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July 19, 2000

Estrogen as a Treatment for Alzheimer Disease

Author Affiliations

Stephen J.LurieMD, PhD, Contributing EditorIndividualAuthor

JAMA. 2000;284(3):307-308. doi:10.1001/jama.284.3.303

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.

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