Long-term estrogen replacement is associated with improved nonverbal memory and attentional measures in postmenopausal women

FERTILITY AND STERILITY威 VOL. 76, NO. 6, DECEMBER 2001 Copyright ©2001 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.

MENOPAUSE

Long-term estrogen replacement is associated with improved nonverbal memory and attentional measures in postmenopausal women Yolanda R. Smith, M.D.,a Bruno Giordani, Ph.D.,b Renee Lajiness-O’Neill, Ph.D.,b,d and Jon-Kar Zubieta, M.D., Ph.D.b,c Departments of Obstetrics and Gynecology, and Psychiatry, and the Mental Health Research Institute, University of Michigan Hospitals and Health Centers, Ann Arbor, Michigan

Received February 21, 2001; revised and accepted June 14, 2001. Financial support: American Society for Reproductive Medicine/ Organon Inc. M.D. Research Grant in Reproductive Medicine and The Claude Pepper Older Americans Independence Center Pilot Grant, University of Michigan. Reprint requests: Yolanda R. Smith, M.D., Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Room L4224 Women’s Hospital, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109-0276 (FAX 734-6479727; E-mail: ysmith@ umich.edu). a Department of Obstetrics and Gynecology. b Department of Psychiatry. c Mental Health Research Institute. d Current address: Henry Ford Health Systems, Department of Behavioral Health, Division of Neuropsychology, Detroit, Michigan. 0015-0282/01/$20.00 PII S0015-0282(01)02902-8

Objective: To determine the cognitive domains improved or preserved by long-term hormone replacement therapy (HRT). Design: A comprehensive neuropsychological test battery was administered to healthy postmenopausal women who had been treated or not treated with long-term HRT without interruption since menopause. Setting: Women were recruited by advertisement from a university town and surrounding areas. Patient(s): Women 60 years or older were studied who were treated (n ⫽ 16) or not treated (n ⫽ 13) with HRT. Intervention(s): Neuropsychological testing included tests of memory, verbal fluency, executive functions, attention and concentration, and psychomotor function. Tests of intellectual function, depressive symptoms, and emotional functioning assessed general functions and comparability of the groups. Main Outcome Measure(s): Neuropsychological testing scores were compared between groups. Result(s): No statistically significant differences between the groups were found for general demographic, intellectual, and psychological measures. Scores from both the Weschler Memory Scale Visual Reproduction (delayed recall) and the Digit Vigilance Test (attention) showed statistically significant better performance and fewer errors in the group of women on HRT. Conclusion(s): Long-term postmenopausal HRT is associated with higher scores in tests of nonverbal memory and attention. (Fertil Steril威 2001;76:1101–7. ©2001 by American Society for Reproductive Medicine.) Key Words: Neuropsychological testing, memory, cognition, hormones, estrogen, menopause, postmenopause, aging, brain

For many postmenopausal women, estrogen replacement therapy has improved their quality of life by ameliorating hot flashes and genital atrophy and by preventing heart disease and osteoporotic fractures. There is also increasing evidence that estrogen may have neuroprotective effects, possibly by influencing the production of neuronal growth factors and increasing synaptic plasticity (1). The decision to use long-term estrogen replacement therapy in women is balanced by concerns regarding uterine bleeding and the possibility of increasing the frequency of certain types of estrogen-dependent tumors (2). An area that has received considerable attention in recent years is the study of the effects

of hormone replacement therapy (HRT) on cognitive functions. It has been hypothesized that the hormonal milieu may induce dynamic changes in cognitive performance, based on data suggesting that men and women tend to present with differential aptitudes in certain cognitive domains (3–5). Halbreich et al. (6) addressed the possibility that age-associated changes in some cognitive functions may be influenced by the presence of gonadal steroids by studying samples of premenopausal and postmenopausal women. Age-related declines in complex visuospatial and motor function tasks were found to be more pronounced in postmenopausal women. 1101

