
memory, but did not differ in tests of episodic memory or attention. It
therefore seems that with prolonged use, the benefits of HRT on episodic memory
may disappear and impairments in other cognitive tasks may emerge.
The possibility that long-term use of HRT may no longer convey beneficial
cognitive effects, and may even have harmful ones, is extremely important and
there is a paucity of studies investigating this in older healthy women (see
Hogervorst et al. 2000). The two large controlled studies that are currently
underway (WHIMS, Shumaker et al. 1998 and WISDOM, Wren 1998) are using
conjugated equine oestrogens, and these have not been found to improve cognitive
function (see Hogervorst 2000, for review). The purpose of the present study was
therefore to evaluate the effects on memory, attention and frontal lobe function
of ten years of treatment with oestradiol implants. These implants give rise to
much higher oestradiol concentrations than do oral or transdermal preparations.
If the cognitive effects are related to oestradiol concentrations, then this
form of HRT would be expected to have more marked effects. It is possible that
the lack of effect on episodic memory of long-term treatment with tibolone
(Fluck et al. 2000, 2002) is because this form of HRT has only weak oestrogenic
activity. Tests of episodic and semantic memory were chosen because it is in
tests of memory that there is the strongest evidence for an improvement with
oestrogen replacement therapy, and we selected both verbal and non-verbal tasks.
Tests of frontal function were also included because long-term treatment with
tibolone was found to cause impairments in these tasks (Fluck et al. 2000,
2002).
Materials and methods
Subjects
In an open study, patients with English as their first language were
recruited from the Guy's Hospital menopause implant clinic over a 6-month
period. All patients had undergone a surgical menopause, i.e. had received a
hysterectomy with bilateral oophorectomy about 10 years previously
(mean±SEM=9.7±1.1 years). Patients were excluded if they were on any current
psychoactive medication or had any current acute illness. Their test scores were
also excluded if they had anxiety or depression scores in the clinical range of
the Hospital Anxiety and Depression (HAD) scale, or if their estimated IQ scores
were <90. Of the 31 patients recruited, six were excluded for low IQ and 3
for high levels of anxiety or depression. For four of the patients we were
unable to find a pair-matched control subject. The control group was recruited
through notices on the Guy's campus. The same exclusion criteria applied and one was
excluded for low IQ, but none had anxiety or depression scores in the clinical
range. Members of the control group were individually matched to each implant
patient for age, IQ, years of education and occupation, providing 18 pairs of
closely matched women in the two groups. It can be seen from Table I that the
groups did not differ significantly in their alcohol (F=1.3, NS) or caffeine
(F<1.0, NS) consumption. The higher mean alcohol consumption in the implant
group is due to one patient who drank 20 units per week, but even this is not
regarded as high alcohol consumption. Few of our subjects smoked, only one in
the control group and four in the implant group. The patients were tested just
before receiving a new implant and the oestradiol concentrations at this trough
time were in the range 646-727 pmol/l. The study was approved by the local
Ethics Committee and all subjects gave written informed consent before the start
of testing.
Table 1 Mean±SEM age (years), estimated IQ (NART), weekly alcohol intake
(units), daily caffeine consumption (cups) and scores on the Hospital Anxiety (HADA)
and Depression (HADD) scale for women who had never received
HRT (Control) and for those treated with oestradiol implants for 10 years
(Implant)
Control Implant
Age 58.5±1.1 56.3±1.4
IQ 108.8±2.5 106±2.6
Weekly alcohol 2.9±0.9 6.0±2.6
Caffeine daily 6.2±0.6 6.8±0.8
HADA 5.2±0.8 6.2±0.7
HADD 2.4±0.5 3.8±0.6(*)
(*) P<0.06 compared with control
Procedure
Measures of IQ, anxiety, depression and menopausal symptoms
An estimate of verbal IQ was obtained using the National Adult Reading Test
revised version (NART R; Nelson and Willison 1991) and anxiety and depression
measured with the Hospital Anxiety and Depression Scale (HAD; Zigmond and Snaith
1983). The volunteers completed the Green climacteric scale (Greene 1991, 1998).
