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Behavioral Neuroscience2012, Vol. 126, No.1, 123-127

2011 American Psychological Association0735-7044/11/$12.00 DOl: 10.1037/a0025539

Estrogen and Cognitive Functioning in Women: Lessons We Have LearnedBarbara B. Sherwin

McGill University

Extant research findings allow several conclusions regarding the relationship between estrogen andcognitive functioning across the female life span. First, performance on tests of verbal memory fluctuatesin concert with physiological changes in ovarian hormone production during the menstrual cycle andduring pregnancy and the postpartum period. Estrogen therapy (ET) prevents the decrease in verbalmemory when administered immediately following the surgical removal of both ovaries in premeno-pausal women. Some, but relatively little evidence is available to support the idea that ET, initiated at thetime of a natural or a surgical menopause for a few years, may protect against cognitive decline 30 yearslater and more research in this area is urgently needed. Finally, the evidence to date strongly suggests thatthe initiation of ET decades after the menopause has occurred does not protect against cognitive declineor dementia. Taken together, these findings support the so-called "window of opportunity" hypothesiswhich holds that ET will be neuroprotective only when administered closely in time to a natural orsurgical menopause.

Keywords: estrogen, cognitive functioning, pregnancy, postmenopause

The considerable volume of research findings on the impact ofestrogen on brain structure and function and its consequent influ-ence on aspects of cognitive functioning in both animals andhumans during the past two and a half decades has providedimportant and intriguing but often conflicting evidence. Althoughsome of the inconsistency in the human literature could be ex-plained by methodological differences between studies, such as thecharacteristics of the populations enrolled, the dose, drug, and theirroutes of administration, and methodological issues, to name afew, these differences failed to convincingly explain discrepanciesbetween studies in this area. During the past decade, one differ-entiating factor, the age of women at the time of the initiation ofestrogen therapy (ET), has garnered considerable validity and ledto the formulation of the critical period hypothesis, or the "windowof opportunity" maxim that, to this point, provides guidelines forthe necessary and sufficient conditions for the neuroprotectiveeffects of estrogen on cognitive functioning in women. Sincenumerous recent comprehensive reviews of the area are avail-able (Sherwin & Henry, 2008; Maki & Sunderrnann, 2009), thisarticle will instead focus on what the extant evidence tells us,and the directions it provides for potentially fruitful avenues forfuture investigation.

This article was published Online First October 17, 2011.Barbara B. Sherwin, Department of Psychology, McGill University.The preparation of this article was supported by a grant from the

Canadian Institutes of Health Research, MOP-89960, awarded to B.B.Sherwin.

Correspondence concerning this article should be addressed to BarbaraB. Sherwin, PhD, McGill University, Department of Psychology, 1205 Dr.Penfield Avenue, Montreal, Quebec, Canada H3A 1B1. E-mail:barbara.sherwin@mcgill.ca

I. Performance on Tests of Some Aspects of CognitiveFunctioning Fluctuate in Concert With Physiological

Changes in Sex Hormone Production DuringReproductive Events in Premenopausal Women

Considerable information is available to support the idea thatwomen's performance on tests of specific cognitive domains fluc-tuates during the normal menstrual cycle. For example, womenperformed better on cognitive tests favoring females (c.g., verbalfluency, fine motor skills, perceptual speed) during the midlutealphase of the cycle when levels of estradiol (Ez) were high ascompared with the menstrual phase of the cycle, and they per-formed better on cognitive skills favoring males (e.g., spatialability) during the menstrual phase of the cycle when Ez levelswere low (Hampson, 1990). Lower scores on a test of visualmemory occurred during the menstrual phase of the cycle, whereasscores on a test of verbal memory correlated positively with verbalmemory scores during the midluteal phase (Phillips & Sherwin,1992). Similarly, Ez levels correlated positively with verbal flu-ency and negatively with scores on a test of spatial ability inyoung, cycling women (Maki, Rich, & Rosenbaum, 2002). Othershave found that higher scores on a test of verbal working memorywere associated with high Ez levels at midcycle (Rosenberg &Park, 2002). These findings serve to underline the fact that mod-ifications in brain plasticity induced by high levels of sex-hormoneproduction can occur within a timeframe of several days, asevidenced by the cognitive changes observed from one menstrualcycle phase to the next. They also establish that Ez enhancesperformance on tasks in which females typically excel, whereasthe relative absence of Ez results in an enhancement in cognitiveskills in which males typically excel, as the literature on sexdifferences in cognitive functioning implies (Halpern, 1992).Therefore, extant human evidence strongly supports the view that,in young, reproductive-aged women, changes in the quantities ofovarian sex hormones during a normal menstrual cycle influence

