JAGS 50:1826–1830, 2002© 2002 by the American Geriatrics Society 0002-8614/02/$15.00

Mood Symptoms and Cognitive Performance in Women Estrogen Users and Nonusers and Men

Karen J. Miller, PhD,

*

Janet C. Conney, MD,

*

Natalie L. Rasgon, MD, PhD,

*

Lynn A. Fairbanks, PhD,

*

and Gary W. Small, MD

*

†‡

OBJECTIVES:

Previous studies have suggested sex differ-ences in mood and cognition and that estrogen effects maypartially explain such differences. In this study, we exploresex differences for a range of mood symptoms and forneuropsychological performance in men and postmeno-pausal women and assess the potential influence of estro-gen on these measures.

DESIGN:

Cross-sectional study of men and women exam-ining mood, neuropsychological test data, and estrogen re-placement therapy (ERT) use.

SETTING:

Outpatient study at an urban teaching hospi-tal with subjects recruited from the community.

PARTICIPANTS:

All subjects (N

�

96) were between theages of 57 and 75 and included 31 women using ERT, 16non-ERT users, and 49 men. Subjects did not have majordepression and were nondemented.

MEASUREMENT:

The three groups were compared ac-cording to profile of mood states and neuropsychologicalperformance, and statistical analyses were controlled forsocioeconomic status, age, and education level.

RESULTS:

Female ERT users were less depressed and lessangry and performed better on measures of verbal fluencyand working memory than the other subject groups.

CONCLUSION:

Postmenopausal estrogen use is associ-ated with better mood and cognitive performance on tasksof fluency and working memory. These results suggest thatestrogen should be examined as a potentially critical vari-able influencing late-life sex differences in mood and cog-nition.

J Am Geriatr Soc 50:1826–1830, 2002.Key words: cognition; estrogen; memory; mood

P

revious research has noted sex differences in mood andcognitive symptoms in older adults. The influence of

hormones on the aging process may partially explain suchsex differences. Although men continue to have an intrin-sic supply of estrogen by the conversion of testosteronewell into their seventh and eighth decades of life, estrogendeclines more rapidly in women after menopause.

1

Nondepressed postmenopausal women experience en-

hanced moods when exposed to estrogen.

2–7

In studies ofestrogen replacement therapy (ERT) in postmenopausal de-pressed women, results are conflicting; some investigatorshave reported that ERT improves symptoms of depres-sion,

8–12

whereas other groups have failed to detect anyantidepressant effects from ERT use.

13–16

Few previous studies have compared older men andwomen according to mood. In a cross-sectional study ofolder adults, Barrett-Connor et al. reported that womenhad greater symptoms of depression than men, and estro-gen use had no influence on these differences men.

17

Carl-son et al. used the Profile of Mood States (POMS) to com-pare female ERT users and nonusers and men and foundthat the ERT users were more depressed, more anxious,and more angry than men and non-ERT users, but, whenthe investigators excluded women using progesterone inaddition to estrogen, the mood scores between the threegroups were no longer significant.

18

Studies of cognitive performance in nondemented-olderwomen indicate that ERT users perform better than non-ERT users on measures of verbal memory,

19–24

verbal flu-ency,

25

and recall of proper names.

21

Recent meta-analyses,moreover, confirmed the benefits of estrogen replacementon verbal memory in women.

26,27

In sex comparison studies, men tend to have betterquantitative and visual spatial skills, whereas women per-form better on verbal skill measures.

28–31

ERT users andnonusers perform better on tests of verbal recall and mem-ory than do men.

18

Nondemented ERT users and mendemonstrate higher scores on measures of working mem-ory,

17,32

and ERT users and nonusers perform better oncategory fluency than men.

17,18

In a study of patients withAlzheimer’s disease, ERT users and men scored compara-bly on a naming task of semantic generation, but ERT us-ers scored significantly better than nonusers.

22

To expand the limited available data on the potentialinfluence of estrogen on mood and cognition and how that

From the *Department of Psychiatry and Biobehavioral Sciences, the Neu-

ropsychiatric Institute,

†

Alzheimer’s Disease Center, and

‡

Center on Aging, University of California at Los Angeles, Los Angeles, California.

Supported by Grants MH52453, AG13308, AG10123, and MO1 RR00856-21 from the National Institutes of Health; IIRG94101 from the Alzheimer’s Association; 95–23330 from the California Department of Health Services; the Montgomery Street Foundation; and the Fran and Ray Stark Foundation Fund for Alzheimer’s Disease Research.

