High Estrogen Levels Linked to Dementia in Elderly Men

UTRECHT, The Netherlands, July 24 -- For men ages 70 to 91, Alzheimer's disease and other dementias have been associated with high levels of endogenous estrogen, but not high levels of testosterone, researchers here reported.

The retrospective analysis of the role of endogenous hormones in elderly men emerged from analysis of data in the prospective cohort of 2,974 Japanese-American men, ages 71 to 91, in the Honolulu-Asia Aging Study. The men were dementia-free at baseline in 1991 to 1993.

The investigators undertook the analysis in the light of contradictory evidence for the effect of testosterone on cognition in older men, and the unexpected results from the Women's Health Initiative Memory Study, which found that women receiving estrogen therapy had an increased risk for cognitive impairment and dementia. So wrote Mirjam Geerling, Ph.D., at the University Medical Center Utrecht here and colleagues in an online report in the August Annals of Neurology.

Blood samples were drawn at baseline and then three more times over an average of six years for evidence of cognitive decline or dementia, using the Cognitive Abilities Screening Instrument (CASI).

A quantitative competitive immunoassay was used to measure 17-beta estradiol, while total testosterone was measured by a chemiluminescent enzyme immunoassay.

A total of 134 men developed Alzheimer's, including 40 with contributing cerebrovascular disease, while 44 developed vascular dementia, the analysis said.

Adjusting for age and other covariates, the researchers found that testosterone was not associated with a risk for dementia (using Cox regression analyses) or cognitive decline (using random coefficient analyses).

On the other hand, higher levels of estradiol were associated with an increased risk for Alzheimer's disease. With each standard deviation increase in estradiol level, the risk for Alzheimer's went up 25% (hazard ratio per standard deviation increase, 1.25; 95% CI, 1.05-1.47), Dr. Geerlings and colleagues reported.

For each standard deviation increase in estradiol level, the risk for Alzheimer's with cerebrovascular disease rose almost 20% (HR, 1.19; CI 1.02-1.38), he added.

Furthermore, compared with the lowest tertile of estradiol, men in the middle and highest tertiles scored 0.24 and 0.28 points lower on the CASI test, respectively, for each year increase in age.

In the original dementia-free cohort, the mean total testosterone level was 16.8 nmol/L; the mean bioavailable testosterone and free levels were 8.3and 0.3 nmol/L, respectively.

In these dementia-free participants, the mean total 17-beta Estradiol (E2) level was 94.9 pmol/L, and the mean bio-E2 and free-E2 levels were 62.7 and 2.2 pmol/L, respectively. With increasing testosterone levels, estradiol levels also increased, the researcher said.

The researchers hypothesized that the estradiol association with impaired cognition could be explained by increased aromatase activity in the brain, which might be associated with a neurodegenerative process.

Or, perhaps, it's the converse. Neurodegeneration as a result of early Alzheimer's could lead to increased aromatase expression and a consequent increase in estradiol production in the brain. If this hypothesis is correct, they wrote, the results of this study would suggest that relatively high levels of estradiol were a consequence of an early marker, rather than a cause of the disease. It is possible, Dr.Geerlings said, that "the disease itself disrupts hormone regulation."

According to the investigators, the strengths of the study included the large size of the cohort, that it was a prospective population-based study, and the fact that both hormones were examined in the same study.

Limitations included the loss to follow-up of 23% of the subjects, the inability to run the hormone assays in duplicate, and the fact that the levels of cognitive decline, though statistically significant, were based on group differences and could not be interpreted on an individual level.

Little consensus exists as to what constitutes a normal sex hormone profile for an aging man or what specific effect the male andropause has on cognitive function, Dr. Geerlings said. Future research, he said, should focus on defining a normal balance between these two hormones not only in the periphery, but also in the brain.

The finding of an increased risk for cognitive decline and Alzheimer's with higher levels of estradiol are similar to the recent finding in postmenopausal women, so that further studies are needed to examine the possible mechanisms for this risk.

However, Dr. Geerlings said, androgen replacement to increase testosterone levels in healthy men is not recommended.