Tuesday, December 4, 2012

What is Link between Estrogen Replacement Therapy and Risk of Azheimer’s in Postmenopausal Women?

Some animal studies have shown that estrogen has several protective effects on the brain, including increased cerebral blood flow, stimulation of the cholinergic neurotransmitter system, acting as a co-factor with nerve growth factors, prevention of neural atrophy, and reversal of damage caused by Glucocorticoids. There is also some epidemiological evidence suggesting that estrogen replacement therapy in post-menopausal women may have a protective effect. A meta-analysis of such studies found that estrogen reduced the risk of AD by around 30%. However, women who take estrogen tend to be better educated and may differ in other ways. So, education may itself be protective. Randomized trials are needed to establish whether there is an effect. Currently in the United States, the Women's Health Initiative Memory Study is looking at the effects of estrogen replacement therapy on the incidence of dementia in over 8000 women.

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Positive Effects of Estrogen Replacement Therapy on AD

Postmenopausal women who receive ERT are 40-60% less likely to be diagnosed with Alzheimer's. Estrogen Replacement Therapy (ERT) has been found to both reduce the risk of developing AD and slow its progression in many studies. Women who receive ERT perform better on cognitive tasks than untreated women, which suggest that estrogen lessens the severity of AD. A study by Asthana et al., (1999) looked at the effects of 17 beta-estradiol, the most potent form of estrogen, on several cognitive domains typically impaired in patients with AD. Subjects, all women with mild-moderate AD were randomly placed in one of two groups. The first group received 0.05 mg/day of 17-b-estradiol and the second group received a placebo, both via a skin patch for 8 weeks. Before treatment, and then every two to three weeks following treatment, a battery of tests were administered which targeted several cognitive domains, including memory, attention, and language that are characteristically impaired by AD.

It was found that treatment with estradiol improved aspects of attention and verbal memory, but did not improve language. The authors speculate that the beneficial effects of estrogen may be restricted to certain cognitive domains. Moreover, estrogen-induced enhancements in both memory and attention diminished when treatment was terminated. The results indicate that short-term administration of estrogen has the potential to enhance cognition for postmenopausal women. Numerous other studies have found similar results.

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Long-term vs. Short-term Estrogen Replacement Therapy

Long-Term ERT is Good

In other study on the topic it was reported that hormone replacement therapy (HRT) may prevent Alzheimer's disease in women, but the benefit accrues only when the therapy lasts 10 years or more. No protective benefit was seen from HRT that had not begun at least several years prior to the onset of mental decline.

"Our findings, along with other recent work, suggest that HRT may be effective for the primary prevention of Alzheimer's disease--if not for its treatment," write the authors, from the Department of Veterans Affairs (VA) Puget Sound Health Care System, Johns Hopkins University, Duke University, University of Washington and Banner Health System in Phoenix.

The researchers compared the rates of Alzheimer's disease between 1995 and 2000 in 1,357 men and 1,889 women, all elderly, in Cache County, Utah. They found that women who had taken HRT for at least a decade were 2.5 times less likely than women who had never used HRT to develop Alzheimer's. This lower rate among the long-term HRT users was comparable to that of the men in the study.

The study, funded by the National Institutes of Health, also looked at the use of calcium supplements and multivitamins to see if these had a preventive effect, but none was found. But the researchers do not rule out the possibility that the lower Alzheimer's rate among the long-term HRT users was due to some factor other than the HRT.

HRT, using estrogen and progestin, was the treatment of choice until very recently for millions of menopausal women seeking to halt the bone loss that causes osteoporosis, and to help with other symptoms, such as hot flashes and mood swings. Based on brain-imaging studies, the therapy had also been thought to slow mental decline and stall the onset of Alzheimer's disease, although clinical trials on this issue had produced mixed results. The therapy was associated with a small increase in the risk for uterine and breast cancer, but the benefits were thought to outweigh the risks.

This belief was challenged in July 2002 when the National Heart, Lung and Blood Institute stopped a major clinical trial after finding significantly increased rates of breast cancer and cardiovascular disease in women taking HRT, compared to women on placebo. Soon after, a report in the British journal The Lancet showed an increased risk of breast cancer, stroke and blood clots for women on HRT.

The new JAMA study shows that HRT may in fact help prevent mental decline, but raises questions about the window of effectiveness. In an editorial accompanying the research report, Drs. Susan Resnick and Victor Henderson point out that the results offer hope as to a brain-protective effect of HRT, but show it may be difficult to determine the best timing of treatment.

According to the authors: "A new finding in this study is an apparent limited window of time during which sustained HRT exposure seems to reduce the risk of Alzheimer's disease. We found that, in contrast with [use earlier in life], HRT exposures within 10 years of Alzheimer's onset yielded little, if any, apparent benefit." They theorize that estrogen, like non-steroidal anti-inflammatory drugs (NSAIDS), may exert a protective effect against Alzheimer's only before extensive damage occurs in the brain.

Long-term ERT is Bad

Completely opposite results were received in a different respectable study from researchers at the University of Arizona, when it was shown that postmenopausal women with Alzheimer's disease who undergo long-term estrogen replacement therapy (ERT) may make their memory loss worse.

The study used female rats to study the effect of ERT on memory. The findings are transferable to humans because the conditions reproduced in the study are analogous to that of postmenopausal women who have existing brain inflammation caused by a neurodegenerative illness like Alzheimer's or by head trauma and then choose to undergo long-term ERT.