Hampson (7) and Phillips and Sherwin (8) have studied women during various phases of the menstrual cycle in an attempt to relate the presence of varying levels of gonadal steroids to the regulation of specific cognitive functions. During the late follicular phase, when estradiol levels in plasma are rising, articulatory and motor skills were higher than in the menstrual phase, when estradiol levels are lowest (7). In the study by Phillips and Sherwin (8) performed during the luteal and menstrual phases—when levels of estradiol and progesterone are highest and lowest, respectively— higher scores in measures of nonverbal memory were noted during the luteal phase. No statistically significant differences in tests of verbal or nonverbal learning, verbal memory, or attention were detected by this study. However, an increase in verbal learning (paired-associate learning) was associated with elevations in estradiol levels in the luteal phase. Subsequently, a number of reports have examined the cognitive status of postmenopausal women treated or not treated with short-term HRT. The effect of short-term administration of estrogen alone, or estrogen in combination with testosterone has been examined in two placebo-controlled studies of surgically menopausal women (9, 10). In an initial report (9), treatment with gonadal steroids, whether estrogen alone, testosterone alone, or a combination of both, was associated with better performance on tests of abstract reasoning, verbal learning and memory, attention, and perceptual speed. Further study revealed that estrogen replacement therapy after oophorectomy resulted in better verbal learning scores when compared to the placebo condition (10). In a more recent study, Sherwin and Tulandi (11) reported on a study of 19 premenopausal women receiving a GnRH agonist prior to surgery to cause hypoestrogenemia and randomized them to estrogen or placebo add-back therapy for 8 weeks. They found that there was a statistically significant decrease in verbal memory scores with hypoestrogenemia that was reversed with estrogen therapy. In a population study of postmenopausal women, BarrettConnor and Kritz-Silverstein (12) examined the possible association between the reported use of estrogen after menopause and cognitive performance, and did not find any consistent differences between them. However, a subgroup of women treated for more than 20 years with HRT showed better performance in a test of verbal fluency than those never treated with HRT, although this difference did not reach statistical significance. In another population study by Resnick et al. (13), women on estrogen replacement therapy at the time of neuropsychological testing (years of reported estrogen use ranging from ⬍1 to ⬎20) had improved performance on a test of nonverbal memory compared to estrogen nonusers. Robinson et al. (14) provided data on 72 women treated with HRT compared to age-matched and education-matched controls. The study participants underwent an evaluation for 1102 Smith et al.

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neuropsychological performance of verbal memory, but not nonverbal memory. Statistically significant differences between groups were noted in a test of proper name recall, with higher scores in the estrogen-treated sample, although a high level of variability in the data was noted for that group. Kampen and Sherwin (15) also found that current estrogen users had better scores on tests of verbal learning and verbal memory than nonusers. Using a more extensive neuropsychological battery, Kimura (16) reported that estrogen users had generally better performance in all tests, which included measures of verbal learning and memory, verbal fluency and spatial skills, and perceptual speed and abstraction. However, in many of these studies the duration of estrogen use was not reported, or it varied significantly. In general, it appears that there is evidence supporting a positive effect of HRT on cognitive functions in postmenopausal women. The available data emphasize its effects on measures of verbal function and verbal memory, but also suggest potential effects on nonverbal memory. Yet there is no general agreement as to the specific cognitive domains improved or preserved by HRT, or whether these improvements are sustained after long-term use. This information may give further justification for the long-term use of HRT after menopause. Furthermore, some of the variability in the data reported may be related to factors such as the types of tests administered, but also may be due to the type of hormonal preparation, the length of its use, or whether it was taken without interruption since menopause. These are factors typically not controlled for in the majority of studies published. As part of a study examining the effect of long-term HRT on brain neurochemical markers (17), we tested, with a comprehensive neuropsychological battery, a sample of healthy women 60 years of age or older who had been treated or not treated with HRT without interruption since menopause.

MATERIALS AND METHODS Patients Two groups of healthy postmenopausal women were recruited by advertisement (Table 1). They were selected so that they were 60 years old or older, and had either received HRT without interruption after the menopause, or received no HRT. In the group of women on HRT, the treatment had been begun within 2 years of menopause. All women on HRT were using the same dose and preparation of estrogen (conjugated equine estrogens, Premarin, 0.625 mg/day) with or without cyclic or continuous medroxyprogesterone acetate at various doses, ranging from 2.5 to 10 mg. Women were excluded who had interrupted HRT for more than 1 month at a time, and who had more than three 1-month periods of HRT interruption. Menopause was defined as the absence of menstrual peVol. 76, No. 6, December 2001

TABLE 1 Demographics, characteristics, and measures of general function and cognition.

