Matching Items (15)

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An Evaluation of the Cognitive Effects of Clinically Used Combination Hormone Therapy

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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

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.

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  • 2016-12

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Cognitive efficacy of three bioidentical, endogenously circulating estrogens given as hormone therapy: Extending prior findings and navigating into unchartered territory

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

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.

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  • 2015-05

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Do anabolic steroids impact cognition? An evaluation of Androstenedione's impact on spatial cognitive performance in the young male rodent

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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

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.

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Date Created
  • 2014-05

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Physical Activity and its Relation to Physical Fitness and Motor Skill Performance in Women Ages 45 - 65 Years

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This study examined the relationships between the amount of physical activity engagement and two sets of health-related tests: measures of physical fitness (abdominal curl-ups, push-ups, handgrip strength, hip flexibility, and

This study examined the relationships between the amount of physical activity engagement and two sets of health-related tests: measures of physical fitness (abdominal curl-ups, push-ups, handgrip strength, hip flexibility, and cardiorespiratory fitness) as well as measures of motor skill performance (kicking, throwing, jumping, hopping, running, and standing from a supine position) in mid-life women (ages 45-65). Physical activity engagement was assessed using 7-day accelerometer readings and the Stanford Brief Activity Survey. Motor skill performance was assessed using scores of maximum kicking, throwing, jumping, hopping, and running speeds and maximum jumping distance. Physical fitness was assessed using scores of maximum abdominal curl-ups, push-ups, handgrip strength, hip flexibility, and cardiorespiratory fitness. Results suggest that regular participation in moderate lifestyle, walking, and vigorous physical activity are related to better performances in curl-ups, push-ups, cardiorespiratory fitness on a submaximal treadmill test, kicking, throwing, and transitioning from a supine position to standing. These data represent the feasibility of selected motor skills and physical fitness tests for mid-life women and suggest that a relationship may be present between selected motor skills and health-related physical fitness measures and physical activity.

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Date Created
  • 2013-05

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Increasing Perimenopausal Patient and Clinician Satisfaction with Care Through Use of Shared Decision Making

Description

Vasomotor symptoms (VMS) associated with menopause vary greatly, as do the multitude of available treatment options. It can be difficult for clinicians to manage these symptoms while balancing patient safety

Vasomotor symptoms (VMS) associated with menopause vary greatly, as do the multitude of available treatment options. It can be difficult for clinicians to manage these symptoms while balancing patient safety concerns and preferences. Shared decision-making (SDM) can assist both the provider and patient to navigate the various treatment options, minimizing gaps between their preferences.

To assess the effect of SDM in a nurse-led practice in the Southwest, two nurse practitioners (NP) were invited to use a menopausal decision aid (DA). Women aged 40 to 64 years experiencing VMS were invited to participate in the project. Following a visit with the NP in which the DA was used, patients completed a six question post-intervention survey based on both the Decisional Conflict Scale (DCS) and SDM-Q-9 surveys. Patients were also asked to complete a telephone interview about the process 1-2 weeks post-intervention. The NP completed a post-intervention survey based on the SDM-Q-Doc to assess clinician satisfaction with the SDM process. Eight patients (mean age, 47.9 years), presenting with a range of 2 to 6 perimenopausal symptoms participated in the project.

All patients (100%) strongly or completely agreed that the clinician precisely explained the advantages & disadvantages of treatment options, helped them understand all the information, reached an agreement on how to proceed with care, and were extremely satisfied or satisfied with their decision and making an informed choice. Both clinicians completely agreed they had come to an agreement on how to proceed, and completely or strongly agreed they helped the patient understand all information. There was a correlation between the use of SDM patient’s age, making an informed choice, and being satisfied with their decision. Incorporating a perimenopausal DA can enhance patient and clinician satisfaction with SDM to understand their treatment options and make an informed menopausal decision.

