The Basics of Menopause and Hormone Therapy III: Cognitive Consequences

This is the third part in an overview of menopause and hormone therapy. Parts one and two are here and here. This time around I describe changes in cognitive and behavioral profiles for women and animal models of menopause. I may decide to expand on a handful of studies at a later date, but for now I wanted to provide a very brief overview of human studies, problems inherent to human studies, and animal studies. I think the next part of this series will focus on the quality of our animal models and what they have to tell us. But for now, anyone who is interested in these issues knows where to start digging!

Granted, some of the info in this series is a bit dated, but I'll do future posts to expand on recent findings. I also posted a follow-up on factors to consider when evaluating hormone therapy use and comparing new findings to "common wisdom".

Cognitive Changes in Postmenopausal Women

Postmenopausal women frequently complain about problems with attention and concentration, and increased forgetfulness (Kopera 1972; Anderson et al., 1987; Oldenhave and Netelenbos, 1994). Controlled studies of the cognitive effects of menopause and HRT, however, have been controversial. While a number of studies have found improvements on learning, memory, and attention following ERT (Hackman and Galbraith, 1976; Vanhulle and Demol, 1976, Fedor-Freybergh, 1977; Kampen and Sherwin, 1994; Robinson et al., 1994), others have failed to do so (Rauramo et al., 1975; Ditkoff et al., 1991; Barrett-Connor and Kritz-Silverstein, 1993). Some studies suggest that addition of a progestin may reduce any benefit of ERT (Okhura et al., 1995; Schneider et al., 1996; Rice et al., 1997; Rice et al., 2000), but other studies found no effect (Kampen and Sherwin, 1994) or an enhancement in a small group which was not borne out in an observational study in the same report (Hogervorst et al., 1999). Studies in surgically menopausal women have also been conducted, with disparate results on cognition (Sherwin, 1988; Phillips and Sherwin, 1992; Ditkoff et al., 1999; Duka et al., 2000; Binder et al., 2001).

Imaging studies have tried to correlate cognitive changes with neurobiology in postmenopausal women, relying mostly on measures of metabolic activation and cerebral blood flow. Resnick et al (1998) found that ERT or HRT enhanced memory while producing changes in cerebral blood flow patterns relative to placebo, while other studies have found dissociations between cognitive effects and brain activation. ERT altered cerebral blood flow in parietal, temporal, and prefrontal regions without affecting cognition (Berman et al., 1997) and also affected metabolic activation in parietal and frontal areas without affecting verbal and nonverbal memory (Shaywitz et al., 1999). Another study found that temporal blood flow was altered with HRT, but measures of visual and verbal memory were unaffected (Maki and Resnick, 2000). Other studies have looked at binding of ligands specific to neurotransmitter systems, but have not included behavioral analyses. Binding of a cholinergic ligand as assessed by positron emission tomography (PET) was significantly positively correlated with length of HRT in multiple cortical areas, and ERT appeared to have higher cholinergic binding than HRT (Smith et al., 2001). ERT may also alter dopamine transporter availability as assessed by PET (Gardiner et al., 2004).

Problems with Human Studies

A number of difficulties exist when conducting studies of menopause in humans. Sample bias can occur in observational trials, as women who are more highly educated are more likely to seek treatment, and inappropriate controls for education, socioeconomic status, diet, or depression are often used. Compliance can be an issue when many clinical studies rely on self-reports to determine compliance with treatment; serum assays to determine compliance or efficacy of treatment are rarely employed. There is little consistency between studies with regards to the neuropsychological measures being employed, and the dose, route, duration, and type of hormone replacement may vary significantly. Often women have previously taken some form of hormone replacement. Observational studies especially do not usually have the luxury of separating groups based upon type of therapy or duration of exposure and must settle for groups comprising many types of HRT at different doses, which can confound the results.

Animal models allow for the circumvention of many problems. Specifically, a uniform hormone therapy can be employed without concerns of compliance, and more invasive procedures can be performed. Multiple tests across the entire lifespan can easily be performed, and postmortem studies can be conducted in animals. Results of animal studies can often resolve questions which are difficult if not impossible to address in humans.

Animal Models of Menopause: Cognition

Most animal studies of the cognitive consequences of menopause have been conducted in rodents, and these investigations have primarily employed ERT as treatment. ERT administered to ovariectomized (OVX) rats enhances both the acquisition (Daniel et al., 1997; Fader et al., 1998; Luine et al., 1998; Gibbs, 1999) and memory (Packard and Teather, 1997; Luine et al., 1998; Bimonte and Denenberg, 1999; Fader et al., 1999) of spatial tasks, although the enhancements are not always consistent across studies. For example, acquisition but not memory on a delayed match-to-position (DMP) task or T-maze alternation task is enhanced in some studies (Fader et al., 1998; Dohanich et al., 1994) but the opposite is true on spatial water maze and water radial maze tasks (Bimonte and Denenberg, 1999). Some subsets of memory, such as working memory, may be more susceptible to changes in ovarian hormones than are others (e.g. reference memory, Fader et al., 1999), although reference memory enhancements due to ERT have been reported (Rissanen et al., 1999).

