Variations in Hormones During Menopause - Effects on Cognitive and Brain Aging

Variations in Hormones During Menopause - Effects on Cognitive and Brain Aging Variations in Hormones During Menopause: Effects on Cognitive and Brain Aging 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. Despite insight the Ovx model yields, surgical menopause only models<13% of women. Data from the initial grant lay the foundation for testing new hypotheses regarding transitional versus surgical menopause. In women, the menopause transition relates to memory changes, and clinical and basic science studies link surgical menopause to cognitive decline. 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 relates to impaired memory. We hypothesize that androstenediones conversion to estrone impairs memory, since it is a precursor to estrone, and we found estrone-induced memory impairments. Aim 1 tests whether androstenediones 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 MPA impaired cognition in Ovx rats, and decreased hippocampal glutamic acid decarboxylase (GAD) protein, possibly a compensatory mechanism to GABAA receptor (GABAAR) stimulation. Another clinically used 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 most common clinically-used HT, Prempro (CEE+MPA); NETA was chosen because of its potential to be part of a novel combination treatment, as it is used in contraceptives and it enhanced rat cognition. In each study, we will quantify brains of cognitively characterized rats for GAD and cholinergic markers, each previously shown to relate to cognition. 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. Variations in Hormones During Menopause: Effects on Cognitive and Brain Aging