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ESTROGEN AND PREVENTION OF ALZHEIMER’S - MORE ENCOURAGING
AND DISCOURAGING EVIDENCE
(February 2004)
Whether estrogens taken postmenopausally reduce the risk of developing
Alzheimer Disease is not clear. Some studies conclude estrogens are ineffective,
but a few studies suggest estrogen use can reduce risk by as much as 50
percent. The Journal of the American Medical Association of November 6,
2002 includes a well-conducted study of 1,357 men and 1,889 women, average
age 73 to 74 years, who were followed for three years. During that time,
35 men and 88 women developed Alzheimer’s.
After age 80, women were about twice as likely to develop the disease.
The estrogen users were divided into current and past use and by duration
of use (less than three years, three to ten years, more than ten years).
These were the findings:
- Women who used for at least ten years had a 60 percent reduced risk
of developing Alzheimer’s. Those using three to ten years had a
40 percent reduction, but it was not statistically significant.
- Past use for three to ten years was associated with a 68 percent reduced
risk; past use for more than ten years reduced risk by 83 percent.
- Surprisingly, current users overall showed no protection. Indeed, those
using less than ten years seemed to have a somewhat increased risk, but
the findings were not statistically significant. Current users for more
than ten years had a 45 percent reduction that was not statistically significant.
Of the current users, more than two-thirds were taking only an estrogen
(not an estrogen-progestin combination).
The authors suggest that women need to take estrogens shortly after the
menopause to get the benefit and, according to the findings, continue
it for at least three years, preferably for more than ten years.
That study sounds quite encouraging in regard to estrogen
treatment, but most women would now have to take a combination of estrogen
and progestin because of the increased risk of uterine cancer with estrogens
alone; ordinarily, only women who have had a hysterectomy would be candidates
for estrogen alone. Unfortunately, the combination hormone treatment (estrogen
plus progestin) took a double hit in regard to Alzheimer’s and mental
function in the May 28, 2003 issue of the Journal of the American Medical
Association. Both studies were from The Women’s Health Initiative
and are well-conducted randomized trials.
In the first study, more than 4,500 women age 65 and older received either
the combination of estrogen and progestin or an inactive placebo. Over
a five-year followup period, 61 cases of dementia occurred, two-thirds
in the estrogen-progestin group. Alzheimer’s was the diagnosis in
about one-half the cases, and almost two-thirds of the Alzheimer’s
cases occurred in the estrogen-progestin group. The overall probability
of dementia in the estrogen-progestin group was doubled. The increased
risk was found in years 2, 3, and 4 of the followup, but, interestingly,
in year 5, there were double the number of new cases of dementia in the
placebo group.
The second study focused just on mental functioning of the same group
of 4,500 participants. The test of mental function was administered annually
over the five-year followup period. There was no evidence of a benefit
in mental function from the estrogen-progestin combination; however, estrogen-progestin
users showed a somewhat higher percentage of women who had a marked decrease
in mental functioning scores during the followup period (6.7% of women
assigned to estrogen-progestin versus 4.8% of women assigned to placebo).
The authors conclude the estrogen-progestin combination does not protect
women from decline in mental functioning during aging and appeared significantly
detrimental to the mental functioning of a small percentage of the women.
Commentary: On the surface, the two studies on Alzheimer’s appear
to be completely contradictory. That may not be the case. In both studies,
current users of either estrogen or the estrogen-progestin combination
showed no reduction in Alzheimer’s occurrence and, perhaps, even
some increased risk. Both studies analyzed older women and, in both, there
was at least a suggestion that longer use (five years in one study, ten
years in the other) might actually reduce the risk of Alzheimer’s.
The finding in the first study that past use reduced the risk of developing
Alzheimer’s is intriguing and suggests that early postmenopausal
use of estrogens or the combination of estrogen-progestin might, indeed,
reduce the risk of Alzheimer’s. That, of course, has to be proved.
The Women’s Health Initiative study on dementia has to be interpreted
cautiously because of the small number of cases. Clearly, any increased
risk is small. The increase in risk of dementia within two years suggests
that the estrogen-progestin combination accelerated dementia that was
already in progress and that the mechanism may be by causing small strokes;
that would be consistent with a recent study showing greater risk of strokes
after treatment with a combination of estrogen and progestin. Additional
followup is necessary because of the observation, totally ignored in the
discussion, that, in the fifth year, more cases of dementia occurred in
the placebo group, raising the possibility that long-term treatment could
actually be protective.
It is worth noting the investigators also analyzed a possible protective
effect for multivitamins. There was no evidence that taking multivitamins
offered any protection from developing Alzheimer’s.
The study on mental functioning gives no support to the notion that estrogens
protect against mental function decline during aging. The finding that
a greater percentage of women given estrogen and progestin showed marked
decline in mental function is interesting, but the difference between
placebo and estrogen-progestin is less than two percent; if valid, it
could be related to estrogen-progestin-induced small strokes.
At present, the bottom line is that we have no documented way of preventing
either mental decline with aging or Alzheimers - no hormones, no diet,
no medications that have convincingly supportive evidence.
Rating (for the whole area of estrogen-progestin treatment):
for the evidence that estrogen plus progestin treatment can cause real
harm. The investigators from the Women’s Health Initiative concluded
“the risks from estrogen plus progestin outweigh the benefits”.
They are probably correct. The harms are clear: a
modest increase in breast cancer, including invasive disease; a modest
increase in risk of heart attack and stroke; a modest increase in clots
in the legs with the potential to break off and go to the lungs, in some
cases, producing life-threatening disease.
On the other hand, there are benefits: decrease in menopausal symptoms;
increase in libido and sexual functioning; reduced risk of osteoporosis;
and maybe (inadequately documented at present) reduction in risk of bowel
cancer and adult onset diabetes; and possible (totally unproved at present)
a reduction in risk of Alzheimer’s if started shortly after the
menopause.
It should also be noted that long-term estrogen treatment (that is, estrogen
given alone) could actually protect against heart attacks. The definitive
study is now ongoing.Estrogens given alone increase the risk of breast
cancer to a modest extent and increase the risk of uterine cancer.
So, there are both harms and benefits to estrogen-progestin treatment,
(most experts believe the harms outweigh the benefits) and probably more
benefits than harms with use of estrogen alone - but, only women whose
uterus has been removed should take estrogens for an extended period (estrogens
taken for less than two years probably do not increase risk of uterine
cancer). If the current Women’s Health Initiative study shows that
estrogens taken alone are beneficial in reducing heart attack risk, that
recommendation may change and include postmenopausal women with an intact
uterus.
Zandi, P.P., et al. Hormone replacement therapy and incidence of Alzheimer
disease in older women. Journal of the American Medical Association. Vol
288 (November 6) Pgs 2123-2129. 2002.
Estrogen plus progestin and the incidence of dementia and mild cognitive
impairment in postmenopausal women.
Effect of estrogen plus progestin on global cognitive function in postmenopausal
women.
Journal of the American Medical Association. Vol 289 (May 28) Pgs 2651-2684.
2003.
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