Address correspondence to Dr. Karen J. Miller, UCLA Neuropsychiatric Institute, 760 Westwood Plaza, Suite 88–201, Los Angeles, CA 90024. E-mail: kmiller@mednet.ucla.edu

JAGS NOVEMBER 2002–VOL. 50, NO. 11

ESTROGEN, COGNITION, AND MOOD

1827

might be related to sex differences, we are reporting the re-sults of mood and cognitive measures from our cross-sec-tional study for three subject groups: female ERT users andnonusers and men.

METHODS

The subjects were 47 women (mean age

�

standard devia-tion (SD)

�

65.90

�

8.99) and 49 men (65.90

�

8.46) re-cruited through newspaper advertisements for people withmild memory complaints or family history of dementia, re-ferred by colleagues, or self-referred in response to mediacoverage of recent research findings. Volunteers with anymajor neurological, medical, or psychiatric condition (e.g.,major depression, dementia) that could affect memory orcognitive processing were excluded. Each subject wasscreened for any history of depression (e.g., major depres-sion, bipolar disorder, dysthymia), and those with suchhistories or those receiving any treatment for depressionwere excluded. In addition, each subject was administeredthe Hamilton Depression Rating Scale (Ham-D), and sub-jects scoring greater than 7 were excluded. The mean scorefor subjects included was 4. Each subject also received neu-rological and psychiatric assessments and screening labora-tory tests to exclude treatable causes of cognitive impair-ment.

33

To ensure that subjects did not have mild cognitiveimpairment (MCI) or dementia, those with Mini-MentalState Examination (MMSE) scores of 27 or lower or show-ing any evidence of MCI or dementia were excluded.

In addition to the Ham-D, we administered the Profileof Mood States (POMS-six), a self-administered instru-ment with six subscales (depression, anger, tension, vigor,fatigue, and confusion). The POMS focuses on emotionalaspects of depression (feeling unhappy, sad, blue, unwor-thy, discouraged, gloomy, helpless, etc.). The subscalesrange from 0 to 60, depending on the subscale; for exam-ple, the depression subscale ranges from 0 to 60, with ascore of 30 or greater indicating clinical depression. Theanger subscale ranges from 0 to 48. By contrast, the Ham-Dis an observer rating instrument that focuses on somatic,behavioral, and emotional symptoms of depression (sad-ness, guilt, suicidal thinking, sleep disturbance, physicalsymptoms, weight loss, etc.). This scale ranges from 0 to101, with a score of 10 or greater indicating mild to severeclinical depression, depending on the total score.

A neuropsychological test battery was also included,with measures of phonemic fluency (generating words start-ing with the letters C, F, and L); semantic fluency (generat-ing words in a category: fruits and vegetables); contextualverbal memory (Logical Memory from the Wechsler Mem-ory Scale—Revised (WMS-R), and the 12-item list fromBushke-Fuld); attention and working memory (Digit Spanfrom Wechsler Adult Intelligence Scale—Revised); and vi-sual memory (Rey-O and Benton Visual Retention Test).

The total years of estrogen exposure in women wasalso calculated by combining how long the women hadbeen exposed to estrogen naturally throughout their yearsof menarche with the duration of postmenopausal estro-gen replacement therapy, if any. The ERT users had an av-erage estrogen exposure of 41.43

�

13.79 years, and thenonusers had an average exposure of 33.13

�

6.42 years.Univariate analysis of variance (anova) was used for a

three-way group comparison for each measure of mood

and cognition. Post hoc analyses, least squared mean dif-ferences, were used to determine the specific nature of sig-nificant analysis of variance (ANOVA) results. Analyseswere based on ERT use and nonuse, not on duration ofuse. To ensure that subject characteristics were not the sourceof the between-groups differences, we controlled for age,education, socioeconomic status, and by using analysis ofcovariance models in a linear regression. ANOVA wasperformed to detect any between-groups (ERT, non-ERT,men) differences in the neurocognitive tests. Furthermore,alpha was adjusted due to multiple comparisons, using acorrected model for the univariate ANOVA.

Information regarding estrogen and progesterone usewas collected in a retrospective phone interview. Writteninformed consent was obtained in accordance with theprocedures set by the University of California at Los Ange-les Human Subjects Protection Committee.

RESULTS

Subjects

The ERT users were significantly younger than nonusers(63.45

�

9.83 and 69.95

�

8.95, respectively); therefore,age was controlled for in the statistical analyses. Most par-ticipants had completed several years of college, and groupsdid not differ according to mean years of educationalachievement (men: 15.98

�

2.58, ERT-users: 15.63

�

2.55,female nonusers: 15.38

�

1.93). The average length of ERTuse was 12.26

�

10.76 years. Nineteen of the 31 ERT userswere taking estrogen/progesterone combinations.