Analogue self-rating scales
The volunteers then completed analogue ratings of mood and bodily symptoms.
These consisted of ten pairs of opposing adjectives separated by a 100 mm line.
The volunteers marked a point along each line that corresponded to how they felt
at the present time. These adjectives were selected from the Bond and Lader mood
scales (Bond and Lader 1974, 1986). The mood rating scale was also completed at
the end of cognitive testing. The particular items were selected because they
have proved sensitive to changes in mood after the stress of cognitive testing
(File et al. 2001; Fluck et al. 2002).
Tests of episodic memory
In a test of immediate memory, a short story (from the Weschler Memory Scale
, revised; Weschler 1987) with 25 units of information was read at the rate of
one unit per second and volunteers were told to try and remember this as closely
as possible. They were asked for their recall immediately at the end of the
story and the number of correctly recalled units was scored. Long-term episodic
memory was measured by presenting a set of 20 pictures of common objects, each
picture was shown for 3 s and then 20 min later the volunteers were asked to
recall as many of these as possible.
Tests of frontal function
Two tests were selected from the Cambridge Neuropsychological Automated
Battery (CANTAB; CeNeS Ltd, Cambridge, UK) that provide measures of frontal lobe
function. A test of rule reversal that provides a measure of mental flexibility
(Owen et al. 1991) and the Stockings of Cambridge test of planning ability (Owen
et al 1990). In the rule reversal test, a series of pairs of patterns was
presented on a computer screen and the task was to learn which of two patterns
was correct. When criterion was reached (six consecutive correct responses) the
rule was reversed and the previously incorrect stimulus now became correct. The
time taken to reach criterion for rule reversal was measured. In the Stockings
of Cambridge test, the computer screen showed two sets of three coloured balls
that could be housed in three stockings. The task was to move the balls in the
lower part of the screen so that the pattern exactly matched that in the upper
part and to use as few moves as possible. Four different puzzles were presented,
each of which could be solved in three moves. The time taken to complete the
three moves task was recorded.
Category generation
In a category generation task the volunteers were given 20 s each to name as
many animals as possible that fell first in the category of farm animals and
then in the category of jungle animals. This is a task that has components of
semantic memory and, unlike a letter fluency task, has been shown to activate
the left medial emporal lobe (Pihlajamaki et al. 2000).
Test of attention
The Paced Auditory Serial Addition Test (PASAT) was used to measure sustained
attention (Sprees and Strauss 1991). This involves adding together successive
pairs of digits read from a list of 61 numbers, presented at the rate of one
digit every 2.4 s. The total number of correct responses (maximum 60) was
recorded. This test is very stressful, so it served the additional purpose of
allowing a comparison between the groups of the mood change in response to
stress.
Statistics
The data from the episodic and frontal lobe tests were first analysed by
multivariate analyses of variance (MANOVA), which permits analysis of the
effects of HRT whilst controlling for intercorrelations among measures, thus
reducing the risk of false positives from a series of univariate analyses.
Because both of the MANOVAs showed significant group effects these were then
followed by one-way analyses of variance (ANOVA) for the individual tests. The
self-ratings were analysed by two-way analyses of variance with group (implant
or control) as the independent factor and stress (before and after) as the
repeated measure. In order to determine whether the group differences in
menopausal symptoms could account for the cognitive differences analyses of
covariance were conducted with depressive and somatic symptoms as covariates.
When effects were close to or reached significance, both F values and
probability levels are quoted. Where results did not reach significance only the
F ratios are presented, and non-significance indicated (NS).
