Estrogen, Menopause, and the Brain Research Program
The overarching goal of this program is to conduct clinical research studies that seek to understand the mechanisms behind changes in cognition and behavior that occur in women after menopause. Menopause produces significant and sustained changes in the levels of sex hormones (e.g. estrogen) that have profound effects on brain functioning and may produce changes in mood, memory, and learning. These changes may account for gender-related differences between older women and men, especially regarding rates of neurodegenerative disorders, some of which tend to be higher in women (e.g. Alzheimer's disease).
The studies utilized intensive, repeated-measures designs focusing on the effects of neuropharmacologic probes combined with sophisticated cognitive testing, functional brain imaging, and behavioral paradigms in older women. Most of the studies take place at the University of Vermont General Clinical Research Center (GCRC).
We are most grateful for the enthusiastic participation of our post-menopausal women volunteers, without whom none of this research could take place.
Faculty and staff involved in this research program include:
We are currently conducting the following projects:
Sex Hormone Effects on Cognition and Memory after Menopause
The primary goal of these projects, funded by the National Institute on Aging (NIA) and the National Center for Research Resources (NCRR) is to examine in detail the effects of estrogen, estrogen antagonists, and progesterone on cognitive functions that are affected by cholinergic systems of the brain in postmenopausal women. These systems have critical relevance for the development of age-related cognitive and behavioral changes as well as the symptoms of dementing disorders such as Alzheimer's disease. Changes in estrogen levels after surgical and natural menopause are associated with negative changes in cognitive and behavioral functioning which are preventable by estrogen administration. Administration of estrogen after menopause is associated with a lower risk of Alzheimer's disease.
These studies examine the effects of estrogen and related gonadal steroids on the cholinergic system of the human brain that is thought to be critical for attention, learning, memory, and psychomotor performance. These studies utilize a well-established method for probing the integrity of central cholinergic mechanisms utilizing cholinergic (muscarinic and nicotinic) antagonists. Preliminary data suggests that short-term administration of estrogen partially protects women from the negative cognitive effects of cholinergic antagonists. This effect could be mediated by trophic effects of estrogen on central cholinergic neurons. Estrogen has a substantial effect on the expression and activity of trophic factors such as Nerve Growth Factor (NGF) and its receptors, thereby directly producing neuroprotective and trophic effects, particularly in cholinergic neurons of the basal forebrain. Estrogen also appears to have signal-transduction modulating properties.
However, recent studies from the WHI/WHIMS studies have raised concerns regarding the effects of long-term use of certain estrogen-progesterone combinations on dementia incidence. In addition, many women are now taking agents which may antagonize or modify estrogen effects such as progesterone and the anti-estrogen tamoxifen.
We are currently conducting three studies focusing on the effects of sex hormones on brain functioning and cognition in older women. These include:
Single dose estrogen versus three-month treatment with estrogen on anti-cholinergic induced cognitive changes
Effects of combined estrogen-progesterone versus estrogen alone on cholinergic integrity
Effects of the estrogen antagonist tamoxifen on the cholinergic system.
These studies will provide knowledge regarding the magnitude and type of effects of estrogen on cholinergic system integrity and will contribute to an understanding of the potential impact of estrogen in late life for maintenance of cognitive functioning during normal aging. In addition, the results may have an impact on the prevention and/or treatment of age-related cognitive disorders such as mild cognitive impairment and Alzheimer's disease.
Our collaborators on these projects include Robert Astur, Ph.D. (Institute of Living/Yale University).
These studies are for post menopausal women ages 50 and over who are non-smokers, not currently taking HRT or antidepressants, and have no history of breast cancer. Participants will receive free physical and cognitive screening, free study medications, and reimbursement for time and travel expenses. Please call Sally Ross Nolan, M.S. at 802-847-9488 for more information.
Brain Cholinergic System Activity in Post-Menopausal Women Measured by Functional Magnetic Resonance Imaging (fMRI)
The primary goal of this project, funded by the FAHC Research Development Fund and the National Center for Research Resources (NCRR), is to examine in detail the effects of the cholinergic antagonists scopolamine and mecamylamine on brain system activity during working memory tasks in healthy postmenopausal women. These systems have critical relevance for the development of age-related cognitive and behavioral changes as well as the symptoms of dementing disorders such as Alzheimer's disease.
This study will allow us to localize the effects of the cholinergic drugs on cholinergic system-related brain activity that is thought to be critical for attention, learning, memory, and psychomotor performance. These studies utilize a method that we have established for probing the integrity of central cholinergic mechanisms utilizing cholinergic (muscarinic and nicotinic) antagonists.
This study will provide knowledge regarding our ability to obtain quantifiable imaging data from our model of late-life cognitive impairment that is relevant to cholinergic system integrity. We then hope to examine directly the effects of estrogen on this model. This will contribute to an understanding of the potential use of estrogen in late life for maintenance of cognitive functioning during normal aging and treatment of age-related cognitive disorders such as mild cognitive impairment and Alzheimer's disease.
This study is for post menopausal women ages 50 and over who are non-smokers and not currently taking HRT or antidepressants. Participants will receive free physical and cognitive screening, and reimbursement for time and travel expenses. Please call Sally Ross Nolan, M.S. at 802-847-9488 for more information.
To learn about the latest options for treatment of menopause-related symptoms, see the FDA's new website on menopause and hormone replacement at http://www.fda.gov/womens/menopause. To learn about the Women's Health Initiative Study, visit the NIH website regarding the WHI.