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124performance on cogmuve tests although the magnitude of thechanges reported in the majority of studies suggests that thesechanges would not be clinically significant.

There is also evidence that modifications in aspects of cognitivefunction occur under the influence of the drastic changes in thehormonal milieu during pregnancy and the postpartum period.Impairments in verbal free recall, in working memory (Henry &Rendell, 2007; Janes, Casey, Huntsdale, & Angus, 1999), in wordfluency, and in word list learning (de Groot, Homstra, Roozendaal,& Jolles, 2003) in performance on priming tasks and incidentallearning tasks (Sharp, Brindle, Brown, & Turner, 1993) occur inpregnant women, as compared with nonpregnant controls. Duringthe third trimester and the early postpartum period, women per-formed more poorly on a task of verbal recall as compared withnonpregnant controls (Glynn, 2010) and, in a longitudinal study,pregnant women performed worse than nonpregnant controls ontwo tests of verbal memory, on a visuospatial task, and on a taskof processing speed (Henry & Sherwin, 2011). These findingssupport the view that changes in sex hormone production withinthe physiological range that occur during reproductive eventsmodify performance on a variety of cognitive functions.

Investigations on the pharmacological suppression of ovarianfunction in young, cycling women treated with a gonadotropinreleasing-hormone analog (GnRH-a) provide further support.When cycling women were treated with a GnRH-a, levels of E2decreased significantly in concert with a significant decrease inscores on tests of verbal memory and learning (Sherwin & Tulandi,1996) and on scores on tests of working memory (Grigorova &Sherwin, 2006). In both studies, the cognitive deficit was reversedonly in the group that randomly received add-back conjugatedequine estrogen (CEE) plus the GnRH-a while scores of those whoreceived add-back placebo plus the GnRH-a remained depressedindicating that E2was the critical ovarian hormone responsible forthe maintenance of verbal and working memory in these youngwomen.

II. ET Protects Aspects of Cognitive Function inSurgically Menopausal Women Treated Immediately

After Their SurgeryBecause surgical menopause (the removal of the uterus and both

ovaries) is frequently undertaken for benign gynecological disor-ders in premenopausal women, it is of interest to ask whetherdepriving women of several years of estrogen exposure has anyinfluence on cognition in either the short or long term. In theearliest, prospective, randomized, controlled trial (RCT) of surgi-cally menopausal women who had been premenopausal prior totheir surgery for benign conditions, standardized neuropsycholog-ical tests were used to investigate whether estrogen and/or andro-gen influenced aspects of cognition in postmenopausal women(Sherwin, 1988). In this crossover design, women who receivedany of the active hormonal drugs maintained their performance ona test of verbal memory, whereas scores decreased significantly inthose who had received a placebo. Moreover, it was determinedthat the estrogenic protection of verbal memory in the women didnot occur secondary to the alleviation of hot flashes. In a replica-tion of that study, in which a more comprehensive battery ofneuropsychological tests were used, surgically menopausal womenwho randomly received E2 valerate, 10 mg intramuscularly every

