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)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Wagster, Molly V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Arizona State University-Tempe Campus
Schools of Arts and Sciences
United States
Zip Code
Braden, B Blair; Andrews, Madeline G; Acosta, Jazmin I et al. (2016) A comparison of progestins within three classes: Differential effects on learning and memory in the aging surgically menopausal rat. Behav Brain Res :
Koebele, Stephanie V; Bimonte-Nelson, Heather A (2016) Modeling menopause: The utility of rodents in translational behavioral endocrinology research. Maturitas 87:5-17
Koebele, Stephanie V; Bimonte-Nelson, Heather A (2015) Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it? Horm Behav 74:86-104
Mennenga, Sarah E; Gerson, Julia E; Dunckley, Travis et al. (2015) Harmine treatment enhances short-term memory in old rats: Dissociation of cognition and the ability to perform the procedural requirements of maze testing. Physiol Behav 138:260-5
Braden, B Blair; Kingston, Melissa L; Koenig, Elizabeth N et al. (2015) The GABAA antagonist bicuculline attenuates progesterone-induced memory impairments in middle-aged ovariectomized rats. Front Aging Neurosci 7:149
Mennenga, Sarah E; Gerson, Julia E; Koebele, Stephanie V et al. (2015) Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity. Psychoneuroendocrinology 54:1-13
Prokai, Laszlo; Nguyen, Vien; Szarka, Szabolcs et al. (2015) The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders. Sci Transl Med 7:297ra113
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

Showing the most recent 10 out of 22 publications