Age (years) Education (years) Age at menopause (years) Bilateral SO Unilateral SO Years post-menopause Alcoholic beverages/week Estradiol plasma level (pg/mL)* Testosterone plasma level (ng/mL) MMSE score Geriatric depression scale Self-rating scale WAIS-R vocabulary WAIS-R block design WRAT reading

HRT group (n ⫽ 16)

No HRT group (n ⫽ 13)

65 ⫾ 4 15 ⫾ 2 48 ⫾ 5 4 2 17 ⫾ 6 4⫾6 89 ⫾ 39 0.28 ⫾ 0.12 28.0 ⫾ 1.7 5.4 ⫾ 4.2 42.0 ⫾ 2.3 14.2 ⫾ 3.3 12.7 ⫾ 2.4 108.6 ⫾ 5.5

67 ⫾ 6 16 ⫾ 3 51 ⫾ 3 0 1 17 ⫾ 6 3⫾3 20 ⫾ 13 0.27 ⫾ 0.07 27.5 ⫾ 1.8 9.2 ⫾ 6.3 40.7 ⫾ 4.5 13.9 ⫾ 3.7 11.8 ⫾ 3.5 108.8 ⫾ 12.7

Data are expressed as the mean ⫾ S.D. SO, salpingo-oophorectomy; HRT, hormone replacement therapy. Plasma levels of estradiol and testosterone were obtained immediately prior to scanning. MMSE, Mini-Mental State Examination; WAIS-R, Weschler Adult Intelligence Scale, Revised, standardized scores; WRAT, Wide Range Achievement Test-Third Edition, standardized scores. * Statistically significant difference between groups, unpaired, two-tailed t-tests, P ⬍.05. Smith. HRT and cognition. Fertil Steril 2001.

riods for 1 year for those with intact reproductive organs or the time of hysterectomy with bilateral salpingo-oophorectomy. In women with a prior hysterectomy without bilateral salpingo-oophorectomy, menopause was defined as the onset of hot flashes. Eight women had been treated with continuous estrogen replacement therapy, and eight with estrogen and progestin. The second group of postmenopausal women did not receive HRT at any time since menopause and was age-matched to the hormone-treated sample. After an initial phone screening, the women had personal interviews in which medical and psychiatric histories were obtained and systems were evaluated. Women were included who were free of significant general medical, neurological, or psychiatric illness; had never experienced a head injury with loss of consciousness; and had no drug or alcohol abuse or dependence. All participants were right handed, were nonsmokers, and were taking no medications with actions on the central nervous system. After a full description of the study, written informed consent was obtained. All procedures were approved by the University of Michigan institutional review board. On the day of testing, blood plasma was obtained for estradiol and testosterone measurements.

Hormone Assays Blood samples for the determination of estradiol and testosterone were obtained immediately prior to scanning. FERTILITY & STERILITY威

After collection, all samples were refrigerated, centrifuged, and stored at ⫺30°C until analysis. Plasma estradiol and testosterone were determined by the use of an enhanced chemiluminescence immunoassay instrument (reagents by Amersham UK Ortho Clinical Diagnostics, Inc., Rochester, NY). For the estradiol assay the intra-assay and interassay coefficients of variation were ⬍5.0% and 8.92%, respectively. The sensitivity of the estradiol assay was 15 pg/mL. The cross-reactivity at 50% of zero standard binding was less than 0.5% for estriol, less than 3.1% for estrone, and zero for other steroids. For the testosterone assay the intraassay and interassay coefficients of variation were ⬍5.0% and 7.90%, respectively. The cross-reactivity at 50% of zero standard binding was less than 0.5% for androstenedione, less than 0.6% for 5-alpha-dihydrotestosterone, less than 0.3% for 5-beta-dihydroxytestosterone, less than 6.2% for 11-beta-dihydrotestosterone, less than 10% for 11-ketotestosterone, less than 3.6% for nortestosterone, and zero for all other steroids.

Neuropsychological Testing Measures The women completed a battery of neuropsychological tests covering several cognitive domains, as follows (all references are listed in (18) unless otherwise noted). 1. Memory: Verbal Memory: Wechsler Memory Scale (Logical Passages and Verbal Paired Associates subtests, immediate and delayed recall), California Verbal Learning Test (CVLT) (19). Nonverbal memory: Wechsler Memory Scale Visual Reproduction subtest, immediate and delayed recall. 2. Verbal fluency: Controlled Oral Word Association Test (CFL version). 3. Executive functions: Stroop Test. 4. Attention, concentration: Test of Variables of Attention (TOVA) (20), Digit Vigilance Test. 5. Psychomotor function: Finger Tapping Test, Manual Imitation Test (21).

