Variations in Hormone Therapy: Effects on Cognition and Markers on Brain Aging

Project: Research project

Description

The broad goal of this grant is to determine which variables influence whether hormone therapy (HT) acts as a protectant or a risk factor for cognitive functioning and brain aging. Ovarian hormone loss due to menopause has been linked with cognitive decline and increased risk of Alzheimer's disease. While there is evidence that HT decreases such effects, recent clinical trials failed to find positive effects, and some found detrimental effects. However, abundant basic science evidence suggests that estrogens exert beneficial effects on cognition and neurobiological variables related to memory. Hence, despite the null and negative findings in some clinical trials, the numerous animal and clinical studies showing positive effects of hormone treatment begs the question of what factors determine whether HT acts as a protectant or a risk factor for brain functioning and brain aging. We use the rat to systematically evaluate variations in current HTs, testing whether they are beneficial or detrimental to cognition, neurotrophins, and microtubule associated protein 2 (MAP2) and synaptophysin levels, which are markers of synaptic plasticity. Based on prior research, what factors might influence the outcome of estrogen replacement? 1. Dose and type of estrogen. Specific Aim I compares the dose-specific effects of three estrogen preparations: the most commonly used estrogen in animal studies (estradiol), the most commonly used estrogen therapy in the clinic (Premarin, or conjugated equine estrogens), and a promising estrogen therapy that has positive effects on menopausal symptoms (estriol). Neither Premarin nor estriol have been tested for cognition in the rodent. 2. Unopposed vs. opposed estrogen treatment. We recently found that progesterone, given alone, is detrimental to spatial memory, and that tonic estradiol replacement enhances memory and alters neurotrophins in cognitive brain regions in aged rats. When progesterone was added to estradiol treatment, the cognitive and neurotrophin alterations due to estradiol were completely reversed. Specific Aim 2 tests whether the three most common clinically-used progestins alter cognition and the brain when given alone, and counteract estrogen-induced alterations when given as part of combination HT. Further, we will also test a mechanism of progesterone's effects on cognition. We hypothesize that progesterone is impairing memory by increasing GABAA stimulation, in turn resulting in greater hippocampal inhibition thereby impairing memory. By using GABAA antagonists and agonists as well as metabolites of progesterone that mediate the actions of GABA on the GABAA receptor, Specific Aim 3 will test progesterone's negative effects on cognition.

Description

The broad goal of this grant is to determine which variables influence whether hormone therapy acts as a protectant or a risk factor for cognitive functioning and brain aging. Ovarian hormone loss due to menopause has been linked with cognitive decline and increased risk of Alzheimer's disease. While there is evidence that hormone replacement decreases such effects, recent clinical trials failed to find positive effects, and some found detrimental effects. However, abundant basic science evidence suggests that estrogens exert beneficial effects on cognition and neurobiological variables related to memory. Hence, despite the null and negative findings in some clinical trials, the numerous animal and clinical studies showing positive effects of hormone treatment begs the question of what factors determine whether hormone therapy acts as a protectant or a risk factor for brain functioning and brain aging. We will use the rat model to systematically evaluate variations in current hormone therapies, testing whether they are beneficial or detrimental to cognition, neurotrophins, and microtubule associated protein 2 (MAP2) and synaptophysin levels, markers of synaptic plasticity. Based on prior research, what factors might influence the outcome of estrogen replacement? 1. Dose and type of estrogen.Drop
StatusFinished
Effective start/end date9/1/078/31/13

Funding

  • HHS: National Institutes of Health (NIH): $1,465,201.00

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Cognition
Hormones
Estrogens
Brain
Progesterone
Nerve Growth Factors
Conjugated (USP) Estrogens
Therapeutics
Estradiol
Clinical Trials
Estriol
Synaptophysin
Neuronal Plasticity
Estrogen Replacement Therapy
Microtubule-Associated Proteins
Organized Financing
Menopause
Alzheimer Disease
GABA-A Receptor Agonists
GABA-A Receptor Antagonists