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Stephen J.LurieMD, PhD, Contributing EditorIndividualAuthor
To the Editor: The negative results of ERT
reported by Dr Mulnard and colleagues1 in
patients with mild to moderate AD have to be interpreted within the context
of the mechanism of estrogen action in the central nervous system. The therapeutic
potential of estrogen did not receive a fair evaluation because the experimental
design failed to take this information into account. The sample comprised
elderly women with AD with previous hysterectomies. These women were likely
to have been profoundly deprived of estrogen, possibly for decades, because
of the oophorectomy that generally accompanies hysterectomy.
After prolonged estrogen deprivation, estrogen sensitivity of the brain
declines.2 Prolonged estrogen deprivation
also results in irreversible changes in the structure and function of estrogen
target neurons in the brain3,4
and an inability of estrogen subsequently to restore this neuronal phenotype.
If the estrogen-responsive neurons have been rendered refractory or are already
dead, it is difficult to see how estrogen treatment could be effective. For
this reason, estrogen replacement is likely to be more effective in preventing
and delaying the onset of AD5 and not in
treatment after symptoms are already clinically apparent.
It also appears counterproductive to expose the brain to unopposed estrogen
for prolonged (12 months) periods, even in women who have had a hysterectomy.
Estrogen down-regulates the levels of its own receptor in the adult brain.6 Continuous exposure to estrogen results in significantly
lower levels of estrogen binding to its receptors, gradually leading to a
decrease in neuronal responsiveness to estrogen. For this reason, all women
receiving ERT probably should be encouraged to discontinue estrogen treatment
for 3 to 4 days each month. While the treatment regimen used by the authors
may seem theoretically appealing as a means of obtaining a clear indication
of estrogen effects, in actuality, continuous estrogen exposure represents
a devastating and catastrophic environment for normally aging estrogen target
neurons, let alone neurons already affected by AD. The negative results of
the trial may, in fact, reflect the way in which the hormone was presented,
rather than lack of estrogen responsiveness per se.
Fontanarosa PB, Toran-Allerand CD. Estrogen as a Treatment for Alzheimer Disease. JAMA. 2000;284(3):307–308. doi:10.1001/jama.284.3.303
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