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4 weeks following the surgical removal of their ovaries had sig-nificantly higher scores on tests of short-and long-term verbalmemory as compared with women who had received placebo(Phillips & Sherwin, 1992). In both studies, there was a specificityof the estrogenic effect on verbal memory; in neither study did ETenhance performance on tests of visual memory or spatial abilities.In 65-year-old postmenopausal women who had never been treatedwith ET, those who received 7.8 mg E2 per week transdermally for3 weeks experienced a selective improvement in performance ontasks of visual learning and memory (Duka, Tasker, & McGowan,2000). No tests of verbal memory were administered in that study.This evidence underlines the observation that declines in verbalmemory shortly following the surgical removal of both ovaries ina premenopausal woman can be obviated by the administrationofET.

On the other hand, several RCTs failed to find an effect of ETon cognitive functioning When 62 midlife women 47 to 65 yearsof age were treated with transdermal E2 for 12 weeks versusplacebo, no effect of hormonal treatment was evident (Pola-Kantola et al., 1998) but verbal episodic memory was not assessed.Similarly, 53-year-old women who were treated with CEE severalyears following their surgical menopause did not perform betterthan placebo-treated women on tests of attention, the only neuro-psychological tests administered in that study.

Because impairments in cognition associated with normal agingaccelerate after the age of 60 years (Hedden & Gabrielli, 2004), acritical issue is whether its benefits would be enduring followingthe discontinuation of treatment. In a prospective longitudinalstudy, the outcome measures included the Telephone Interview forCognitive Status-modified and a brief dementia questionnaire alsoadministered by telephone (Rocca et al., 2007). Women who hadundergone bilateral oophorectomy prior to the onset of their nat-ural menopause, and had been untreated, had an increased risk ofcognitive impairment or dementia 30 years later as compared withreferent women [hazard ratio (HR) =1.46; 95% confidence inter-val (CI) 1.13 to 1.90]; however, those who had been administeredET until at least the age of 50 years (approximate time of a naturalmenopause) had no increased risk of cognitive impairment ordementia as compared with naturally menopausal women 30 yearslater. These results extend the findings from the surgical meno-pause studies that showed a benefit of ET in the short term(Sherwin, 1988; Phillips & Sherwin, 1992) by demonstrating thatthe neuroprotective effect on cognitive functioning of ET initiatedimmediately following a surgical menopause for several years isenduring 30 years later.

Only one study is available to support the possibility that, wheninitiated closely in time to the natural menopause, ET also has aneuroprotective effect. In a series of RCTs undertaken to deter-mine whether ET protected against osteoporosis, 479 women hadbeen randomly assigned to treatment with E2 or placebo for 2 or 3years and participated in follow-up cognitive testing 5-15 yearslater (Bagger, 'I'anko, Alexandersen, Qin, & Christiansen, 2005).Women who had originally been randomized to hormone therapy-HT; (estrogen [E] + progesterone [P])-for 2 to 3 years and thenstopped treatment (past-users) had a 64% decreased risk of cog-nitive impairment 5-15 years later, as compared with those whohad originally been randomized to placebo and never took HT(never-users; OR: 0.36,95% CI, 0.15-0.90, P =.03). Moreover,women who had been randomly assigned to HT and who contin-

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ESTROGEN AND COGNITION IN WOMEN 125ued to take it (long-term users) had a 66% decreased risk ofcognitive impairment 5- 15 years later (OR: 0.36,95% CI, 0.16-0.80; p =.01). The finding that 2 to 3 years of HT, initiated closelyin time to the menopause, was equally as protective against the riskof cognitive impairment, relative to long-term treatment, suggeststhat 2 to 3 years of ET may endow enduring cognitive protectionwhen initiated at the time of menopause Because of the importantclinical implications of this finding, it urgently needs to be repli-cated in both animal and human studies.