Mood

Significant differences were observed among the threegroups on overall depression symptoms as measured bythe POMS (

F

�

3.652;

df

�

3,

P

�

.015). Two-way com-parisons indicated that women using ERT were less de-pressed than non-ERT users (

R

�

5.893,

P

�

.005) andmen (

R

�

3.395,

P

�

.027). For the POMS anger subscalescores, significant differences also were observed amongthe three groups (

F

�

5.459;

df

�

3,

P

�

.002). Two-waycomparisons indicated that the ERT users were less angrythan nonusers (

R

�

5.094,

P

�

.001) and men (

R

�

2.187,

P

�

.044) and that men were less angry than nonusers (

R

�

2.907,

P

�

.034) (Figure 1). Groups differed on overall de-pression symptoms as measured by the Ham-D. Meanscores for the Ham-D were as follows: ERT users 4.63

�

4.91, nonusers 4.94

�

3.94, and men 4.28

�

4.87. Therewas no significant correlation between POMS subscalescores and Ham-D scores. Furthermore, neither durationof lifetime estrogen use nor use of an estrogen/progester-one combination had an effect on these results.

Cognition

Several verbal cognitive measures indicated significantgroup differences. For the semantic fluency (generatingwords in a category), significant differences were observedamong the three groups (

F

�

4.769;

df

�

3,

P

�

.004).Women using ERT demonstrated better semantic fluencythan did men (

R

�

2.762,

P

�

.008). The three groupsalso differed significantly in measures of attention andworking memory (

F

�

4.562,

P

�

.006). Two-way com-parisons indicated that ERT users performed better than

1828

MILLER ET AL.

NOVEMBER 2002–VOL. 50, NO. 11 JAGS

did nonusers (

R

�

3.536,

P

�

.011). Men also performedbetter on the attention and working memory measuredthan did women non-ERT users (

R

�

3.133,

P

� .015)(Figure 2). Although we found no significant group differ-ences on a contextual verbal memory measure (WMS-RLogical Memory), there was a trend for the ERT users toperform better on the verbal list learning task (Bushke-Fuld; F � 5.211, P � .002), although the between-groupcomparisons were nonsignificant when all three groupswere compared. Neither duration of lifetime estrogen usenor use of an estrogen/progesterone combination had aneffect on these results. There were no significant correla-tions between the cognitive factors and the mood vari-ables.

DISCUSSIONThis study confirms and extends previous work on thepossible influence of estrogen on mood and cognition. Ourresults indicate that women using ERT have less-severesymptoms of depression and anger and better verbal flu-ency and working memory than non-ERT users. Men alsohave lower levels of anger and better working memorythan women who do not use ERT.

The findings that female ERT users reported less-severedepressive symptoms than men or nonusers are consistentwith previous reports demonstrating relationships betweenestrogen use and fewer depressive symptoms.2–7 Unlike mostother studies, other aspects of mood were examined andfound that ERT users and men were less angry than femalenonusers. These results are actually contrary to those ofCarlson et al., who found that ERT users were less elated,

less composed, and less agreeable (i.e., more angry) thanmen and nonusers.17 However, these differences were nolonger significant when women using both estrogen andprogesterone were excluded from the analysis. In thisstudy, use of an estrogen/progesterone combination hadno influence on our results.

The current findings are consistent with previouswork supporting the beneficial effects of estrogen use onverbal fluency and working memory.2,17,19,34,20 Previous re-search found ERT use to be positively correlated with en-hanced contextual verbal memory (memory for informa-tion within a context15,19,21,35). The results of this did notsupport this association, but the research did not contra-dict the previous research. In fact, on another test of ver-bal memory, there was a trend for ERT users to performbetter than nonusers or men. The results may not havereplicated the previous findings because of the large intra-group scatter in scores (i.e., large standard deviations forthe verbal memory tests, thus high variability within eachgroup itself).

The majority of these estrogen studies have been con-venience sample studies of nondemented persons, usingsamples much like the one in this study, but other researchhas addressed the role of estrogen in the dementia process.Two large meta-analyses reported that ERT was associ-ated with a decreased risk of developing dementia and withenhanced specific verbal memory tasks and associated brainregions.26,27 Other research suggests that estrogen does notprevent cognitive decline in demented patients.1

Furthermore, there have been some randomized stud-ies examining the effect of estrogen on mood and cognition.For example, Phillips et al. randomized postmenopausal

Figure 1. Histograms indicate mean Profile of Mood Scale(POMS) Subscale scores; horizontal lines indicate standard de-viations.