Results
HAD and Greene climacteric scales
From the scores on the HAD, the groups did not differ in their anxiety
scores, but the implant group did suffer from more depression [F(1,35)=3.6,
P=0.06), although this just missed significance, see Table 1. In addition, we
had already excluded several women from the implant group because their scores
on depression fell in the clinical range on this scale. From their ratings on
the Greene climacteric scale, compared with the women who had never received
HRT, the women with oestradiol implants had the same incidence of vasomotor
symptoms, but experienced significantly more somatic [F(1,25)=7.4, P=0.01] and
psychological symptoms [F(1,25)=3.8, P=0.06]. There was no difference in the
symptoms of anxiety, but those in the implant group suffered significantly more
depressive symptoms [F(1,25)=6.5, P<0.02], see Fig. 1.
Episodic memory
There was a significant overall effect on the factor measuring episodic
memory [MANOVA, F(2,33)=4.0, P<0.03], with the patients in the implant group
showing worse recall than those in the control group. The difference was
particularly marked in the test of long-term memory, with the implant group
recalling significantly fewer pictures [F(1,35)=7.1, P=0.01], but they also had
poorer short-term memory, recalling fewer items of the story [F(1,35)=3.5,
P=0.07], see Fig. 2.
Fig. 1 Mean (±SEM) scores for somatic and depressive symptoms on the Green
climacteric scale for women never treated with HRT (CON) and those treated
with oestradiol implants for 10 years (IMP). **P<0.01, *P<0.05 compared
with control
Fig.2 Mean (±SEM) numbers of pictures recalled after 20 min and items of a
story recalled immediately by women never treated with HRT (CON) and by those
treated with oestradiol implants (IMP) for 10 years. **P<0.01, (*)P<0.10
compared with control
Fig. 3 Mean (±SEM) time (ms) to reach criterion in a rule reversal and a
planning task by women never treated with HRT (CON) and by those treated with
oestradiol implants (IMP) for 10 years. *P<0.05, (*) P<0.10, compared
with control
Tests of frontal lobe function
The implant group performed worse than the controls in the factor measuring
frontal lobe function [MANOVA, F(1,31)=3.8, P<0.05]. The implant group took
significantly longer to learn a rule reversal [F(1,35)=5.3, P<0.03] and in
the task of planning ability they took longer to complete the 3 moves tasks
[F(1,35)=3.4, P<0.08], see Fig. 3.
Category generation
There were no significant differences between the groups in the category
generation task (F<1.0, NS, see Table 2).
Table 2 Mean±SEM number of farm
and jungle animals recalled in the category generation task and correct
responses in the Paced Auditory Serial Addition Task (PASAT) by women who had
never received HRT (Control) and by those treated with oestradiol implants for
10 years (Implant)
Control Implant .
Farm animals 7.8±0.4 7.8±0.4
Jungle animals 6.9±0.8 6.3±0.5
PASAT 36.8±2.8 28.5±4.3(*)
(*) P<0.10 compared with control
Table 3 Mean±SEM scores on rating scales before and after cognitive testing of women who had never received HRT
(Control) and those who had received oestradiol implants for 10 years (Implant)
Control Implant .
Before After Before After
testing testing testing testing .
Calm*** 64.9±5.2 53.2±6.3 80.0±4.1 55.8±6.6
Coordinated*** 65.5±5.2 44.7±6.2 76.3±5.4 46.3±5.8
Tranquil* 68.8±6.0 53.0±6.9 71.3±7.0 60.0±6.4
Quickwitted*** 55.4±5.8 40.3±6.4 60.0±5.9 31.8±5.8
Relaxed* 62.2±6.1 50.2±7.3 64.9±6.3 50.9±7.2
Outgoing 69.3±6.2 64.3±6.32 70.9±6.4 64.1±6.1
Peaceful*** 83.3 ±3.2 59.6±5.4 76.9±5.4 64.7±4.0
Affable* 85.6±3.1 70.8±4.8 81.4±4.5 78.9±3.8
Friendly* 88.8±2.2 76.7±4.9 83.9±3.7 80.9±3.8
Compliant** 84.1±3.6 67.8±5.2 78.9±4.8 71.6±5.6
Anxiety*** 21.0±4.2 42.6±6.4 15.3±4.2 34.6±6.4
Sweating* 13.3±4.0 18.1±4.9 7.6±4.0 20.1±4.9
Palpitations* 19.3±4.1 23.8±4.6 9.4±4.1 18.3±4.6
Irritability*** 13.1±2.6 23.6±4.3 9.4±2.6 22.4±4.3
***P<0.0001, **P<0.001, *P<0.02, change after cognitive testing
Sustained attention
The implant group performed worse than the controls in the PASAT, but this
failed to reach significance [F(1,34)=2.6, P=0.1 ], see Table 2.