The clinical requirement to coadminister progesterone (P) or asynthetic progestin (HT) along with E to naturally postmenopausalwomen to protect the uterus against the stimulatory effects of E hasbeen frequently overlooked in analyses of the findings. Numerous,chemically different progestins (synthetic P) were used in studieson naturally menopausal women that investigated cognition. Al-though a micronized P preparation which more closely resemblesendogenous P is currently available, most studies on E + P andcognition in postmenopausal women coadministered a synthetic Palong with E, the most common being medroxyprogesterone ace-tate (MPA). There is reason to believe that progestins, and MPA inparticular, might have an independent negative effect on cognitionand/or may attenuate the beneficial effect of the coadministeredestrogen. For example, the decrease in apical dendritic spinedensity in the CA 1 area of the hippocampus that occurs during theestrus phase of the rat cycle was prevented by the administration ofRU-486, a P receptor antagonist, suggesting that P causes thedecrease in spine density (Gould, Woolley, Frankfurt, &McEwen,1990). Such oppositional effects of MPA to E2 have also beendocumented in humans. Whereas scores on a global measure ofcognitive functioning improved over time in a longitudinal studyof elderly women taking unopposed ET, cognitive scores actuallyworsened during the same timeframe in those treated with E2 +MPA (Rice et al., 2000). Finally, in a recent single photon emis-sion computerized tomography (SPECT) study, the duration of ETcorrelated positively with the density of cortical cholinergic ter-minal concentrations, but the effect was attenuated in women whowere also taking a progestin along with estrogen, suggesting that,in women, progestins may adversely influence neuronal integrity(Smith, Jonides, Marshuetz, & Koeppe, 1998). These findingsemphasize the importance of analyzing separately studies usingE-alone and those using E + P.

III. ET Initiated in Surgically or in NaturallyMenopausal Women One or More Decades FollowingTheir Menopause Does Not Protect Against Cognitive

Decline With AgingThe Women's Health Initiative Memory Study, an ancillary

study to the Women's Health Initiative (WHI), was the largestRCT designed to examine the effects of the continuous adminis-tration of E-alone or E + P on cognitive functioning. Seventy-two-year-old surgically menopausal women free of probable de-mentia were randomized to receive either CEE 0.625 mg daily orplacebo for approximately five years until the study was termi-nated (Espeland et al., 2004). Global cognitive function was mea-sured annually with the Modified Mini-Mental State Examination(3MSE). Mean 3MSE scores in the CEE group were significantlylower than those given placebo (p = .04). When data from

nonadherent women were censored, the difference was no longersignificant.

In the treatment arms of the approximately 72-year-old naturallymenopausal women in the WHIMS, there was a significantlyhigher risk of probable, all-cause dementia in the active groupcompared with placebo (HR =2.05,95% CI =1.21-3.48) but nodifference between the groups in the incidence of mild cognitiveimpairment, thought to be a precursor to Alzheimer's diseaseShumaker et al., 2003). Also, naturally menopausal women whohad been randomly assigned to CEE + MPA for 4 years had asmall increased risk in cognitive decline, as compared with womenwho had received placebo (p =.008) (Rapp et al., 2003). There-fore, the findings from the largest RCT undertaken on womenapproximately 72 years of age at the time of enrollment, failed toconfirm previous evidence from smaller RCTs, from longitudinal,and from cross-sectional studies that estrogen protected againstcognitive aging in postmenopausal women.

On the other hand, a preliminary reanalysis of the WHIMS databy age found that women who took ET before the age of 65 years(prior to their enrollment in the WHI) were 50% less likely todevelop all-cause dementia as compared with nonusers (Hender-son, Espeland, Hogan, Rapp, & Stefanick, 2007). However, thefinding was not affected by timing, by age at prior hormoneinitiation, or by the duration or recentness of use. This supports thenotion that ET has neuroprotective effects when taken by womenyounger than 65 years of age and has no effects, or may even causeharm, when initiated in older women. These findings are consistentwith the so-called "healthy cell bias" of estrogen action, whichproposes that there is a beneficial effect of estrogen on the survivalof neurons that are healthy at the time of their exposure to this sexhormone, but that an exacerbation of neurological demise occurs ifexposure to estrogen occurred in previously compromised neurons(Chen, Nilsen, & Brinton, 2006). Other possible reasons for theneutral or harmful effect of ET initiated decades after the meno-pause have been discussed comprehensively (Sherwin & Henry,2008).

