In this renewal, we hypothesize that type of menopause and associated hormone changes relate to cognitive responsiveness to hormone therapy (HT). The initial grant used rats to assess variations in HTs with surgical menopause (Ovx), and transitional menopause using 4-vinylcyclohexene diepoxide (VCD). VCD-treated rats undergo ovarian failure;follicles and estrogens deplete, androgens become unopposed, and gonadotropins increase, a profile resembling transitionally menopausal women. Data from the initial grant lay the foundation for testing new hypotheses regarding transitional versus surgical menopause. In women, both transitional and surgical menopause have been related to memory changes. However, most rodent studies have tested cognitive effects after Ovx. Despite insight rat models yield regarding surgical hormone loss, surgical menopause models <13% of women. Here, we examine how different menopause types impact cognitive and brain aging, and aim to determine optimal parameters for the menopause transition and HT.
Four aims are proposed, using rats:
Aim 1) We found that androstenedione (Andro) relates to impaired memory. Since Andro is directly converted to estrone, and we have shown estrone-induced memory impairments, we hypothesize that Andro's conversion to estrone impairs memory.
Aim 1 tests whether Andro's conversion to estrogens, or androgen receptor stimulation, underlies its cognitive detriments.
Aim 2) Clinical studies support a critical window during which HT benefits cognition. Rat studies support this;however, these studies used Ovx rats, and gave only 17?-estradiol (E2). E2 is naturally-occurring in women and rats, but is present only in trace amounts in conjugated equine estrogens (CEE) HT. In rats, we found that CEE enhanced memory after surgical menopause, but impaired memory after transitional menopause when given after follicle depletion.
Aim 2 tests cognitive change during and after different types of menopause, and whether giving CEE before or during follicular depletion impairs memory, as compared to E2.
Aim 3) We found that the HT progestin medroxyprogesterone acetate (MPA) impaired cognition in Ovx rats, and decreased hippocampal glutamic acid decarboxylase (GAD) protein, possibly compensating for GABAA receptor (GABAAR) stimulation. Another progestin, norethindrone acetate (NETA), enhanced memory in Ovx rats. We hypothesize that NETA antagonizes the GABAAR, reducing GABAAR-mediated inhibition, enhancing memory.
Aim 3 will determine whether the GABAergic system underlies MPA- and NETA-induced memory changes.
Aim 4). This aim tests whether MPA or NETA impacts the effects of CEE or E2. MPA was chosen for this aim to test the HT Prempro (CEE+MPA);NETA was chosen due to its potential to be part of a novel combination HT, as it is used in contraceptives and it enhanced rat cognition. In each study, we will quantify GAD and cholinergic markers, each previously shown to relate to cognition, in brains of cognitively characterized rats. Multiple regression and growth modeling will test relations between the GABAergic system, cholinergic system, hormone levels, and cognition in both menopause models. This work will yield insight into cognitive effects of the menopause transition, variations in menopause type and HTs, and related mechanisms.

Public Health Relevance

The overarching goal of our continued program of research is to use the rat model to understand how menopause and related ovarian hormone changes impact cognitive and brain aging, and to use this information to determine optimal parameters of the menopause transition and hormone therapies. In this renewal, we systematically assess the trajectory of hormonal and cognitive change with transitional versus surgical menopause, and test whether hormone therapy effects are altered by background hormone milieu, menopause type, type of estrogen and progestin, and temporal period since menopause initiation. A key goal is to determine an optimal window of sensitivity for hormone therapy, for both transitional and surgical menopause, as well as gain understanding of underlying mechanisms of the cognitive effects.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Wagster, Molly V
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Arizona State University-Tempe Campus
Schools of Arts and Sciences
United States
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Mennenga, Sarah E; Koebele, Stephanie V; Mousa, Abeer A et al. (2015) Pharmacological blockade of the aromatase enzyme, but not the androgen receptor, reverses androstenedione-induced cognitive impairments in young surgically menopausal rats. Steroids 99:16-25
Talboom, Joshua S; West, Stephen G; Engler-Chiurazzi, Elizabeth B et al. (2014) Learning to remember: cognitive training-induced attenuation of age-related memory decline depends on sex and cognitive demand, and can transfer to untrained cognitive domains. Neurobiol Aging 35:2791-802
Acosta, J I; Hiroi, R; Camp, B W et al. (2013) An update on the cognitive impact of clinically-used hormone therapies in the female rat: models, mazes, and mechanisms. Brain Res 1514:18-39
Mennenga, S E; Bimonte-Nelson, H A (2013) Translational cognitive endocrinology: designing rodent experiments with the goal to ultimately enhance cognitive health in women. Brain Res 1514:50-62
Braden, B Blair; Garcia, Alexandra N; Mennenga, Sarah E et al. (2011) Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time. Psychopharmacology (Berl) 218:405-18
Engler-Chiurazzi, Elizabeth; Tsang, Candy; Nonnenmacher, Sean et al. (2011) Tonic Premarin dose-dependently enhances memory, affects neurotrophin protein levels and alters gene expression in middle-aged rats. Neurobiol Aging 32:680-97
Acosta, Jazmin I; Mayer, Loretta P; Braden, B Blair et al. (2010) The cognitive effects of conjugated equine estrogens depend on whether menopause etiology is transitional or surgical. Endocrinology 151:3795-804
Talboom, Joshua S; Engler-Chiurazzi, Elizabeth B; Whiteaker, Paul et al. (2010) A component of Premarin(®) enhances multiple cognitive functions and influences nicotinic receptor expression. Horm Behav 58:917-28
Braden, B Blair; Talboom, Joshua S; Crain, Ian D et al. (2010) Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats. Neurobiol Learn Mem 93:444-53
Bimonte-Nelson, Heather A; Acosta, Jazmin I; Talboom, Joshua S (2010) Neuroscientists as cartographers: mapping the crossroads of gonadal hormones, memory and age using animal models. Molecules 15:6050-105

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