Menopause III: Cognitive Consequences
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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