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- All Subjects: Menopause
- Creators: Bimonte-Nelson, Heather
- Creators: Conrad, Cheryl
Description
Women are now living longer than ever before, yet the age of spontaneous menopause has remained stable. This results in an increasing realization of the need for an effective treatment of cognitive and physiological menopausal and post-menopausal symptoms. The most common estrogen component of hormone therapy, conjugated equine estrogens (CEE; Premarin) contains many estrogens that are not endogenous to the human body, and that may or may not be detrimental to cognition (Campbell and Whitehead, 1977; Engler-Chiurazzi et al., 2011; Acosta et al., 2010). We propose the use of a novel treatment option in the form of a naturally-circulating (bioidentical) estrogen called estriol. Due to estriol’s observed positive effects on synaptic functioning and neuroprotective effects in the hippocampus (Ziehn et al., 2012; Goodman et al., 1996), a brain structure important for spatial learning and memory, estriol is promising as a hormone therapy option that may attenuate menopausal- and age- related memory decline. In the current study, we administered one of the three bioidentical estrogens (17β-Estradiol, 4.0 µg/day; Estrone, 8.0 µg/day; Estriol, 8.0 µg/day) or the vehicle polyethylene glycol by subcutaneous osmotic pump to ovariectomized Fisher-344 rats. We compared these groups to each other using a battery of spatial learning tasks, including the water radial-arm maze (WRAM), Morris water maze (MM), and delayed-match-to-sample maze (DMS). We found that all estrogens impaired performance on the WRAM compared to vehicle, while 17β-estradiol administration improved overnight forgetting performance for the MM. The estriol group showed no cognitive enhancements relative to vehicle; however, there were several factors indicating that both our estriol and estradiol doses were too high, so future studies should investigate whether lower doses of estriol may be beneficial to cognition.
ContributorsStonebarger, Gail Ashley (Author) / Bimonte-Nelson, Heather (Thesis director) / Knight, George (Committee member) / Engler-Chiurrazzi, Elizabeth (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2015-05
Description
Following natural menopause, androstenedione becomes the main hormone secreted by the follicle-depleted ovaries. We have previously evaluated high physiological doses of androstenedione in the female rodent, and found relations between higher androstenedione levels and spatial memory impairment; this relationship was shown when androstenedione levels were of endogenous, or exogenous, origin (Acosta et al., 2009, Camp et al., 2012). This androstenedione-induced memory impairment in females led us to question whether this androgen also impairs memory in males; no study has yet evaluated androstenedione's impact on cognition in the male rodent model. This is a clinically relevant question, as androstenedione is a steroid of abuse. In the current study, four-month old male rats were given either a daily injection of androstenedione, androstenedione with anastrozole or vehicle (polyethylene glycol). Subjects completed a battery of cognitive tasks evaluating spatial working, reference, and recent memory including the water radial arm maze (WRAM), Morris water maze (MM), and delayed match-to-sample maze (DMTS). We found that androstenedione administration impaired spatial cognitive performance in MM on early overnight forgetting and DMTS early recent memory trials across all days of testing. In addition, we found that androstenedione with anastrozole administration impaired spatial cognitive performance in the learning phases and early overnight forgetting in the MM but had no impact in DMTS testing. There were no significant differences in the WRAM maze for either group. Our findings suggest that androstenedione can impair spatial reference and early recent memory, and that anastrozole reverses this impairment for early recent memory, but not reference memory. Interpreted in the context of hormone conversion, androstenedione's effects on spatial learning and memory may be due, in part, to its conversion to estrone.
ContributorsTorres, Laura Maria (Co-author) / Camp, Bryan (Co-author) / Karber, Lily (Co-author) / Hiroi, Ryoko (Co-author, Committee member) / Bimonte-Nelson, Heather (Co-author, Thesis director) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2014-05
Description
Estradiol (E2) and Levonorgestrel (Levo) are two hormones commonly used in hormone therapy (HT) to decrease symptoms associated with menopause. Both of these hormones have been shown to have beneficial effects on cognition when given alone in a rodent model of menopause. However, it is unknown whether these hormones, when taken in combination, are beneficial or harmful to cognition. This is a critically important question given that these hormones are most often given in combination versus separately. This thesis is composed of two studies examining the cognitive effects of E2 and Levo using a rat model of surgical menopause. Study 1 assessed how the dose of E2 treatment in rats impacted cognitive performance, and found that low dose E2 enhanced working memory performance. Next, based on the results from Study 1, Study 2 used low dose E2 in combination with different doses of Levo to examine the cognitive effects of several E2 to Levo ratio combinations. The results from Study 2 demonstrated that the combination of low dose E2 with a high dose of Levo at a 1:2 ratio impaired cognition, and that the ratio currently used in HT, 3:1, may also negatively impact cognition. Indeed, there was a dose response effect indicating that working and reference memory performance was incrementally impaired as Levo dose increased. The findings in this thesis suggest that the E2 plus Levo combination is likely not neutral for cognitive function, and prompts further evaluation in menopausal women, as well as drug discovery research to optimize HT using highly controlled preclinical models.