*Analysis of variance (ANOVA) of Depression Subscale scoresindicated significant differences among the three groups (F �3.652, P � .002); post hoc comparisons indicated the followingdifferences: estrogen replacement therapy (ERT) versus no ERT(R � 5.893, P � .005) and ERT vs men (R � 3.395, P � .027).

†ANOVA of the Anger Subscale indicated significant differencesamong the three groups (F � 5.459, P � .015); post hoc compar-isons indicated the following differences: ERT vs no ERT (R �5.459, P � .001), ERT vs men (R � 2.187, P � .044), and noERT vs men (R � 2.907, P � .034).

Depression subscale ANOVA indicated significant differencesamong the three groups (F3,652, P � .002).

Figure 2. Histograms indicate mean Verbal Cognitive scores;horizontal lines indicate standard deviation.

*Analysis of variance (ANOVA) of Fluency scores indicated signif-icant differences among the three groups (F � 4.769, P � .004);post hoc comparisons indicated the following difference: estrogenreplacement therapy (ERT) vs men (R � 2.762, P � .008).

†ANOVA of Attention and Working Memory scores indicated sig-nificant differences among the three groups (F � 4.562, P � .006);posthoc comparisons indicated the following differences: ERT vsno ERT (R � 3.536, P � .011) and men vs no ERT (R �3.133, P � .015).

Fluency ANOVA indicated significant differences among thethree groups (F � 4,769, P � .004).

JAGS NOVEMBER 2002–VOL. 50, NO. 11 ESTROGEN, COGNITION, AND MOOD 1829

women to placebo or ERT.19 They found that ERT usersperformed better on verbal fluency and verbal memory. Theresults of the large, randomized samples addressing preven-tion are not yet complete, thus the recommendation to useestrogen as a preventative for future cognitive decline mustawait results of such trials. The findings in this report re-garding estrogen’s effects on mood would be consistent withthe possibility that estrogen use may have a place in treatingdepression and related symptoms, but such recommenda-tions must await results of randomized clinical trials.

Understanding of how estrogen influences the brainand, in turn, mood and cognition, is derived from severalsources, including basic laboratory studies (inferencesfrom comparisons of sex differences, observational epide-miological studies, and clinical trials).35 Mood effectscould result from estrogen’s modulation of serotonergic,�-adrenergic, and noradrenergic neurotransmitters.36–38 Inaddition, estrogen may modulate mood through monoamineoxidase inhibition at high levels, tryptophan displace-ment from plasma albumin binding sites, and effects on5-hydroxytryptamine receptor binding and downregula-tion. Other brain effects of estrogen could influence cogni-tive performance, including its cholinergic neuroprotectiveand neurotrophic effects and its ability to foster dendriticgrowth.36–39 In this study, it is interesting to note that ERTwas associated with several variables that are modulatedby the orbitofrontal areas, namely mood, verbal fluency,and working memory. This is certainly consistent with thefact that estrogen receptors are found in higher concentra-tions intraneuronally in the basal forebrain (origin of cho-linergic pathways), frontal lobe (modulates the verbal en-coding and retrieval system), and locus ceruleus (site ofnorepinephrine production) in addition to the hippocam-pus (modulates learning and semantic memory).34

Studies of regional cerebral glucose metabolism usingpositron emission tomography (PET) have found higherglucose metabolic rates in the CA-1 hippocampal regionand the prefrontal cortex in premenopausal women thanin age-matched men; moreover, postmenopausal non-ERTusers show lower metabolic activity than age-matchedmen.19,37,38,40–42 Other PET studies support the observationthat ERT use is associated with increased brain activity intemporal regions, areas known to be involved in cognitivefunction.15,43

An inherent limitation of the present study is its retro-spective design, but the inclusion of a male comparisongroup provides additional insights into potential estrogeneffects on mood and cognition. In particular, it argues forcareful consideration of estrogen use patterns in studiescomparing older men and women. In future controlledclinical trials, attention to specific forms of hormone re-placements, duration of use, and brain activity patterns us-ing PET and other imaging modalities will help accountfor some of the variability in results and provide more ho-mogenous data for analysis.

ACKNOWLEDGMENTSThe authors thank Andrea Kaplan, BS, Deborah Dorsey,RN, and Gwendolyn Byrd, MA, for their efforts in subjectrecruitment.

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