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Hormone Therapy and Risk for Dementia: Where Do We Go From Here?

Posted on: Wednesday, 23 February 2005, 03:00 CST

Key words: HORMONE THERAPY, COGNITION, MEMORY, NEUROPROTECTION, REVIEW

ABSTRACT

Prospective observational studies surest that hormone therapy (HT) might confer protection against the development of Alzheimer's disease. In contrast, recent findings from the Women's Health Initiative Memory Study (WHIMS) indicated a doubling of the risk of all-cause dementia in women randomized to receive HT after age 64. The discrepancy between findings from observational studies and the WHIMS is commonly attributed to the lack of treatment bias in the randomized trial. However, there are other potentially important differences between the WHIMS and the observational studies. These include timing of initiation of HT and type of HT regimen used. The present review focuses on the clinical and basic science studies bearing on these clinically important issues. Additional clinical studies are needed to understand the external generalizability of the WHIMS results to populations of women for whom HT remains an indication.

INTRODUCTION

Alzheimer's disease (AD) is currently an irreversible disease of aging and its prevalence will increase dramatically as the population ages. According to a recent report from the Centers for Disease Control and Prevention, AD is the eighth leading cause of death in the United States . More strikingly, the death rate from AD has increased more dramatically over the last 10 years than that from any other leading cause of death1. A recent epidemiological study predicted that the prevalence of AD will triple over the next 50 years to 13.7 million Americans unless treatments are identified that lower disease risk or delay disease onset2. Women have a longer life expectancy than men, and many more women than men die of AD. In 2001, the death rate from AD among women was almost 2.5 times higher than that among men. It is unclear whether the higher prevalence of AD among women is due entirely to women's greater life expectancy or whether some other factor or combination of factors might put women at increased risk of the disease. There is a pressing need for information about factors that might increase or decrease a woman's risk of AD.

OBSERVATIONAL STUDIES OF HORMONE THERAPY AND THE NEED FOR A RANDOMIZED CLINICAL TRIAL

The impact of hormone therapy (HT) on dementia became a topic of great interest with findings from observational studies of a significantly decreased risk for AD among women with a history of HT use3. Particularly notable were consistent findings from three prospective observational studies of HT and AD, each suggesting that HT reduced the risk of AD by 39-50%4-6. However, researchers were cautious in attributing the reduced risk to HT, because HT users tended be better educated and healthier than women choosing not to receive HT7. A high level of education is associated with a decreased risk for AD, particularly for women8.

Concerns about treatment bias in the observational studies prompted the Women's Health Initiative Memory Study (WHIMS), an ancillary study to the Women's Health Initiative (WHI) involving 4563 women aged over 65 years who were randomized to receive either combined estrogen and progesterone (0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA) daily) or placebo. The selection of oral CEE was justified in that CEE was the predominant form of HT used in observational studies showing decreased risks of AD. The inclusion of only older women was due to the practical need for a sufficient number of dementia cases over the planned 8.5-year study to detect a treatment effect; younger women would have a much lower risk of developing dementia over the length of the study. The study addressed a very important question: can older women initiate the most commonly used form of HT to decrease their risk of dementia?

Although the WHI was planned to be an 8.5-year study, the CEE/ MPA arm terminated after 5.6 years owing to an increase in breast cancer in the treatment group and a global index that suggested greater harm than benefit9. Findings from the CEE/ MPA arm of WHIMS showed a doubling of the risk for all-cause dementia among women randomized to HT10. After an average of 4 years of treatment, there were 40 cases of all-cause dementia in the HT group compared with 21 in the placebo group (relative risk (RR) 2.05, 95% confidence interval (CI) 1.21-3.48). There was no increase in mild cognitive impairment, the preclinical phase of dementia11, with HT. Findings from the CEE alone arm, by contrast, did not show a significant increase in all-cause dementia or mild cognitive impairment12. After an average 5.2 years of treatment, there were 37 cases of all-cause dementia per 10 000 person-years in the treatment group compared with 25 in the placebo group (RR 1.49, 95% CI 0.832.66, p = 0.18). A few limitations of WHIMS are notable. First, the majority of participants (55%) were not compliant with therapy at some point during the study. Second, the number of cases was appreciably smaller than expected, in part due to the early termination of the primary study. Third, diagnoses were not available for approximately 40% of cases referred for dementia evaluation based on impaired cognitive function, because they refused further testing or had incomplete data. However, despite these limitations, the study provided important information about the use of HT in older women, suggesting that HT does not prevent all-cause dementia in this group, but rather confers a small but significant risk for all- cause dementia. The WHIMS investigators suggested that the increase in risk of developing dementia might have been due primarily to an increase in vascularrelated dementia10. In WHI (RR 1.44, 95% CI 1.09- 1.90) the risk of ischemic stroke was higher in the CEE/MPA group, with an average excess of 8 strokes per 10000 women followed for 1 year9.