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  • 2017-05-03

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The Gender Differences in Heart Disease and the Cardiovascular Benefits of Estrogen

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Heart disease is the number one killer of men and women in the world. The incidence of cardiovascular disease is known to be much higher in men than women until

Heart disease is the number one killer of men and women in the world. The incidence of cardiovascular disease is known to be much higher in men than women until around the ages of 60-75 years, when the occurrence of the disease becomes approximately equal in both sexes. Additionally, the occurrence of heart disease is significantly lower in premenopausal women than postmenopausal women. Since men have a higher risk for heart disease than women until 10-15 years after the average age of menopause and postmenopausal women have a higher risk of cardiovascular disease than premenopausal women, it is hypothesized that endogenous estrogen exposure throughout the fertile period of a woman's life postpones the onset of cardiovascular disease. Research shows estrogen has beneficial effects on the cardiovascular system by regulating multiple metabolic processes including lipid metabolism, vasodilation, nitric oxide synthesis, cytochrome c apoptosis, and mitochondrial antioxidant production. Though estrogen has been found to have cardiovascular benefits on individual metabolic processes, the treatment of synthetic estrogen on postmenopausal women and men to reduce the overall risk of heart disease is very controversial. The controversy of synthetic estrogen is partially due to the fact that most studies done using estrogen replacement therapy on postmenopausal women and men resulted in either no effects or harmful effects on the cardiovascular system. Hormone replacement therapy has also been associated with a higher risk of multiple medical conditions, especially venous thromboembolism and breast cancer. This review will explore these topics and consider the costs and benefits of estrogen replacement therapy.

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Date Created
  • 2019-05

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Effects of a Tai Chi/Qigong Intervention on Body Composition, Sleep Quality, and Emotional Eating in Midlife and Older Women

Description

Weight gain and unfavorable body composition are prevalent among midlife and older women; shifts in these characteristics can have detrimental implications on emotional and physical health and longevity. Efforts

Weight gain and unfavorable body composition are prevalent among midlife and older women; shifts in these characteristics can have detrimental implications on emotional and physical health and longevity. Efforts to attenuate weight-related factors detailing the potential development of obesity are traditionally driven by manipulation of nutrition and/or physical activity; however, sustained results are limited. Novel and integrative approaches are needed to reduce the burden of adverse changes in weight and associated consequences.

This dissertation is built around a model of effects of Tai Chi/Qigong in body composition and a pilot test of this intervention and model factors in a group of midlife/older women (N = 36). Three resulting manuscripts include: 1) a proposed biobehavioral model detailing how a Tai Chi/Qigong intervention may improve weight-related outcomes through psychological, behavioral, and physiological pathways, 2) a paper examining pre- to post- intervention differences in the primary outcomes of percent body fat, sleep quality, and emotional eating and the exploratory outcomes of perceived stress, mood state, mindfulness, self-compassion and body awareness; and 3) an exploratory analysis examining correlations between primary (sleep quality, emotional eating), exploratory (perceived stress, mood state, mindfulness, self-compassion and body awareness), and neurophysiological (heart rate variability) outcomes of interest—further, regression models were conducted to explore the predictive value of the independent variables on the dependent variables and associated changes.

In manuscript two, dependent t-tests were used to assess pre/post-differences (percent body fat and survey measures); this single group study (8-weeks of Tai Chi/Qigong) did not have a control group. Results of manuscript two demonstrate significant changes in sleep quality (p = .04), perceived stress (p = .05), and body awareness (p = .01). Findings of manuscript three indicate changes in the dependent variable of sleep quality were partially explained by perceived stress (adjusted R2 = 13.4%) and changes in the dependent variable of emotional eating were significantly explained by self-compassion (adjusted R2 = 42.1%). In the context of weight gain and unfavorable body composition in midlife/older women, results of this pilot study, using a standardized Tai Chi/Qigong intervention, indicate that select psycho-emotional factors may be important to explore further.