Effect of menopausal symptoms on cognitive function
In order to determine whether differences in the incidence of depressive or
somatic symptoms could account for the group differences in cognitive
performance a series of ANCOVAs were conducted using the symptoms as covariates.
When depression was accounted for, the implant group still performed
significantly worse in the test of long-term memory [F(1,33)=5.4, P<0.03] and
in rule reversal [F(1,33)=5.2, P<0.05] and they also performed more poorly in
both tests when somatic symptoms were accounted for (P<0.05 in both cases).
Self ratings of mood and bodily symptoms
Table 3 shows the mean scores on the mood analogue rating scales before and
after the cognitive test battery. All the women showed a marked deterioration in
mood after the stress of the cognitive tests [MANOVA, time F(10,22)=6.2, P<0.0001] and there were significant changes on all of the adjectives, except
outgoing.
After the stress of cognitive testing, there was also a marked increase in
the ratings of bodily symptoms [MANOVA, time F(8,27)=3.4, P<0.01],
but there was no difference between the two groups (treaimentxtime, F<1.0,
NS). The individual bodily symptoms that showed significant increases after the
stress were anxiety [F(1,34)=30.5, P<0.0001], sweating [F(1,34)=6.1,
P<0.02], palpitations [F(1,34)=4.2, P<0.05] and
irritability [F(1,34)=15.8, P<0.000I], see Table 3.
Discussion
The women treated with oestradiol implants experienced significantly more
somatic and psychological menopausal symptoms than did those who had never
received HRT. In completing the Greene climacteric scale, the women commented
that their symptoms emerged at the end of the life of the implant and that it
was the emergence of these symptoms that would prompt them to have the implant
replaced. This strongly suggests that at least these menopausal symptoms result
from the decreasing oestradiol concentrations. It is unlikely that they were the
result of low oestradiol concentrations per se, since even at the trough, the
levels were 2-5 times higher than those achieved with transdermal or oral
oestrogen treatment (Kampen and Sherwin 1994; Polo-Kantola et al. 1998; Wolf et
al. 1999). The oestradiol concentrations in non-users are generally below 50
pmol/1 and certainly in these women about 10 years after the menopause, the
incidence of symptoms was very low. This is further evidence that the symptoms
do not derive from low concentrations of oestradiol. Interestingly, neither
group reported vasomotor symptoms, suggesting either that tolerance develops to
these or that they are produced by the excessive oestrogen concentrations during
the transitional period. Both the HAD and Greene scales detected an increased
severity of depressive symptoms in the implant group and since the questions on
the HAD scale relate to "how you normally feel", increased depressive
symptoms may be especially sensitive to fluctuating hormonal levels. Certainly,
an increased score on the HADD scale was not found in women
treated for 10 years with tibolone, an oral preparation with low oestrogenic
activity (Fluck et al. 2002).
Our results provide no evidence that 10 years of oestradiol implants conveys
any cognitive advantage when performance is compared with that shown by a group
of women who had never used HRT In a recent study, Duff and Hampson (2000) found
that women who had received oestradiol treatment from 2 months to 20 years did
not show better performance in tests of episodic memory, although they did
perform better in tests of working memory. In a study that controlled for age of
onset of menopause, education and hysterectomy, Binder et al. (2001) found no
evidence of cognitive improvement. Women treated with tibolone for 10 years
performed better in tests of episodic memory than a pair-matched control group
who had never received HRT, but the tibolone group performed more poorly in
tests of mental flexibility and planning (Fluck et al. 2000, 2002). The results
of our two studies suggest that whereas long-term treatment with a low dose of
oestrogen can have beneficial effects on memory, long-term treatment with a much
higher dose does not necessarily do so and may even cause impaired performance.
