Timing of Hormone Therapy May Affect Alzheimer’s Prevention

  • April 1, 2013
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Timing of Hormone Therapy May Affect Alzheimer’s Prevention - HRT San Antonio

A new study further supports the theory of a critical window around the time of menopause during which initiation of hormone therapy (HT) protects against Alzheimer’s disease (AD).

The study found that the relationship between HT and AD not only varies with timing of the therapy initiation but also with its type and duration. Women who started taking HT — either unopposed or opposed (estrogen combined with progestin) — within 5 years of menopause had a 30% reduced risk of developing AD. That risk was further reduced if they took the hormones for 10 or more years.

“The data we report suggest that the hypothesis that the timing is very important has some merit,” said study author Peter P. Zandi, PhD, Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.

However, this single study does not provide enough clear evidence to change behaviors surrounding hormone use, he said. “Unfortunately, there isn’t a concrete answer for women who are trying to decide what to do about hormone replacement therapy because there is still this ambiguity in the field.”

Although previous observational studies linked hormone use to lower AD risk, the Women’s Health Initiative Memory Study (WHIMS), which enrolled women older than age 65 years, found an increased risk for dementia with hormone use.

“We should continue to look at this relationship to see if there is some explanation for the different results, so we can capitalize on that to design interventions that really help women,” said Dr. Zandi.

The study is published online October 24 in Neurology.

Cache County Study

The results are from the latest wave of the Cache County Study (CCS), a prospective observational study of residents of Cache County, Utah, who were 65 years of age or older as of January 1, 1995 (wave I). Participants who did not have dementia at baseline were followed up in 1998-1999 (wave II), 2002-2003 (wave III), and 2005-2006 (wave IV). At each wave, participants were evaluated for dementia and completed a battery of neuropsychological tests.

The current analysis involved 1769 women who completed the Women’s Health Questionnaire (WHQ) between waves I and II. The WHQ included questions about reproductive history, use of HT therapy, age at initiation of HT, and duration of HT.

Researchers followed the participants for an average of 7 years, during which time 176 received a diagnosis of definite, probable, or possible AD. This included 87 of the 1105 women who had taken HT and 89 of the 663 who didn’t use HT.

The study found that HT initiated within 5 years of menopause was associated with significantly lower AD risk (adjusted hazard ratio [aHR], 0.70; 95% confidence interval [CI], 0.49 – 0.99). There was no such association among women who initiated HT later (aHR, 1.03; 95% CI, 0.68 – 1.55).

Although it’s not clear why taking hormones around the time of menopause might optimize AD risk reduction, there are some theories. It might be that this protects against some “provoking consequence of a sudden depletion of endogenous estrogen,” said Dr. Zandi. HT taken at different stages may have varying effects on the brain in terms of the pathologic chain of events involved in AD, which is probably a chronic disease that takes years to develop, he said.

Although HT taken around menopause and used for less than a decade was associated with a trend toward AD risk reduction, use for 10 years or more was associated with a further statistically significant reduction (aHR, 0.63; 95% CI, 0.41 – 0.98).

“There was clearly a duration response effect in what we saw,” said Dr. Zandi. “The women who started hormone therapy within 5 years of menopause and took it for more than 10 years had a lower risk of developing AD than similar women who started hormone therapy at menopause but took it for less than 10 years.”

He speculated that women might need that further exposure to ease the transition following the sudden depletion of endogenous estrogen. “Maybe the longer you take it, the longer you shift the course of initiating a pathological event of AD.”

The risk was about the same for women taking opposed or unopposed HT around menopause, although only unopposed HT was statistically significant. There was an increased risk with opposed HT when started at age 65 years or later, said Dr. Zandi.

Interestingly, opposed HT started within 3 years of the baseline was associated with an increased but nonsignificant risk for AD (aHR, 1.93; 95% CI, 0.94 – 3.96) not seen with unopposed HT. This risk estimate is about the same as that of the WHIMS participants who took combined therapy.

Careful Decision

The study results should not change women’s behavior surrounding the use of HT at menopause, stressed Dr. Zandi. “Women should be very careful in making their decision about starting hormone replacement therapy; they should make that decision in consultation with their clinician.”