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Date Created
  • 2019

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High serum androstenedione levels correlate with impaired memory in the surgically menopausal rat: a replication and new findings

Description

After natural menopause in women, androstenedione becomes the primary hormone secreted by the residual follicle deplete ovaries. Two independent studies, in rodents that had undergone ovarian follicular depletion, found that

After natural menopause in women, androstenedione becomes the primary hormone secreted by the residual follicle deplete ovaries. Two independent studies, in rodents that had undergone ovarian follicular depletion, found that higher serum androstenedione levels correlated with increased working memory errors. This led to the hypothesis that androstenedione impairs memory. The current study directly tested this hypothesis, examining the cognitive effects of androstenedione administration in a rodent model. Middle-aged ovariectomized rats received vehicle or one of two doses of androstenedione (4 or 8 mg/kg daily). Rats were tested on a spatial working and reference memory maze battery including the water radial arm maze, Morris maze, and delay-match-to-sample task. Results showed that androstenedione at the highest dose impaired reference memory and working memory, including ability to maintain performance as memory demand was elevated. The latter was true for both high temporal demand memory retention of one item of spatial information, as well as the ability to handle multiple items of spatial working memory information. Glutamic acid decarboxylase (GAD) levels were measured in multiple brain regions to determine whether the gamma-aminobutyric acid (GABA) system mediates androstenedione's cognitive impairments. Results showed that higher entorhinal cortex GAD levels were correlated with poorer Morris maze performance, regardless of androstenedione treatment. These findings suggest that androstenedione, the main hormone produced by the follicle deplete ovary, is detrimental to spatial learning, reference memory, and working memory, and that spatial reference memory performance might be related to the GABAergic system.

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Date Created
  • 2012

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Progestogens impact cognition during the transition to menopause in the rat: dissociation of progestogen- and memory- type

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.

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.

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Date Created
  • 2019

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Variations in Menopause Etiology Affect Cognitive Outcomes: How Age, Menopause Type, and Exogenous Ovarian Hormone Exposures Across the Lifespan Impact the Trajectory of Brain Aging

Description

Reproductive hormones are recognized for their diverse functions beyond reproduction itself, including a vital role in brain organization, structure, and function throughout the lifespan. From puberty to reproductive senescence, the

Reproductive hormones are recognized for their diverse functions beyond reproduction itself, including a vital role in brain organization, structure, and function throughout the lifespan. From puberty to reproductive senescence, the female is characterized by inherent responsiveness to hormonal cyclicity. For most women, a natural transition to menopause occurs in midlife, wherein the endogenous hormonal milieu undergoes significant changes and marks the end of the reproductive life stage. Although most women experience natural menopause, many women will undergo gynecological surgery during their lifetime, which can lead to an abrupt surgical menopause. It is of critical importance to better understand how endogenous and exogenous reproductive hormone exposures across the lifespan influence cognitive and brain aging, as women are at a greater risk for developing a variety of diseases after menopause, including dementia. Using rodent models, this dissertation explores how the etiology of reproductive senescence, that is, whether it is transitional or surgical, influences the female phenotype to result in divergent cognitive outcomes dependent upon a variety of factors, with an emphasis on age at the time of intervention playing a key role in brain outcomes. Furthermore, the impact of exogenous hormone therapy on cognition is evaluated in the context of surgical menopause. A novel rat model of hysterectomy is also presented, with results demonstrating for the first time that the nonpregnant uterus, which is typically considered to be a quiescent organ, may play a unique, direct role in modulating cognitive outcomes. Neurobiological mechanisms associated with reproductive hormones and aging are assessed to better recognize neural correlates underlying the observed behavior changes. The overarching goal of this dissertation was to elucidate novel factors contributing to cognitive aging outcomes in females. Collectively, the data presented herein indicate that the age at the onset of reproductive senescence has significant implications for learning and memory outcomes, and that variations in gynecological surgery can have unique, long-lasting effects on the brain and cognition. Translationally, this series of experiments moves the field forward toward the goal of improving the health and quality of life for women throughout the lifespan.

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Date Created
  • 2019