Hormone replacement therapy for cognitive function in postmenopausal women
ABSTRACT As estrogens have been found in animal models to be associated with the maintenance and protection of brain structures, it is biologically plausible that maintaining high levels of estrogens in postmenopausal women by medication could be protective against cognitive decline.
To investigate the effect of ERT (estrogens only) or HRT (estrogens combined with a progestagen) in comparison with placebo in RCTs on cognitive function in postmenopausal women.
The CDCIG Specialized Register was searched 7 March 2006. Additional searches were made of MEDLINE (1966-2006/02); EMBASE (1985-2006/02); PsycINFO (1967-2006/02) and CINAHL (1982-2006/01).
All double-blind RCTs trials of the effect of ERT or HRT on cognitive function over a treatment period of at least two weeks in postmenopausal women.
Selection of studies, assessment of quality and extraction of data were undertaken independently by three reviewers with disagreements resolved by discussion.
In total, 24 trials were included, but only 16 (10,114 women) had analysable data. Meta-analyses showed no effects of either ERT or HRT on prevention of cognitive impairment after five and four years of treatment, respectively (odds ratio 1.34, 95% CI 0.95 to 1.9; odds ratio 1.05, 95% CI 0.72 to 1.54 respectively) (trend favouring control in both instances). Analyses assessing the effects of treatment over time found that both ERT and HRT did not maintain or improve cognitive function and may even adversely affect this outcome (WMD = -0.45, 95% CI -0.99 to 0.09; WMD = -0.16, 95% CI -0.58 to 0.26, respectively at maximum follow up). Negative effects were found for ERT after one year and HRT after three and four years of therapy. Results from smaller trials assessing effects on individual cognitive domains mostly reported no evidence of benefit.
There is good evidence that both ERT and HRT do not prevent cognitive decline in older postmenopausal women when given as short term or longer term (up to five years) therapy. It is not known whether either specific types of ERT or HRT have specific effects in subgroups of women, although there was evidence that combined hormone therapy in similarly aged women was associated with a decrement in a number of verbal memory tests and a small improvement in a test of figural memory. There is insufficient evidence to determine whether subgroups of women using specific types of hormone therapy could benefit from treatment. It remains to be determined whether factors such as younger age (< 60 years of age), type of menopause (surgical or natural) and type of treatment (type of estrogen with or without a progestagen), mode of delivery (transdermal, oral or intramuscular) and dosage have positive effects at a clinically relevant level. In addition, whether the absence or presence of menopausal symptoms can modify treatment effects should be investigated in more detail. Large RCTs currently underway in the USA may be able to provide answers to these uncertainties by the year 2010. In the meantime, based on the available evidence, ERT or HRT cannot be recommended for overall cognitive improvement or maintenance in older postmenopausal women without cognitive impairment.
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ABSTRACT: The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review and revise its first (2006) Guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A to D, with A having the strongest evidence base (from randomized controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and brain imaging can improve diagnostic accuracy (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for mild to moderate Alzheimer's disease (A) and memantine for moderate to severe Alzheimer's disease (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer's disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), especially for neuropsychiatric symptoms (A). Cholinesterase inhibitors and memantine can produce cognitive improvements in DLB (A). There is no clear evidence that any intervention can prevent or delay the onset of dementia. Although the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition are in progress. Although results of pivotal studies are awaited, results to date have been equivocal and no disease-modifying agents are either licensed or can be currently recommended for clinical use.Journal of Psychopharmacology 11/2010; 25(8):997-1019. DOI:10.1177/0269881110387547 · 2.81 Impact Factor
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ABSTRACT: Associations between postmenopausal hormone therapy (HT) and cognitive decline may depend on apolipoprotein E (APOE) status or timing of initiation. We included 16,514 Nurses' Health Study participants aged 70-81 years who were followed since 1976 and completed up to 3 telephone cognitive assessments (2 years apart), between 1995 and 2006. The tests assessed general cognition (Telephone Interview of Cognitive Status; TICS), verbal memory, and category fluency. We used longitudinal analyses to estimate differences in cognitive decline across hormone groups. APOE genotype was available in 3697 participants. Compared with never users, past or current HT users showed modest but statistically significant worse rates of decline in the TICS: the multivariable-adjusted difference in annual rate of decline in the TICS among current estrogen only users versus never users was -0.04 (95% confidence interval, -0.07 to -0.004); for current estrogen + progestin users, the mean difference was -0.05 (95% confidence interval, -0.10 to -0.002). These differences were equivalent to those observed in women who are 1-2 years apart in age. We observed no protective associations with early timing of hormone initiation. We found suggestive interactions with APOE e4 status (e.g., on TICS, p interaction, 0.10), where the fastest rate of decline was observed among APOE e4 carriers who were current HT users. Regardless of timing of initiation, HT may be associated with worse rates of decline in general cognition, especially among those with an APOE e4 allele.Neurobiology of aging 11/2010; 33(7):1129-37. DOI:10.1016/j.neurobiolaging.2010.10.007 · 4.85 Impact Factor
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ABSTRACT: The neuroprotective effects of estrogen have been demonstrated consistently in cellular and animal studies but the evidence in women remains conflicted. We explored the window of opportunity hypothesis in relation to cognitive aging and dementia. In particular, we reviewed existing literature, reanalyzed some of our data, and combined results graphically. Current evidence suggests that estrogen may have beneficial, neutral, or detrimental effects on the brain depending on age at the time of treatment, type of menopause (natural versus medically or surgically induced), or stage of menopause. The comparison of women who underwent bilateral oophorectomy with referent women provided evidence for a sizeable neuroprotective effect of estrogen before age 50 years. Several case-control studies and cohort studies also showed neuroprotective effects in women who received estrogen treatment (ET) in the early postmenopausal stage (most commonly at ages 50-60 years). The majority of women in those observational studies had undergone natural menopause and were treated for the relief of menopausal symptoms. However, recent clinical trials by the Women's Health Initiative showed that women who initiated ET alone or in combination with a progestin in the late postmenopausal stage (ages 65-79 years) experienced an increased risk of dementia and cognitive decline regardless of the type of menopause. The current conflicting data can be explained by the window of opportunity hypothesis suggesting that the neuroprotective effects of estrogen depend on age at the time of administration, type of menopause, and stage of menopause. Therefore, women who underwent bilateral oophorectomy before the onset of menopause or women who experienced premature or early natural menopause should be considered for hormonal treatment until approximately age 51 years.Brain research 10/2010; 1379:188-98. DOI:10.1016/j.brainres.2010.10.031 · 2.83 Impact Factor