The extent and magnitude of the impairments that we found in the present study
are similar to the extent and magnitude of improvements found in other studies
(e.g. Duka et al. 2000; Verghese et al. 2060). This, together with the studies
that reported no differences in cognitive performance between HRT users and
non-users, suggests that benefits are by no means universal.
An important question that arises is whether the increased incidence of
depressive or somatic symptoms in the implant group could account for their
poorer performance. The analyses of covariance showed that this was not the
case. If the poorer cognitive function had been an indirect result of more
menopausal symptoms, then the deficit might have been reduced when the implants
were renewed and symptoms abated. However, given the results of the covariance
analysis, this does not seem to be a very likely possibility and, furthermore in
general, better cognitive performance has not been associated with enhanced mood
resulting from HRT (Hogervorst et al. 2001). There is limited information on the
relationship between oestradiol concentrations and cognitive performance.
However, in a large cross-sectional study no positive correlations were found
between performance in any cognitive test and either total or bioavailable
oestradiol, whereas an inverse relationship was found between oestradiol
concentrations and visual reproductive memory (Barrett-Connor et al. 1999). Our
results would certainly be consistent with the hypothesis that high oestradiol
concentrations may be associated with poorer memory function. Also consistent
with this possibility would be the findings of greater age-related memory
decline in men compared with women (Carlson and Sherwin 1998; Barrett-Connor and
Kritz-Silverstein 1999), since older men have higher oestradiol concentrations
than women. This issue could be addressed further by testing women shortly after
receiving a new implant.
A second important question is whether the difference in mood and cognition
could relate to group differences that existed prior to the menopause. We cannot
exclude the possibility that the groups differed 10 years ago, but there is no
strong reason for thinking that this was the case. The careful pair-matching
technique that we used reduced the probability that the groups differed in
cognitive performance, irrespective of HRT The vast majority of patients
received hysterectomies and oophorectomies for the treatment of fibroids, with a
few having been treated for menorrhagia. Thus the reasons for surgery did not
relate to pre-existing menopausal symptoms, since all were pre-menopausal at the
time of surgery. Furthermore, the patients reported that their symptoms were
variable, and they felt that they related to decreasing hormone concentrations.
It is unlikely that differences in smoking, alcohol or caffeine consumption
could account for the results, since the levels of all of these were very low in
both groups and only two patients had alcohol intakes higher than 10 units per
week. However, in an open study such as this the possibility that the groups did
differ pre-menopause cannot be excluded, as is the case in the many similar
studies.
Finally, the possibility should be considered that the results could have
been confounded because this was an open study. All our subjects were very
co-operative and eager to perform well. The implant group was convinced of the
merits of their HRT and would not have harboured any expectation of performing
more poorly as a group than the group who had never received HRT We ourselves
had no expectation of finding poorer memory in the implant group and the
experimenter conducting the tests had no knowledge of the literature or the
result of our previous study. In the computer-based tests of frontal function it
is very difficult to influence the results and the experimenter did not know
which tests measured frontal function.
In conclusion, within the limitations imposed by this sort of study there is
no evidence of improved cognitive function in the group that received 10 years
of oestradiol implants and sufficient evidence of possible impaired function to
warrant further study. For example, it would be important to determine whether a
relatively short-term treatment with oestradiol implants would also impair
cognition. It is interesting that after the cognitive tests the women in the
implant group showed a greater reduction in their self-ratings of feeling
quick-witted than did the control group, which suggests that they had a quite
accurate perception of their cognitive abilities. Indeed, most remarked
spontaneously that they had noticed deterioration in their memory.
Acknowledgements This research was supported by a grant from the Dunhill
Medical Trust. We are grateful to Debby Holloway, Head Nurse, Gynaecology for
her help in organising the patient appointments.
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