ContributorsBerns-Leone, Claire Elizabeth (Co-author) / Prakapenka, Alesia (Co-author) / Pena, Veronica (Co-author) / Northup-Smith, Steven (Co-author) / Melikian, Ryan (Co-author) / Ladwig, Ducileia (Co-author) / Patel, Shruti (Co-author) / Croft, Corissa (Co-author) / Bimonte-Nelson, Heather (Thesis director) / Glenberg, Arthur (Committee member) / Conrad, Cheryl (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Premature babies are at risk of death from immature lung development. For this reason, pregnant mothers at risk for preterm delivery are administered dexamethasone (DEX), a synthetic glucocorticoid that promotes fetal lung development. However, exposure to DEX in utero is associated with low birth weight and cardiovascular development pathologies. Moreover, our lab found that DEX administration in-utero leads to a sex-specific increase in stress-induced tachycardia in female, but not male offspring. This project seeks to expand on this preliminary finding of the heart by examining local effectors of activity from the sympathetic system (tyrosine hydroxylase and catechol-o-methyltransferase). Tyrosine hydroxylase was measured as it catalyzes the rate limiting step of norepinephrine synthesis while catechol-O- methyltransferase was studied as it catalyzes the degradation of norepinephrine. Acetylcholinesterase was used to measure parasympathetic activity as it catalyzes the degradation of the primary neurotransmitter of the parasympathetic nervous system, acetylcholine. Analyses of sympathetic as well as parasympathetic activity were done to determine influences of in-utero DEX exposure on autonomic regulation in adulthood. Pregnant rats were administered DEX (0.4 mg/kg, i.p.) or vehicle (20% w/v 2-hydroxypropyl ß- cyclodextran) at gestation days 18-21, with euthanasia of offspring occurring at around the time the offspring reached 13-15 weeks of age. Left ventricles and right atria were pulverized, processed and subjected to western blot analysis to determine expression of proteins of interest. Males exposed to DEX in-utero saw a decrease in tyrosine hydroxylase expression in left ventricle and right atrium when compared to vehicle control, a difference not seen with females. In addition, catechol-o-methyltransferase expression was increased in right atria from male, but not female rats. Acetylcholinesterase expression was reduced in the right atria of female, but not male rats. The present findings suggest reduced norepinephrine signaling in the heart of male, but not female DEX-exposed offspring. Given that we have previously found that female, but not male rats exhibit exaggerated stress-induced tachycardia, our current findings suggest that males possess a sex-specific compensatory mechanism allowing the heart to resist increased sympathetic signaling from the brain, one that females do not possess. The underlying mechanics of this proposed mechanism are unclear, and further investigation is needed in this subject to determine the significance of the findings from our study.
ContributorsSharma, Arpan (Author) / Conrad, Cheryl (Thesis director) / Hale, Taben (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
It is well documented that menopause and the related decline in circulatory steroid hormones estrogen and progesterone are associated with memory alterations. Rodent models of surgical menopause can be used to study these effects, including ovariectomy (Ovx), or the surgical removal of the ovaries. This thesis aimed to characterize the effects of surgical menopause on spatial working and reference memory in rats and examine profiles of uterine gene expression alterations that may serve as indications of mechanisms underlying this association. Eighteen female rats were randomly assigned to one of two surgical treatment groups, either Ovx (the surgical menopause group) or sham (the control group). All subjects underwent testing on the water version of the radial arm maze (WRAM) which allows for the assessment of reference memory errors and two types of working memory errors. After behavioral testing, rat uterine tissues were dissected and RNA sequenced. The results showed that Ovx impaired spatial reference memory performance during a maze learning phase, with Ovx rats making reference memory failures earlier in the day, even before working memory load increased, as compared to control rats. There were no surgical menopause effects on spatial working memory, which may be due to the low working memory load and the young age of the rats. Post-hoc analyses showed that reference memory performance was correlated with nerve growth factor (NGF) and acetylcholinesterase (AChE) gene expression in uterine tissues. These findings add to the literature on the impact of estrogen and female cyclicity on memory and cognition. The results suggest that Ovx impairment of the ability to learn long-term spatial memory information relates to uterine gene expression underlying cellular functioning and that NGF and AChE genes are involved in pathways that give way to underlying cellular functioning that impacts cognition. Future studies should continue to evaluate the effects of menopause on memory function and the effectiveness of hormone therapy.