G. L. Wenk, Ph.D., and colleagues at the Arizona Research Laboratories at the University of Arizona had 40 rats perform a water maze task to look at the interaction of two conditions known to exist within the brains of female Alzheimer's patients, 1) the presence of chronic neuroinflammation, and 2) having too much or not enough estrogen. Both of these conditions are likely to precede the onset of symptoms associated with Alzheimer's. As part of the experiment, some of the rats were ovariectomized (had their ovaries surgically removed) to mimic the changes seen in postmenopausal women. Aged rats do not undergo an ovarian failure but ovariectomized rats experience both the ovarian failure and the alterations in gene expression within the hypothalamus that appear in women in menopause.

The researchers found that the removal of the rats' ovaries was not enough to impair performance in the water maze task. However, the introduction of either sustained estrogen replacement therapy or chronic brain inflammation did impair memory performance in the ovariectomized rats. Furthermore, the combined occurrence of both conditions (sustained estrogen replacement therapy and longer term brain inflammation) significantly worsened cognitive performance beyond that produced by either condition alone.

"A therapy designed to mimic the natural cycle of hormone fluctuation may provide a more effective therapy to slow the progression of Alzheimer's disease in postmenopausal women," according to the researchers. They add that their findings were confirmed by a 2000 study in the Journal of the American Medical Association (JAMA) involving a long term, placebo-controlled study that examined the effects of estrogen replacement therapy on cognitive function in large groups of women with mild to moderate Alzheimer's. The effects of ERT were initially beneficial, but the performance of women receiving sustained ERT declined more than that of women receiving the placebo treatment.

"When considered together, the results of this and other clinical trials suggest a pattern of beneficial effects on cognitive function after relatively short-term ERT; however, this beneficial effect is attenuated, and possibly reversed, after much longer treatment regimens," say the authors. "Although a comparison between humans and rodents must be made with caution, it is interesting that continuous long-term estrogen therapy immediately after ovariectomy in the present study parallels the detrimental cognitive effect seen in postmenopausal Alzheimer's disease women who receive continuous, long-term ERT decades after the onset of menopause."

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Negative Effects of Estrogen Replacement Therapy on AD

And going further to question the positive effects of ERD on decreased AD risk for postmenopausal women, another two studies showed that commonly prescribed forms of postmenopausal hormone therapy (with no reference on the time of this treatment) may slightly accelerate the loss of brain tissue in women 65 and older beyond what normally occurs with aging. Both papers report on analyses from the Women's Health Initiative Memory Study, a sub-study of the National Institutes of Health's (NIH's) landmark Women's Health Initiative (WHI) hormone therapy clinical trials.

Previous studies showed that hormone therapy in the form of conjugated equine estrogens (CEEs), with or without added progestin, increased the likelihood that older women would have difficulty with thinking skills and memory and experience dementia or cognitive impairment. Because these drugs are known to increase women's risk for strokes, it had been assumed that these drugs adversely affected women's memory by increasing the rates of "silent strokes" and brain lesions, changes in tissue that occur when blood flow to an area of the brain is reduced or blocked.

Instead, investigators found that the volumes of brain lesions were not significantly increased among women prescribed hormone therapy, but that the total volumes of brain tissue in regions critical to memory were slightly smaller.

In the first of the two studies, a research team led by Laura H. Coker, Ph.D., of Wake Forest University Baptist Medical Center, did not find support for the hypothesis that hormone therapy was linked to increases in small vascular lesions in the brain or silent strokes.

"We asked," Coker said, "what is the most likely mechanism of the negative effect of hormone therapy on thinking and memory? We thought it was silent cerebrovascular disease. So we designed a study to obtain MRI scans of women's brains to look for increased volumes of brain lesions among those participants who had taken hormone therapy, compared to those who had not." More than 1,400 women, ages 71 to 89, who had previously participated in the WHI hormone therapy studies for an average of four to six years, participated. "This is not what we expected to find," Coker said.

In the companion paper, researchers report that the women who had taken hormone therapy had slightly smaller brain volumes in two critical areas of the brain: the frontal lobe and the hippocampus. Both areas are involved in thinking and memory skills, and loss of volume in the hippocampus is a risk factor for dementia.

"Our findings suggest one possible explanation for the increased risk for dementia in older women who had previously taken post-menopausal hormone therapy in the Women's Health Initiative Memory Study," said Susan Resnick, Ph.D., of the National Institute on Aging, which is part of NIH. Resnick was the lead author for the second paper. "Our findings suggest that hormone therapy in older post-menopausal women has a negative effect on brain structures important in maintaining normal memory functioning. However, this negative effect was most pronounced in women who already may have had some memory problems before using hormone therapy, suggesting that the therapy may have accelerated a neurodegenerative disease process that had already begun."

Current recommendations are that hormone therapy be used only if needed to treat menopausal symptoms, and taken at the lowest dose and for the shortest time possible to relieve symptoms, which generally appear in women age 48 to 55. Women age 65 and older should not begin hormone therapy because the risks outweigh possible benefits. The new information suggests that older women who were already having some cognitive problems at the time they began hormone therapy are most at risk for negative effects on the brain. However, the findings also suggest that women who were healthy at the time they began hormone therapy were less likely to have any adverse effects on the brain, Resnick said.

Researchers will next set out to determine whether the negative effects of hormone therapy on brain volumes continue over time through follow-up MRI studies of the women studied. In addition, it will be important to examine younger women who took hormone therapy closer to the timing of menopause to determine whether they show a different pattern of effects on cognitive function and brain structure, Coker said.

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As you may guess, the studies provide totally controversial results on the causal link between ERT and AD, while the data for potential negative impact is piling up. ERT should be considered by affected women when the devastated effects of menopausal symptoms are overwhelming, and the decision to undergo the related treatment should be well considered and overly discussed with your primary physician.

And, reflecting this approach, the U.S. Preventive Services Task Force October 2012 confirmed its earlier recommendation against long-term hormone replacement therapy for menopausal women, saying its risks outweigh the benefits for most patients.

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