Matching Items (2)
Description
Aging and the menopause transition are both intricately linked to cognitive changes
during mid-life and beyond. Clinical literature suggests the age at menopause onset can differentially impact cognitive status later in life. Yet, little is known about the relationship between behavioral and brain changes that occur during the transitional stage into the post-menopausal state. Much of the pre-clinical work evaluating an animal model of menopause involves ovariectomy in rodents; however, ovariectomy results in an abrupt loss of circulating hormones and ovarian tissue, limiting the ability to evaluate gradual follicular depletion. The 4-vinylcyclohexene diepoxide (VCD) model simulates transitional menopause in rodents by selectively depleting the immature ovarian follicle reserve and allowing animals to retain their follicle-deplete ovarian tissue, resulting in a profile similar to the majority of menopausal women. Here, Vehicle or VCD treatment was administered to ovary-intact adult and middle-aged Fischer-344 rats to assess the cognitive effects of transitional menopause via VCD-induced follicular depletion over time, as well as to understand potential interactions with age, with VCD treatment beginning at either six or twelve months of age. Results indicated that subjects that experience menopause onset at a younger age had impaired spatial working memory early in the transition to a follicle-deplete state. Moreover, in the mid- and post- menopause time points, VCD-induced follicular depletion amplified an age effect, whereby Middle-Aged VCD-treated animals had poorer spatial working and reference memory performance than Young VCD-treated animals. Correlations suggested that in middle age, animals with higher circulating estrogen levels tended to perform better on spatial memory tasks. Overall, these findings suggest that the age at menopause onset is a critical parameter to consider when evaluating learning and memory across the transition to reproductive senescence. From a translational perspective, this study informs the field with respect to how the age at menopause onset might impact cognition in menopausal women, as well as provides insight into time points to explore for the window of opportunity for hormone therapy during the menopause transition to attenuate age- and menopause- related cognitive decline, and produce healthy brain aging profiles in women who retain their ovaries throughout the lifespan.
during mid-life and beyond. Clinical literature suggests the age at menopause onset can differentially impact cognitive status later in life. Yet, little is known about the relationship between behavioral and brain changes that occur during the transitional stage into the post-menopausal state. Much of the pre-clinical work evaluating an animal model of menopause involves ovariectomy in rodents; however, ovariectomy results in an abrupt loss of circulating hormones and ovarian tissue, limiting the ability to evaluate gradual follicular depletion. The 4-vinylcyclohexene diepoxide (VCD) model simulates transitional menopause in rodents by selectively depleting the immature ovarian follicle reserve and allowing animals to retain their follicle-deplete ovarian tissue, resulting in a profile similar to the majority of menopausal women. Here, Vehicle or VCD treatment was administered to ovary-intact adult and middle-aged Fischer-344 rats to assess the cognitive effects of transitional menopause via VCD-induced follicular depletion over time, as well as to understand potential interactions with age, with VCD treatment beginning at either six or twelve months of age. Results indicated that subjects that experience menopause onset at a younger age had impaired spatial working memory early in the transition to a follicle-deplete state. Moreover, in the mid- and post- menopause time points, VCD-induced follicular depletion amplified an age effect, whereby Middle-Aged VCD-treated animals had poorer spatial working and reference memory performance than Young VCD-treated animals. Correlations suggested that in middle age, animals with higher circulating estrogen levels tended to perform better on spatial memory tasks. Overall, these findings suggest that the age at menopause onset is a critical parameter to consider when evaluating learning and memory across the transition to reproductive senescence. From a translational perspective, this study informs the field with respect to how the age at menopause onset might impact cognition in menopausal women, as well as provides insight into time points to explore for the window of opportunity for hormone therapy during the menopause transition to attenuate age- and menopause- related cognitive decline, and produce healthy brain aging profiles in women who retain their ovaries throughout the lifespan.
ContributorsKoebele, Stephanie Victoria (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Aiken, Leona S. (Committee member) / Conrad, Cheryl D. (Committee member) / Wynne, Clive DL (Committee member) / Arizona State University (Publisher)
Created2015
Description
Women are exposed to numerous endogenous and exogenous hormones across the lifespan. In the last several decades, the prescription of novel hormonal contraceptives and hormone therapies (HTs) have resulted in aging women that have a unique hormone exposure history; little is known about the impact of these hormone exposures on short- and long- term brain health. The goal of my dissertation was to understand how lifetime hormone exposures shape the female cognitive phenotype using several innovative approaches, including a new human spatial working memory task, the human radial arm maze (HRAM), and several rodent menopause models with variants of clinically used hormone treatments. Using the HRAM (chapter 2) and established human neuropsychological tests, I determined males outperformed females with high endogenous or exogenous estrogen levels on visuospatial tasks and the spatial working memory HRAM (chapter 3). Evaluating the synthetic estrogen in contraceptives, ethinyl estradiol (EE), I found a high EE dose impaired spatial working memory in ovariectomized (Ovx) rats, medium and high EE doses reduced choline-acetyltransferace-immunoreactive neuron population estimates in the basal forebrain following Ovx (chapter 4), and low EE impaired spatial cognition in ovary-intact rats (chapter 5). Assessing the impact of several clinically-used HTs, I identified a window of opportunity around ovarian follicular depletion outside of which the HT conjugated equine estrogens (CEE) was detrimental to spatial memory (chapter 6), as well as therapeutic potentials for synthetic contraceptive hormones (chapter 9) and bioidentical estradiol (chapter 7) during and after the transition to menopause. Chapter 6 and 7 findings, that estradiol and Ovx benefitted cognition after the menopause transition, but CEE did not, are perhaps due to the negative impact of ovarian-produced, androstenedione-derived estrone; indeed, blocking androstenedione’s conversion to estrone prevented its cognitive impairments (chapter 8). Finally, I determined that EE combined with the popular progestin levonorgestrel benefited spatial memory during the transition to menopause, a profile not seen with estradiol, levonorgestrel, or EE alone (chapter 9). This work identifies several cognitively safe, and enhancing, hormonal treatment options at different time points throughout female aging, revealing promising avenues toward optimizing female health.
ContributorsMennenga, Sarah E (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Aiken, Leona (Committee member) / Whiteaker, Paul (Committee member) / Talboom, Joshua (Committee member) / Arizona State University (Publisher)
Created2015