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Of Estrogen, Alzheimer's, and Male and Female Brains


I have read both that the male brain has no estrogen receptors and that testosterone is converted to estrogen in the brain. Where does the truth lie? And what role, if any, does estrogen play in preventing Alzheimer disease in both men and women?

I have read both that the male brain has no estrogen receptors and that testosterone is converted to estrogen in the brain. Where does the truth lie? And what role, if any, does estrogen play in preventing Alzheimer disease in both men and women?

-----Malcolm Wagner, MD
Porterville, Calif

The male brain does have estrogen receptors. The profound effects of estrogen on different tissues, including the brain-in both men and women-appear to involve at least two estrogen receptor (ER) subtypes: ER-alpha and the recently identified ER-beta. ER-alpha and ER-beta messenger RNA and ER-alpha and ER-beta receptor protein are widely distributed throughout both the male and female brain. Although ER-beta seems to be more widely distributed in the female brain than in the male brain, it is nonetheless present in both sexes. Where and how the two ER subtypes mediate estrogen actions is still not known.

Because exposure to estrogen is necessary for many brain functions, testosterone is converted metabolically in the brain and in other organs to estrogen through the actions of an enzyme called aromatase (estrogen synthase). The principal action of aromatase is the transformation of testosterone into estradiol and of androstenedione into estrone. Aromatase can be found in many tissues, including the gonads, brain, adipose tissue, placenta, blood vessels, skin, bone, and endometrium, as well as in uterine fibroids, endometriosis tissue, and breast and endometrial neoplasia.

Estrogen may well play a role in preventing Alzheimer disease in women. Estrogen influences language skills, mood, attention, and a number of other functions, in addition to memory. Estrogen receptors are present in several regions of the brain, including the hippocampus, that when activated by estrogen, initiate processes that are involved in memory and other cognitive functions. In addition, estrogen may raise the levels of certain neurotransmitters, including acetylcholine (implicated in memory), serotonin (implicated in mood), noradrenaline (implicated in mood and other autonomic functions), and dopamine (implicated in motor coordination).

The Women's Health Initiative (WHI) and other studies, because they were not properly carried out, generated confusing data.1,2 (WHI flaws include initiation of treatment too long after menopause, use of non-physiologic horse estrogens and a synthetic progestogen, and continuous exposure of study participants to these hormones for 5 years.) However, a number of epidemiological studies3-7 have indicated that estrogen therapy may reduce the risk of Alzheimer disease in healthy women in whom the disease has not been previously diagnosed. Moreover, the cognitive deficits associated with the absence of estrogen following menopause strongly suggest that estrogen, when replaced in the perimenopause or at the onset of menopause, may have a role in preventing Alzheimer disease in healthy aging women. However, women who start taking estrogen (with or without a progestin) after the age of 65 years appear to be at greater risk for dementia, including Alzheimer disease.

With regard to estrogen and Alzheimer disease in men, little is known. Some highly controversial recent research has suggested that relatively high blood levels of estrogen might boost the risk of Alzheimer disease in elderly men but that levels of circulating testosterone seem not to affect the risk.8 However, this study has not been replicated and is generally viewed with considerable skepticism.

-----Dominique Toran-Allerand, MD, ScD
Professor of Pathology & Cell Biology and Neurology
Columbia University College of Physicians & Surgeons
New York




Mandavilli A. Hormone in the hot seat. Nat Med. 2006;12:8-9.


Toran-Allerand CD. Reply to "Hormone in the hot seat." Nat Med. 2006;12: 379-380.


Sohrabji F. Guarding the blood-brain barrier: a role for estrogen in the etiology of neurodegenerative disease. Gene Expr. 2007;13:311-319.


Burger HG. WHI risks: any relevance to menopause management? Maturitas. 2007;57:6-10.


Alzheimer research forum live discussion: not dead yet: estrogen deserves another chance. J Alzheimers Dis. 2006;10:121-130.


Chen S, Nilsen J, Brinton RD. Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: therapeutic implications. Endocrinology. 2006;147:5303-5313.


Maki PM. Potential importance of early initiation of hormone therapy for cognitive benefit. Menopause. 2006;13:6-7.


Geerlings MI, Strozyk D, Masaki K, et al. Endogenous sex hormones, cognitive decline, and future dementia in old men. Ann Neurol. 2006;60:346-355.

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