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Imaging $hows HRT Affects Key Brain Centers.

NEW YORK -- Magnetic resonance and positron emission tomographic imaging studies show clearly that exogenous estrogen as well as raloxifene have definite metabolic effects on specific brain regions in postmenopausal women.

"Estrogen has profound effect on the brain, not just the reproductive tract. These are direct effects on key brain centers," Dr. Declan Murphy said at the annual meeting of the North American Menopause Society.

Dr. Murphy, a psychiatrist in the department of physiological medicine, King's College, London, and his associates used magnetic resonance spectroscopy to compare neuronal density and myelin sheath breakdown in 21 postmenopausal women receiving conjugated equine estrogen (CEE) replacement therapy, 19 postmenopausal estrogen-deficient women, and 25 young, premenopausal control.

The study, sponsored by Wyeth-Ayerst Pharmaceuticals, is part of an ongoing research effort to define estrogenic effects in the central nervous system and to uncover mechanisms that might explain clinical observations that hormone replacement therapy (HRT) increases cognitive function and memory, reduces risk of Alzheimer's disease (AD), and attenuates symptoms in women already diagnosed with the disorder.

Dr. Murphy's group assessed n-acetyl aspartate, a marker for neuron density, and choline, a marker for myelin sheath degeneration in the hippocampus and the temporal and parietal lobes; these are the parts of the brain that suffer the greatest damage in patients with AD.

The women were matched for intelligence quotient and socioeconomic status.

The mean age of the study participants was 26 years in the premenopausal control group, 64 years in the postmenopausal estrogen-deficient group, and 63 years in the HRT group.

The findings were striking. Compared with the premenopausal controls, the postmenopausal women not taking estrogen showed consistently decreased n-acetyl aspartate and increased choline in the brain regions studied. This suggests a clear pattern of age-associated neural degeneration.

The postmenopausal women taking CEE showed no differences in parietal, temporal, or hippocampal choline levels and only minimal changes in n-acetyl aspartate, compared with younger subjects.

The investigators also looked at the serotoninergic probe D-fenfluramine, the response to which tends to decline with age. The postmenopausal women who weren't on ERT had a blunted response, compared with the premenopausal women. Those on ERT showed no change in D-fenfluramine response.

"HRT significantly modulates aging of brain regions affected in AD and may protect against age-related decreases in neuron density and increases in membrane turnover," Dr. Murphy concluded.

These findings were corroborated in a separate study, also sponsored by Wyeth-Ayerst, and presented by John Metz, Ph.D., chief scientific officer for MIICRO Inc., a Chicago-based research firm specializing in functional neuroimaging.

Using positron-emission tomography with fluorodeoxyglucose as the radioactive tracer, Dr. Metz assessed changes in cerebral glucose metabolism in eight women who had had a hysterectomy all of whom were over age 60.

The patients were treated in serial 2-week periods with CEE (0.625 mg/day), placebo, and raloxifene (60 mg/day). PET scans were obtained after each treatment period, and each woman served as her own control.

Dr. Metz noted that these doses are standard for postmenopausal HRT. He added that PET scanning with fluorodeoxyglucose detects actual metabolic changes in the tissues themselves.

Before and after each scan, the women were asked to complete a Profile of Mood States (POMS) questionnaire. For the first 30 minutes after injection of the tracer, they worked at a standardized visual monitoring test to ensure all were in a comparable state of mental alertness before scanning.

Both drugs had clear effects on cerebral glucose metabolism, but the patterns differed considerably For CEE, there Were "striking decreases in cerebral metabolism in left frontal areas and striking increases in the right frontal areas," Dr. Metz said.

Raloxifene showed metabolic increases in the right frontal area that were, if anything, more prominent than those seen with CEE. But raloxifene did not induce the metabolic decreases in left frontal cortex seen with CEE. He stressed that all patients in the study were right-handed, eliminating the possibility of neurologic differences based on handedness.

"One of the areas of primary difference between the two drugs was in the left frontal cortex, where CEE induced a statistically significant metabolic decrease, but raloxifene showed no effect. In the corresponding area on the right side, both drugs showed an effect. In the thalamus, you saw an effect with raloxifene, but nothing comparable with Premarin."

The metabolic effect sizes were on the order of 10%-15%, "comparable in magnitude to what you see with psychotropic drugs like fluoxetine, paroxetine, venlafaxine, pimozide, amphetamine, and nimodipine. But the distribution is very different," Dr. Metz said in an interview.

While PET scans suggest the psychological and behavioral effects of the two drugs may be different, Dr. Metz stressed that the study was not designed to test behavioral changes and that it is premature to posit psychological or behavioral effects.

There were no spontaneous reports suggesting any of the women had treatment-related mood or behavioral changes, he pointed out.
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Comment:Imaging $hows HRT Affects Key Brain Centers.
Publication:Family Practice News
Geographic Code:1USA
Date:Feb 15, 2000
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