Epidemiological studies have suggested that estrogen replacement therapy (ERT) may reduce the risk of developing Alzheimer?s disease and may slow cognitive decline in demented women. In women without dementia, higher serum estradiol levels have been associated with better memory performance, although there is also evidence that progestins may actually attenuate or reverse many cognitive benefits of estrogens. Neither the mechanisms by which ERT may produce beneficial cognitive effects nor the manner by which progestins could moderate the beneficial effects of estrogen are well-understood. Recent scientific interest has been directed toward investigating estrogen?s effects on glucose transport and utilization within the central nervous system (CNS). Given that glucose is the primary energy source of the brain, that impaired glucose transport promotes ATP depletion and compromise of a number of energy-dependent processes (particularly in synapses), and that estrogen exerts widespread cellular and behavioral effects on the CNS, the relationships between estrogen, glucose metabolism, and CNS functioning appear particularly compelling. It is not known whether ERT may produce an increase in global cerebral metabolic rate of glucose utilization (CMRglc) in humans or whether there are specific regional CMRglc increases that may modulate enhanced cognitive functioning. In this study, we propose a three-arm, randomized, double blind study of the effects of a 3-month intervention period of conjugated equine estrogen (CEE) alone, CEE plus medroxyprogesterone acetate (MPA), and placebo on modulation of global and regional CMRglc in healthy, cognitively intact postmenopausal women aged 60 to 65 years, inclusive. All participants will undergo pre- and post-intervention dynamic FDG-PET studies of CMRglc. The two intervention groups will include 3 women without and 3 with a uterus, respectively, and the placebo group will contain 3 with a uterus. We will use FDG PET to accomplish the following specific aims: 1) To determine whether ERT produces increases in global and/or regional CMRglc after 3 months by comparing hysterectomized women on ERT versus placebo; 2) To determine whether progestin-estrogen replacement therapy (PERT) produces increases in global and/or regional CMRglc after 3 months by comparing women with a uterus on PERT versus placebo; and 3) To determine whether PERT produces a different pattern or magnitude of global and/or regional CMRglc after 3 months compared to ERT. Secondary specific aims are: 1) To use dynamic PET imaging to ascertain whether either ERT or PERT may promote either glucose transport or phosphorylation by determining kinetic rate constants, and 2) To determine if cortical metabolic changes seen following ERT or PERT correlate with general or specific cognitive changes.