Emphasis was placed on verbal functions and motor abilities, as they have been reported to be regulated by the administration of estrogen in prior reports. To assess overall intellectual functioning and the comparability of the two groups of women, a series of tests thought to reflect overall intellectual function were administered. These included the Mini-Mental State Examination (22), Vocabulary and Block Design of the Weschler Adult Intelligence Scale–Revised, found to be reliable and valid estimates of overall Full Scale IQ (23), and the Reading subtest of the Wide Range Achievement Test–Third Edition, a measure found to be relatively resistant to changes in central nervous system functioning; hence, a valid estimate of longterm abilities (18). Similarly, measures of depressive symptomatology (Geriatric Depression Scale) (24) and emotional functioning 1103

TABLE 2 Neuropsychological testing scores in women treated or not treated with long-term estrogen replacement. Neuropsychological measures

HRT group (n ⫽ 16)

No HRT group (n ⫽ 13)

F value

23.18 ⫾ 5.8 18.38 ⫾ 7.3 18.56 ⫾ 3.0 6.81 ⫾ 1.4 54.50 ⫾ 9.1

26.69 ⫾ 9.7 21.00 ⫾ 10.0 18.00 ⫾ 4.6 6.38 ⫾ 1.6 49.46 ⫾ 15.3

1.45 .66 .16 .58 1.21

.24 .42 .70 .45 .28

35.81 ⫾ 3.4 34.19 ⫾ 5.3

32.54 ⫾ 7.3 26.13 ⫾ 11.3

2.55 6.41

.12 .02*

43.06 ⫾ 13.9 58.69 ⫾ 6.9 4.63 ⫾ 4.1

42.08 ⫾ 12.4 54.75 ⫾ 6.1 12.58 ⫾ 13.1

.04 2.43 5.27

.85 .13 .03*

44.58 ⫾ 4.6

42.59 ⫾ 6.0

.74

.40

P

a

Learning and memory Verbal W.M. logical passages immediate W.M. logical passage delayed W.M. paired associates immediate W.M. paired associated delayed CVLT list A total recall Visual W.M. visual reproduction immediate W.M. visual reproduction delayed Additional cognitive measuresb Verbal fluency (CFL total) Stroop interference Digit vigilance (total errors) Motor ability Finger tapping (average)

Data is expressed as the mean ⫾ S.D. W.M. ⫽ Wechsler Memory Scale – Revised. MANOVA for Learning and Memory Variables: F (7, 21) ⫽ 2.6, P⫽.04. b MANOVA for Cognitive Measures Variables: F (3, 24) ⫽ 3.0, P⫽.05. * Statistically significant difference between groups, post-hoc one-way ANOVA, P⬍.05. a

Smith. HRT and cognition. Fertil Steril 2001.

(Self-Rating Scale) (25) were obtained to determine whether other variables related to psychological functioning may have accounted for the variability in test scores. All of the tests were administered by trained neuropsychology personnel in a quiet testing room, according to standard administration conditions. The test administrators were blinded to the test-taker’s status.

Statistics Descriptive statistics as well as an examination of the sample distribution was first conducted to ensure a normal distribution. The comparability of the two groups studied was assessed using global measures of intellectual functioning, depression, and emotional functioning, and possible differences between groups tested with unpaired, two-tailed t-tests at P ⬍.05. Because previous data in this population had suggested specific cognitive effects of estrogen administration, an a priori hypothesis was established, namely that women treated with long-term estrogen replacement therapy would show higher scores in measures of verbal memory, verbal function, and motor skills. No standard correction for multiple comparisons was applied to the data, based on that hypothesis. However, the interpretation of results was based on patterns of differences within clusters of tests assessing similar cognitive domains, as opposed to isolated findings across domains. Group differences in each cluster of tests were assessed with MANOVA, followed by one-way ANOVA for each of the tests included in the cluster, at a level of statistical significance of P ⬍.05. 1104 Smith et al.