The few studies that examine HRT in rodents are conflicting. Sandstrom and Williams (2001) reported that ERT or HRT improved performance on a water delayed match-to-position (DMP) test, and HRT was equally effective as ERT at reversing a scopolamine-induced impairment on T-maze alternations (Donahich et al., 1994). HRT was more effective than ERT at enhancing the learning of a DMP task (Gibbs, 2000b). In contrast, another study found that HRT impaired performance on a spatial Morris Water Maze (Chesler and Juraska, 2000). More recently it was reported that long-term OVX actually results in a performance increase on a water escape radial arm maze in aged rats, due to the removal of high estrapausal levels of progesterone (Bimonte-Nelson et al., 2003). Administration of progesterone alone returned performance of OVX aged rats to the level of sham-operated aged rats (Bimonte-Nelson et al., 2004).

Although no non-human primate studies have examined the effects of HRT on cognition, a few non-human primate studies have examined the effects of ERT. ERT can enhance performance on tests of attention (Voytko, 2002) and memory in monkeys (Rapp et al., 2003; Lacreuse et al., 2002), similar to postmenopausal women receiving ERT. However, performance may vary depending on the age of the animals and the cognitive domain being assessed (reviewed in Tinkler and Voytko, 2005).

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Berman KF, Schmidt PJ, Rubinow DR, Danaceau MA, Van Horn JD, Esposito G, Ostrem JL, Weinberger DR. 1997. Modulation of cognition-specific cortical activity by gonadal steroids: A positron-emission tomography study in women. Proc Natl Acad Sci 94:8836-8841.

Bimonte HA, Denenberg VH. 1999. Estradiol facilitates performance as working memory load increases. Psychoneuroendocrinology 24:161-173.

Bimonte-Nelson HA, Singleton RS, Hunter CL, Price KL, Moore AB, Granholm AC. 2003. Ovarian hormones and cognition in the aged female rat: I. Long-term, but not short-term, ovariectomy enhances spatial performance. Behav.Neurosci. 117:1395-1406.

Bimonte-Nelson HA, Singleton RS, Williams BJ, Granholm AC. 2004. Ovarian hormones and cognition in the aged female rat: II. progesterone supplementation reverses the cognitive enhancing effects of ovariectomy. Behav.Neurosci. 118:707-714.

Binder EF, Schectman KB, Birge SJ, Williams DB, Koher WM. 2001. Effects of hormone replacement therapy on cognitive performance in elderly women. Maturitas 38:137-146.

Chesler EJ, Juraska JM. 2000. Acute administration of estrogen and progesterone impairs the acquisition of the spatial morris water maze in ovariectomized rats. Horm.Behav. 38:234-242.

Daniel JM, Fader AJ, Spencer AL, Dohanich GP. 1997. Estrogen enhances performance of female rats during acquisition of a radial arm maze task. Horm Behav 32:217-225.

Ditkoff EC, Crary WG, Cristo M, Lobo RA. 1991. Estrogen improves psychological function in asymptomatic postmenopausal women. Obstet.Gynecol. 78:991-995.

Dohanich GP, Fader AJ, Javorsky DJ. 1994. Estrogen and estrogen-progesterone treatments counteract the effect of scopolamine on reinforced T-maze alternation in female rats. Behav.Neurosci. 108:988-992.

Duka T, Tasker R, McGowan JF. 2000. The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females. Psychopharmacology (Berl) 149:129-139.

Fader AJ, Hendricson AW, Dohanich GP. 1998. Estrogen improves performance of reinforced t-maze alternation and prevents the amnestic effects of scopolamine administered systematically or intrahippocampally. Neurobiol Learn Mem 69:225-240.

Fader AJ, Johnson PEM, Dohanich GP. 1999. Estrogen improves working but not reference memory and prevents amnestic effects on scopolamine on a radial-arm maze. Pharmacol Biochem Behav 62:711-717.

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Gardiner SA, Morrison MF, Mozley PD, Mozley LH, Brensinger C, Bilker W, Newberg A, Battistini M. 2004. Pilot study on the effect of estrogen replacement therapy on brain dopamine transporter availability in healthy, postmenopausal women. Am J Geriatric Psychiatry 12:621-630.