IV. ET Initiated Following a Diagnosis of Alzheimer'sDisease (AD) Does Not Have Beneficial Effects on

Cognitive FunctioningTwo RCTs investigated whether ET would improve the memory

impairments in women with probable AD. There were no signif-icant posttreatment differences between 78-year-old women withAD randomly treated with CEE 1.25 mg daily for 16 weeks, ascompared with those given placebo on several tests of cognitivefunction (Henderson et al., 2000). In the second RCT, 120 womendiagnosed with mild-to-moderate AD received either CEE 0.625mg/day, CEE 1.25 mg/day of a placebo daily for 12 months(Mulnard et al., 2000). Consistent with the natural course of thisdegenerative disease, the cognitive function of all women deteri-orated somewhat over the year and no differences were apparentbetween groups. One small 8-week treatment RCT using transder-mal E2 found improvements in verbal and in visual memorycompared to placebo in women with probable AD (Asthana et al.,2001).

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126Summary and Future Directions

The extant evidence from basic neuroscience, from animal, andfrom human studies provides compelling evidence that neuropro-tection for optimal cognitive functioning in older women is in linewith the so-called "critical window of opportunity." That is, thereis reason to believe that women who take ET at the time ofmenopause for several years, thereby seamlessly extending thenumber of years their brains are exposed to E2, will have lesscognitive decline with aging and, possibly, a lower risk of AD.However, there is a paucity of data from human studies availableto allow the conclusion that if ET is initiated at the time ofmenopause and terminated after a few years, the neuroprotectiveeffects will endure when cognitive aging begins to accelerate inindividuals above the age of 60 years. Although a 30-year RCT totest this hypothesis would be definitive, logistical, ethical, andfinancial issues associated with such a study make it very unlikelyit will ever be undertaken. Therefore, it is hoped that the devel-opment of animal models and creative ways of asking this questionin humans will provide some answers in the future.

Finally, because all drugs have side effects, it would be impor-tant to understand the risklbenefit ratio for postmenopausal womenwho take ET. Recently, the data from the WHI E-alone arm wasreanalyzed according to the age of the participants at the time ofthe initiation of ET. These reanalyses show that surgically meno-pausal women who were between 50 and 59 years of age whenthey were enrolled in the WHI, who received CEE for approxi-mately 6 years, and were followed for an additional 4.7 yearssubsequent to the cessation of the clinical trial, had neither anincreased nor a decreased risk of coronary heart disease, deep veinthrombosis, stroke, hip fracture, colorectal cancer, and total mor-tality as compared with the women who had randomly receivedplacebo (LaCroix et al., 2011). It was also the case that womentreated with CEE had a significantly lower incidence of breastcancer than placebo-treated women at follow-up. Moreover, theincrease in risk of stroke and venous thromboembolism observedin women randomized to CEE during the intervention period of thetrial dissipated during the follow-up period. However, these find-ings cannot be generalized to the efficacy of combined estrogen +progestin hormone regimens for the treatment of naturally meno-pausal women with an intact uterus. It would therefore seem thatET, initiated soon after the menopause for a few years, has noenduring negative effects on a variety of organ systems whileprotecting cognitive function. On the other hand, this conclusion istempered by the paucity of evidence that ET, given to perimeno-pausal women for a few years and then discontinued, will haveenduring protective effects 15 years later when cognitive agingbecomes manifest. Possibly the most critical issue for this area isto gather data that tests this hypothesis.

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Received May 18, 2011Revision received July 26, 2011

Accepted July 29, 2011

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