[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
Purchase Options:
[Skip to Content Landing]
Citations 0
Letters
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.

References
1.
Mulnard  RACotman  CWKawas  C  et al.  Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease.  JAMA. 2000;283:1007-1015.Google Scholar
2.
Clark  CRMacLusky  NJParsons  BNaftolin  F Effects of estrogen deprivation on brain estrogen and progestin receptor levels and the activation of female sexual behavior.  Horm Behav. 1981;15:289-298.Google Scholar
3.
Crespo  DCos  SFernandez-Viadero  CGonzalez  C Ultrastructural changes in hypothalamic supraoptic nucleus neurons of ovariectomized estrogen-deprived young rats.  Neurosci Lett. 1991;133:253-256.Google Scholar
4.
Simpkins  JWGreen  PSGridley  KESingh  Mde Fiebre  NCRajakumar  G Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer disease.  Am J Med. 1997;103:19S-25S.Google Scholar
5.
Tang  MXJacobs  DStem  Y  et al.  Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease.  Lancet. 1996;348:429-432.Google Scholar
6.
Brown  TJScherz  BHochberg  RBMacLusky  NJ Regulation of estrogen receptor concentrations in the rat brain.  Neuroendocrinology. 1996;63:53-60.Google Scholar
×