What’s the next step to help illuminate the relationship between dementia and hormone use? It would be unethical (because of the potential adverse effects) and logically challenging (because it would take 20 or 30 years to get results) to carry out a randomized controlled clinical trial of HT in menopausal women, said Dr. Zandi.

In the absence of such “gold standard” research, “we have to look in a clever way at more observational data on women who are taking hormone replacement therapy voluntarily because they feel it’s best for them in consultation with their clinician,” he said. Research that follows these women over time may provide new insights into what happens in terms of their risk of developing AD, he said.

Victor W. Henderson, MD, Departments of Health Research and Policy and Neurology, Stanford University, California, who along with Walter A. Rocca, MD, Department of Health Sciences Research at Mayo Clinic College of Medicine, Rochester, Minnesota, contributed a commentary accompanying the paper, agreed that the study findings support the theory of a window around menopause during which relatively short-term hormone use might reduce long-term AD risk.

In an interview, Dr. Henderson told Medscape Medical News he’s somewhat skeptical about extending that window to long-term use, even though the study linked 10-year use to reduced dementia risk.

“People who are less healthy tend to have more side effects and not tolerate long term usage of any medication, not just estrogen, so whenever I see that long-term use is better I’m a little concerned that biases may be playing a larger role than in relatively shorter-term use.”

Although this new study is “pretty close to as good as it gets” for observational research, there are still lingering issues of unrecognized confounding, said Dr. Henderson. “There’s always the lingering concern that maybe there were some factors that just weren’t adjusted for and it makes the level of evidence a little bit weaker than it would be in a clinical trial.”

And results from any study, even clinical trials, are more compelling when there is “converging evidence” from other research, said Dr. Henderson, adding that in this case such evidence might come from other cohorts that are less homogeneous than this one.

Dr. Henderson also emphasized that the study findings should not be used to suggest a clinical indication for preventing AD in women approaching menopause. “There may be a potential benefit,” in terms of dementia risk reduction, he said, “but I don’t think the potential benefit should drive the consideration.”


The results come hard on the heels of release of results of the Kronos Early Estrogen Prevention Study (KEEPS), a randomized trial that showed HT with low-dose oral or transdermal estrogen and cyclic monthly progesterone started soon after the start of menopause — within 5 years — improved depression, anxiety, and cognitive function in healthy women, without any increase in cardiovascular disease risk.

Data were presented earlier this month at the 23rd Annual Meeting of the North American Menopause Society, and reported by Medscape Medical News at that time.

JoAnn E. Manson, MD, MPH, DrPH, professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School and chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, Massachusetts, who presented an overview of the KEEPS rationale, design, and study population, told Medscape Medical News that the KEEPS key findings, “highlight a favorable benefit-risk profile of hormone therapy in newly menopausal women.” She stressed that HRT should be used only for the treatment of menopausal symptoms.

“We certainly would not say at this point in time to initiate hormone therapy for the express purpose of trying to prevent heart disease or cognitive decline; the evidence is not to that point,” Dr. Manson said. “But for women who have menopausal symptoms and who are considering hormone replacement therapy to reduce their symptoms and improve their quality of life related to these symptoms, there were many favorable effects seen of taking hormone therapy for 4 years.”

Asked for comment on the KEEPS trial, Dr. Zandi called the early findings, “very interesting.”

“If they hold up to peer review when the results are ultimately submitted for publication, they provide further evidence that it is worthwhile to look at the effects of hormone replacement therapy taken during the time of menopause,” he told Medscape Medical News.

“Such research is needed to help put women’s minds at rest about the risks and benefits of taking HT for menopausal symptoms,” he added. “It will also be very interesting if the researchers can continue to follow these women over time to determine the effects of HT taken during menopause on downstream cardiovascular and cognitive endpoints.”

Dr. Zandi is funded by National Institutes of Health grant. Dr. Henderson has disclosed no relevant financial relationships.

Neurology. Published online October 24, 2012. Abstract Commentary

— Pauline Anderson

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