ContributorsOyen, Emma (Author) / Bimonte-Nelson, Heather (Thesis director) / Corbin, William (Committee member) / Wilson, Melissa (Committee member) / Lizik, Camryn (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2024-05
Description
Memory as whole is impacted by changes associated with aging and menopause. Different memory types are often tested preclinically utilizing rats in different task paradigms. Most studies have focused on understanding social recognition or working memory, however these memory types have yet to be studied together. This thesis focuses on the process of creating and testing a new social recognition task that incorporates a working memory load. We tested different types of previously used social recognition paradigms with an increasing load and through qualitative and quantitative observations the task was modified until a final task was developed for a social working memory study. Young female rats were tested in this task in progressive, meaning a chronologically increasing load and nonprogressive, meaning non-chronological increase in load cognitions. It was found that young female rats had the ability to distinguish between the familiar and novel conspecifics before memory load exceeded four familiar and one novel conspecifics. Once validated through future studies, this task may be utilized to understand the impact of different types of menopause on social working memory.
ContributorsAsadifar, Sadaf (Author) / Bimonte-Nelson, Heather (Thesis director) / Corbin, William (Committee member) / Verpeut, Jessica (Committee member) / Barrett, The Honors College (Contributor) / School of Human Evolution & Social Change (Contributor) / Department of Psychology (Contributor)
Created2024-05
Description
Progestogens, such as progesterone (P4), medroxyprogesterone acetate (MPA), and micronized progesterone (mP4), are given to ovary-intact women during the transition to menopause to attenuate heavy uterine bleeding and other symptoms. Both progesterone and MPA administration have been shown to impair cognition in ovariectomized (Ovx) rats compared to vehicle-treated controls. mP4, however, has yet to be investigated for cognitive effects in a preclinical setting. Further, progestogens affect the GABA (-aminobutyric acid) ergic system, specifically glutamic acid decarboxylase (GAD) the rate limiting enzyme necessary for synthesizing GABA. The goal of this experiment was to investigate the cognitive impact of P4, MPA, and mP4, in an ovary-intact transitional menopause model using 4-vinylcyclohexene diepoxide (VCD) and assess whether these potential changes were related to the GABAergic system. One group of rats received vehicle injections, and the remainder of the groups received VCD to induce follicular depletion, modeling transitional menopause in women. Vehicle or hormone administration began during perimenopause to model the time period when women often take progestogens alone. Rats then underwent testing to assess spatial working and reference memory in the water radial-arm maze (WRAM) and spatial reference memory in the Morris water maze (MWM). Results indicate that P4 and MPA improved learning for working memory measure, but only MPA impaired memory retention in the WRAM. For the WRAM reference memory measure, VCD only treated rats showed impaired learning and memory retention compared to vehicle controls; progestogens did not impact this impairment. Although GAD expression did not differ between treatment groups, in general, there was a relationship between GAD expression and WRAM performance such that rats that tended to have higher GAD levels also tended to make more WRAM working memory errors. Thus, while P4 and MPA have been previously shown to impair cognition in an Ovx model, giving these hormones early in an ovary-intact perimenopause model elicits divergent effects, such that these progestogens can improve cognition. Additionally, these findings suggest that the cognitive changes seen herein are related to the interaction between progestogens and the GABAergic system. Further investigation into progestogens is warranted to fully understand their impact on cognition given the importance of utilizing progestogens in the clinic.
ContributorsPena, Veronica Leigh (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Conrad, Cheryl (Committee member) / Gipson-Reichardt, Cassandra (Committee member) / Arizona State University (Publisher)
Created2019