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RESULTS No statistically significant differences between the groups were obtained for general demographic, cognitive, and psychological function measures (see Table 1). These were highly educated women, living independently without exception. Slightly higher scores in the Geriatric Depression Scale were obtained in the group not treated with long-term HRT, although these did not reach statistical significance (unpaired, two-tailed t-tests, P ⬍.05). A higher frequency of hysterectomies with bilateral salpingo-oophorectomies was reported in the group treated with long-term HRT. Levels of estradiol in plasma prior to testing were also higher in this group, as would be expected (see Table 1). Group scores in the various cognitive tests administered are presented in Table 2. No statistically significant differences between the two groups were observed for measures of verbal fluency, learning, or memory. Slightly better performance in a measure of prefrontal, executive function (the Stroop Test) was noted in women treated with long-term HRT, although the result did not reach statistical significance. The only tests showing statistically significant differences between the groups were the Weschler Memory Scale Visual Reproduction, delayed recall, and the Digit Vigilance Test (a test of visual scanning and attention). Another test assessing attention and concentration, TOVA, did not show differences between groups. However, due to a software error, Vol. 76, No. 6, December 2001

only 24 out of 29 TOVA scores were properly recorded (data not shown).

DISCUSSION This study showed higher scores in tests measuring nonverbal memory and attention in a selected sample of healthy postmenopausal women treated with long-term HRT when compared to a matched group of women not treated with HRT. An attempt was made to control for factors typically not addressed in previous studies, which included the time elapsed from menopause until initiation of HRT, the discontinued use of HRT, and heterogeneous forms of HRT. Experimental studies support the notion that performance in some cognitive domains declines with advancing age (26, 27). However, previous studies concerning the effect of hormones on cognitive aging are conflicting both in the presence or absence of differences between groups, and in the cognitive domains affected by gonadal steroid administration. The majority of those studies have emphasized the possible effects of estrogen on verbal memory (10, 11, 14, 15, 28). Conversely, Kimura (16) studied a sample of postmenopausal women and found that HRT users had generally better performance in all tests, which included measures of verbal learning and memory, verbal fluency and spatial skills, and perceptual speed and abstraction. In the present study, no effect of hormone therapy was detected for tests of verbal memory. The data presented in this study are more consistent with the neuropsychological performance data obtained in the Baltimore Longitudinal Study of Aging, which revealed that the 116 women on estrogen replacement therapy during the cognitive assessment had improved scores in nonverbal memory (visual memory and perception) compared to 172 not on estrogen replacement therapy (13). Variations in results from different studies may also be related to certain types of tests being more sensitive to the effect of HRT. The present study demonstrated an effect of HRT on an attentional measure, which had also been shown in other studies (29, 30). In this regard, it has been suggested that improved alertness and attentional functions may have a more positive effect on tests that are subject to the use of environmental context (31, 32). The long-term protective effects of estrogen on cognitive domains have not been studied as rigorously as have those of short-term estrogen therapy. Our test population had been on long-term estrogen and demonstrated improvement in two areas of cognitive function. This is of particular interest because epidemiological studies have suggested that postmenopausal HRT initiated before the onset of symptoms may reduce the risk or delay the onset of Alzheimer’s disease (33–39). However, not all studies have supported a negative association between estrogen therapy and Alzheimer’s disease (40 – 43). Also, the administration of estrogen to a large FERTILITY & STERILITY威

sample of women diagnosed with mild to moderate Alzheimer’s disease in a multicenter, placebo-controlled trial has not been shown to be effective in the improvement of the course of this illness (44). There are a number of potential mechanisms through which estrogen may maintain cognitive function. Estrogen receptors are located in brain regions involved in memory and other cognitive functions (45). Estrogen appears to modulate neurotrophic factors and to have effects on neuronal survival and repair (1, 46). In this regard, cholinergic neurons may be specifically involved, because they coexpress both estrogen and nerve growth factor receptors (47). Evidence also suggests that exposing neurons in culture to estrogen increases branching, branch length, and microspikes (48). It also alters amyloid metabolism, favoring the soluble form of amyloid, which does not precipitate plaques in the brain (49). Furthermore, estrogen has antioxidant and anti-inflammatory properties that may reduce the damage of free radicals in the brain (50 –52). Estrogen also has been demonstrated in imaging studies to enhance cerebral blood flow and improve cerebral glucose transport and metabolism (53). Neuroimaging studies have demonstrated the regulation of brain activation patterns by estrogen during the performance of cognitive tasks (54 –56). In the study by Berman et al. (54), premenopausal women underwent a pharmacologically induced menopause with a GnRH agonist and then had estradiol and progesterone (for 4 to 5 weeks) administered as part of a double-blind cross-over design. Positron emission tomography (PET) scans measuring regional cerebral blood flow (rCBF) were obtained during the performance of the Wisconsin Card Sort Test. During the hypoestrogenic state, regional cerebral blood flow responses to test performance were attenuated in prefrontal cortical regions, and were restored after HRT with estrogen or progesterone. Using similar techniques, the effects of estrogen replacement therapy on regional cerebral blood flow activations during the performance of verbal and nonverbal delayedrecognition memory tasks have also been examined in 15 postmenopausal women receiving estrogen replacement therapy (range of estrogen use: 2 to 20 years) and 17 untreated women (55). Estrogen effects were observed in the parahippocampal region, precuneus, anterior thalamus, and in association areas of the frontal, parietal, and visual cortices. Shaywitz et al. (56) performed a randomized, doubleblind, placebo-controlled crossover trial showing that 21 days of estrogen treatment in postmenopausal women altered the functional magnetic resonance imaging activation patterns during verbal and nonverbal working memory tasks (56). Effects of estrogen were observed during both encoding and retrieval of working memory tasks that involved the parietal and frontal cortices. These three studies demonstrate that the hormonal milieu can modulate cognitive-related neural activity in women. 1105