Gibbs RB. 1999. Estrogen replacement enhances acquisition of a spatial memory task and reduces deficits associated with hippocampal muscarinic receptor inhibition. Horm Behav 36:222-233.

Gibbs RB. 2000b. Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. Neurobiol.Aging 21:107-116.

Gibbs RB, Burke AM, Johson DA. 1998. Estrogen replacement attenuates effects of scopolamine and lorazepam on memory acquisition and retention. Horm Behav 34:112-125.

Hackman BW, Galbraith D. 1976. Replacement therapy and piperazine oestrone sulphate ('Harmogen') and its effect on memory. Curr.Med.Res.Opin. 4:303-306.

Hogervorst E, Boshuisen M, Riedel W, Willeken C, Jolles J. 1999. The effect of hormone replacement therapy on cognitive function in elderly women. Psychoneuroendocrinology 24:43-68.

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Kopera H. 1972. Estrogens and psychic functions. Front Hormone Res 2:118-133.

Lacreuse A, Wilson ME, Herndon JG. 2002. Estradiol, but not raloxifene, improves aspects of spatial working memory in aged ovariectomized rhesus monkeys. Neurobiol.Aging 23:589-600.

Luine VN, Richards ST, Wu VY, Beck KD. 1998. Estradiol enhances learning and memory in a spatial memory task and effects levels of monaminergic transmitters. Horm Behav 34:149-162.

Maki PM, Resnick SM. 2000. Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition. Neurobiol Aging 21:373-383.

Okhura T, Kunihiro I, Akazawa K, Hamamota M, Yaoi Y, Hagino N. 1995. Long-term estrogen replacement therapy in female patients with dementia of the Alzhemer type: 7 case reports. Dementia 6:99-107.

Oldenhave A, Netelenbos C. 1994. Pathogenesis of climacteric complaints: Ready for the change? Lancet 343:649-653.

Phillips SM, Sherwin BB. 1992. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 17:485-495.

Rapp PR, Morrison JH, Roberts JA. 2003. Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys. J.Neurosci. 23:5708-5714.

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Resnick SM, Maki PM, Golski S, Kraut MA, Zonderman AB. 1998. Effects of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance. Horm Behav 34:171-182.

Rice MM, Graves AB, McCurry SM, Gibbons LE, Bowen JD, McCormick WC, Larson EB. 2000. Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese women. Arch Intern Med 160:1641-1649.

Rice MM, Graves AB, McCurry SM, Larson EB. 1997. Estrogen replacement therapy and cognitive function in postmenopausal women without dementia. Am J Med 103(3A):26S-35S.

Rissanen A, Poulivali J, van Groen T, Riekkinen Jr P. 1999. In mice tonic estrogen replacement therapy improves non-spatial and spatial memory in a water maze task. Neuroreport 10:1369-1372.

Robinson D, Friedman L, Marcus R, Tinklenberg J, Yesavage J. 1994. Estrogen replacement therapy and memory in older women. J.Am.Geriatr.Soc. 42:919-922.

Sandstrom NJ, Williams CL. 2001. Memory retention is modulated by acute estradiol and progesterone replacement. Behav.Neurosci. 115:384-393.

Schneider LS, Farlow MR, Henderson VW, Pgoda JM. 1996. Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer's disease. Neurology 46:1580-1584.

Shaywitz SE, Shaywitz BA, Pugh KR, Fulbright RK, Skudlarski P, Mancl WE, Constable RT, Naftolin F, Palter SF, Marchione KE, Katz L, Shankweiler DP, Fletcher JM, Lacedie C, Keltz M, Gore JC. 1999. Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 281:1197-1202.

Sherwin BB. 1988. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 13:345-357.

Smith Y, Minoshima S, Kuhl DE, Zubeita JK. 2001. Effects of long-term hormone therapy on cholinergic synaptic concentrations in healthy postmenopausal women. J Clin Endocrinol Metab 86:679-684.

Tinkler GP, Voytko ML. 2005. Estrogen modulates cognitive and cholinergic processes in surgically menopausal monkeys. Prog Neuropsychopharmacol Biol Psychiatry. 2005 Mar;29(3):423-31.

Vanhulle G, Demol R: A double-blind study into the influence of estriol on a number of pscyhological tests in post-menopausal women. In: Concensus on Menopause Research. Eds: van Keep PA, Greenblatt RB, Albeaux-Funet M, MTP Press, London, UK, 94-99 (1976).

Voytko ML. 2002. Estrogen and the cholinergic system modulate visuospatial attention in monkeys (Macaca fascicularis). Behav Neurosci 116:187-197.


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