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Other Agents
Estrogen
This agent is not currently US-FDA approved for the prevention or treatment of AD.
Proposed mechanism of action in AD
Multiple
mechanisms - antioxidant and anti-inflammatory effects may enhance the growth
of select neurons that release acetylcholine. Postulated to enhance growth of
neurons in the basal forebrain, and may prevent the formation of amyloid plaques
by facilitating degradation of APP by a secretase into soluble products.
What is the Evidence?
The research of estrogen and AD in postmenopausal women comes from two different perspectives 1) estrogen as AD prophylaxis and 2) estrogen for the treatment of AD-- related cognitive impairment. Two large prospective observational studies reported reduced odds of developing AD among women who reported ever using any type or dose of estrogen compared with those never using estrogen. Tang and colleagues22 reported that age at onset of Alzheimer's disease was significantly later in women who had taken estrogen than in those who did not and the relative risk of the disease was significantly reduced (5.8% of estrogen users vs. 16.3% of nonusers developed AD during the study period), even after adjustment for differences in education, ethnic origin, and apolipoprotein-e genotype. Use of estrogen longer than one year was associated with even greater risk reduction.
Many have questioned the conclusions that have been drawn from the research to date — a number of the studies published have been uncontrolled, non-blinded, and of short duration. Some studies did not adjust for educational background — higher levels of education are thought to be associated with a lower risk of AD. The effect of racial or ethical differences on efficacy has also not been explored; Caucasian women are the most likely to receive estrogen replacement therapy currently. In addition, drawing definitive conclusions about the preferred estrogen formulation, dose, and length of therapy that is most effective for AD prophylaxis cannot be definitively stated at this time. Because of these types of questions and others, Yaffe and colleagues23 recommended against the use of estrogen to prevent or treat AD following a meta-analysis of published studies.
A fairly recently published study24 reported negative results for the use of estrogen to treat AD related symptoms. A double-blind, placebo-controlled trial of elderly women diagnosed with mild to moderate AD, reported that women randomized to receive 0.625 mg or 1.25 mg of conjugated estrogen per day had no improvement in global, cognitive, or functional outcomes over one year as compared with the group randomized to placebo.
The Women’s Health Initiative Memory Study (WHIMS), the largest and most extensive study to date (published in May 2003), found that the combination of estrogen and progestin did not prevent dementia or slow the progression towards dementia. In fact, the combination increased the risk of dementia in women 65 years of age and older. This effect was found to be sustained during the length of treatment.24a. Critics of the study recommend that hormone therapy should be used only temporarily for the relief of menopausal symptoms.24b
Most common adverse effects
As associated with estrogen replacement therapy for other indications - nausea, breast enlargement/pain, migraine, thromboembolism (increased risk in cigarette smokers). Possible increased risk of some types of gynecological cancers (breast, endometrial) should be discussed with patient prior to commencing therapy.