One of the limitations of the cross-sectional design used in the present study is the lack of treatment randomization between hormone users and nonusers, which may introduce selection biases in the samples. However, this is an issue difficult to resolve in the examination of the long-term effects of HRT unless a longitudinal design is used. In addition, this study relies on the individual’s recall of when medications were initially started and of the dosages used. Although a tendency for estrogen users to be healthier and have higher education levels has been shown in some studies (57, 58), our groups were matched for education level and had no major medical illnesses. In fact, the majority of the women not taking hormones were highly educated (9 of the 13 women in this group had educational levels of 16 years or more), and they had decided against HRT after careful consideration of the risks and benefits. In conclusion, uninterrupted long-term HRT in postmenopausal women was associated with improved nonverbal memory and attention test scores in this pilot study. Further longitudinal studies appear warranted to assess both the specificity of these findings to those cognitive domains and to determine whether the findings are consistent across socioeconomic groups and educational levels. References 1. McEwen BS, Alves SE, Bulloch K, Weiland NG. Ovarian steroids and the brain: Implications for cognition and aging. Neurology 1997;48(5 suppl 7):S8 –15. 2. Grodstein F, Stampfer MJ, Golditz GA, Willett WC, Manson JE, Joffe M, et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336:1769 –75. 3. Burstein B, Bank L, Jarvik LF. Sex differences in cognitive functioning: Evidence, determinants, implications. Hum Dev 1980;23:289 –313. 4. Halpern DF. Sex differences in cognitive abilities. Hillsdale, NJ: Lawrence Erlbaum, 1986. 5. Jarvik LF. Human intelligence: sex differences. Acta Genet Med Gemellol (Roma) 1975;24:189 –211. 6. Halbreich U, Lumley LA, Palter S, Manning C, Gengo F, Joe SH. Possible acceleration of age effects on cognition following menopause. J Psychiatr Res 1995;29:153– 63. 7. Hampson E. Variations in sex-related cognitive abilities across the menstrual cycle. Brain Cogn 1990;14:26 – 43. 8. Phillips SM, Sherwin BB. Variations in memory function and sex steroid hormones across the menstrual cycle. Psychoneuroendocrinology 1992;17:497–506. 9. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneurendocrinology 1988;13:345–57. 10. Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopause women. Psychoneuroendocrinology 1992;17: 485–95. 11. Sherwin BB, Tulandi T. “Add-back” estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. JCEM 1996;81:2545–9. 12. Barrett-Connor E, Kritz-Silverstein D. Estrogen replacement therapy and cognitive function in older women. J Am Med Assoc 1993;269: 2637– 41. 13. Resnick SM, Metter EJ, Zonderman AB. Estrogen replacement therapy and longitudinal decline in visual memory. A possible protective effect? Neurology 1997;49:1491–7. 14. Robinson D, Friedman L, Marcus R, Tinklenberg J, Yesavage J. Estrogen replacement therapy and memory in older women. J Am Geriatr Soc 1994;42:919 –22. 15. Kampen DL, Sherwin BB. Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 1994;83:979 – 83. 16. Kimura D. Estrogen replacement therapy may protect against intellectual decline in postmenopausal women. Horm Behav 1995;29:312–21. 17. Smith YR, Minoshima S, Kuhl DE, Zubieta JK. Effects of long-term hormone replacement therapy on cholinergic synaptic concentrations in healthy postmenopausal women. J Clin Endo Metab 2001;86:679 – 84.

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