Dumas, J., Hancur-Bucci, C., Naylor, M., Sites, C. & Newhouse, P. Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis. Horm. Behav. 53, 159-169

Clinical Neuroscience Research Unit, Department of Psychiatry, University of Vermont College of Medicine, 1 South Prospect St., Burlington, VT 05401, USA.
Hormones and Behavior (Impact Factor: 4.63). 02/2008; 53(1):159-69. DOI: 10.1016/j.yhbeh.2007.09.011
Source: PubMed


Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women. This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger (ages 50-62) and older (ages 70-81) postmenopausal women. Twenty-two postmenopausal women were randomly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed. Subjects were administered either the antimuscarinic drug scopolamine (SCOP), the antinicotinic drug mecamylamine (MECA), or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory (the Buschke Selective Reminding Task) for the younger group only, while estradiol treatment impaired performance of the older group. The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects, supporting the concept of a critical period for postmenopausal estrogen use.

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Available from: Paul Newhouse, Apr 04, 2014
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    • "In contrast, women who received E2 and performed below average on verbal recall at baseline showed no significant difference compared to the placebo group. Dumas et al. concluded that these findings provided support to the healthy cell bias hypothesis, as they considered it improbable that women with a normal score or better had significant neurodegenerative changes [22]. Notably, the women who benefitted from estrogen exposure were age 70 (average) and approximately 20 years postmenopause, suggesting that older women who have intact verbal memory can benefit from a new regimen of ERT late in life, as long as they have not demonstrated memory impairment. "
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    ABSTRACT: Over the past two decades, there has been a significant amount of research investigating the risks and benefits of hormone replacement therapy (HRT) with regards to neurodegenerative disease. Here, we review basic science studies, randomized clinical trials, and epidemiological studies, and discuss the putative neuroprotective effects of HRT in the context of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and HIV-associated neurocognitive disorder. Findings to date suggest a reduced risk of Alzheimer's disease and improved cognitive functioning of postmenopausal women who use 17β-estradiol. With regards to Parkinson's disease, there is consistent evidence from basic science studies for a neuroprotective effect of 17β-estradiol; however, results of clinical and epidemiological studies are inconclusive at this time, and there is a paucity of research examining the association between HRT and Parkinson's-related neurocognitive impairment. Even less understood are the effects of HRT on risk for frontotemporal dementia and HIV-associated neurocognitive disorder. Limits to the existing research are discussed, along with proposed future directions for the investigation of HRT and neurodegenerative diseases.
    Full-text · Article · Apr 2012 · International Journal of Alzheimer's Disease
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    • "Dumas et al. conducted a small, randomized, placebo-controlled trial of oral E2 (17β- estradiol) to test the effect of E2 on cognition in younger (50–62) versus older (70–81) postmenopausal women [46]. Intriguingly, they showed that pre-treatment with oral E2 attenuated anti-cholinergic drug-induced deficits of episodic memory in the younger postmenopausal women but, conversely, further hindered the older postmenopausal women [46]. This critical observation provides supports that E2 may yield neurological benefit if administered within 10 years of menopause but may also exacerbate cognitive deficits if administered more than 20 years after the onset of menopause. "
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    ABSTRACT: 17β-Estradiol (estradiol or E2) is implicated as a neuroprotective factor in a variety of neurodegenerative disorders. This review focuses on the mechanisms underlying E2 neuroprotection in cerebral ischemia, as well as emerging evidence from basic science and clinical studies, which suggests that there is a "critical period" for estradiol's beneficial effect in the brain. Potential mechanisms underlying the critical period are discussed, as are the neurological consequences of long-term E2 deprivation (LTED) in animals and in humans after natural menopause or surgical menopause. We also summarize the major clinical trials concerning postmenopausal hormone therapy (HT), comparing their outcomes with respect to cardiovascular and neurological disease and discussing their relevance to the critical period hypothesis. Finally, potential caveats, controversies and future directions for the field are highlighted and discussed throughout the review.
    Full-text · Article · Nov 2011 · Frontiers in Neuroendocrinology
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    • "Research with muscarinic and nicotinic cholinergic manipulations in healthy subjects (e.g., (Newhouse et al. 2001; Warburton and Rusted 1993) and in animals (e.g., (Sarter et al. 2006) showed that the cholinergic system primarily contributes to effortful attention processes more than memory, the primary deficit in AD. Additionally, recent work has shown that age-related changes in sex hormones such as estradiol can affect cholinergic integrity and cognitive processes (Dumas et al. 2008a; Gibbs 2009). However, with the increased use of functional neuroimaging, new data show support for the role of the cholinergic system in cognitive changes associated with aging and dementia. "
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    ABSTRACT: It is now possible to reevaluate the cholinergic hypothesis of age-related cognitive dysfunction based on a synthesis of new evidence from cholinergic stimulation studies and cognitive models. We propose that a change of functional circuitry that can be observed through a combination of pharmacologic challenge and functional neuroimaging is associated with age-related changes in cholinergic system functioning. Psychopharmacological manipulations using cholinergic agonists and antagonists have been consistent in replicating patterns of aging seen in functional imaging studies. In addition, studies of anticholinesterase drugs in patients with Alzheimer's disease and mild cognitive impairment show support for the proposal that cholinergic compensation causes alterations in task-related brain activity. Thus, the cholinergic hypothesis of age-related cognitive dysfunction deserves further consideration as new methodologies for evaluating its validity are increasingly being used. Future directions for testing hypotheses generated from this model are presented.
    Full-text · Article · Mar 2011 · Pharmacology Biochemistry and Behavior
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