The WHIMS was not designed to examine the effects of HT on age- related changes in memory and other cognitive abilities, but the study provided limited data from a brief measure of cognitive status, the Mini-Mental State Exam. On that measure, most women receiving CEE/MPA did not experience clinically relevant adverse effects on cognition compared with placebo. However, women on active therapy were more likely to show cognitive impairment by performing two standard deviations below average13. This pattern of effects generalized to the estrogen alone treatment group14. More comprehensive cognitive evaluations were carried out in a subset of WHIMS participants in the WHI Study of Cognitive Aging (WHISCA), although the findings are not available at this time.

The WHIMS was not designed to address the impact of early use of HT among symptomatic women. Given that current guidelines recommend HT for symptomatic women, an important and unanswered question is whether the WHIMS dementia findings on women 65 years and older generalize to the typical HT user who initiates therapy earlier in life for the treatment of menopausal symptoms. The extant literature does not provide clear guidelines on this issue. In the absence of firm data to the contrary, it seems clinically prudent to caution those women about the WHIMS findings, recognizing that the absolute risk of dementia in those women is very low and that the clinical benefits to younger symptomatic women outweigh that small risk. At the same time, given that symptomatic women will continue to use HT, it seems prudent to investigate this clinical issue further. The experimental and clinical literature pertaining to the generalizahility of WHIMS to younger women and other estrogen and progesterone preparations is reviewed below.

DIFFERENCES BETWEEN THE WOMEN'S HEALTH INITIATIVE MEMORY STUDY AND PROSPECTIVE OBSERVATIONAL STUDIES

Observational studies predating WHIMS differed from WHIMS not only in terms of whether treatment was randomized but also in other potentially important ways, including timing of initiation of therapy in relation to the menopausal transition and type of therapy initiated. An appropriate design to investigate the impact of timing of initiation of HT on AD would involve one in which women were stratified based on time since menopause and then randomized to HT or placebo. However, given that it is not feasible to carry out a dementia prevention study in younger women, we can look to observational data to provide some insights into timing of initiation.

Data from Cache County Utah suggest a potential limited window of time during which sustained HT use can decrease the risk of AD6. Among women who were on average 74 years of age, past use of HT was associated with a decreased risk for AD whereas current use was associated with an increased risk. The exception was that older women who were long-term users of HT (i.e. 10 or more years of use) also showed a reduced risk of AD. These observational findings suggested that use early in life might be protective, whereas use later in life may be detrimental. The study authors noted that even if treatment trials in older women were to find negative results, HT might confer beneficial effects in women initiating earlier in life.

Other insights into potential windows of opportunity for HT to exert neuroprotection come from randomized clinical trials of cognitive outcomes, particularly verbal memory. Two recent randomized trials examined the cognitive effects of HT in younger midlife women \(age 50-65 years)15,16. One of the studies involving 60 midlife women found beneficial effects on verbal memory and reading, which are two tasks showing a sex difference in favor of females, following 21 days of treatment with estrogen alone (0.625 mg CEE)16. The other, involving 127 midlife women, found that 3 months of treatment with cyclical estrogen plus progesterone (Premelle; 0.625 mg CEE per day for 14 days followed by 2.5 mg MPA for 14 days) provided beneficial effects on delayed verbal recall ".

In contrast, earlier randomized trials of combined estrogen plus progesterone involving older women failed to show benefit on verbal memory . No benefits of HT on verbal memory were evident in a 9- month randomized clinical trial involving 52 elderly women (mean age 82 years) treated for 9 months with CEE at 0.625 nig/day plus trimonthly MPA at 5 mg/day for 13 days18. Similar findings were reported in a study of 1063 women participating in the Heart and Estrogen/progestin Replacement Study (HERS), a secondary prevention study of CEE and MPA (Prempro) on cognitive function in 2763 women with established coronary artery disease17. Older women receiving HT (mean age 71 years) scored significantly lower on a test of verbal fluency (i.e. speeded production of words) compared with women assigned to placebo. In addition, those receiving HT showed a small and statistically non-significant decrement in delayed verbal recall compared with those receiving placebo. Although these differences are too small to be clinically significant, they counter the view that initiation of HT in older women might be beneficial to verbal memory.

Together these studies are consistent with the view that early initiation of hormone therapy might be beneficial but later use may be detrimental. However, the difficulty in interpreting these findings on the basis of timing of initiation is that the groups differ also in type of HT and sample size. Type of HT may have an important impact on cognitive response to HT, and the findings in younger women have not been tested in larger samples.

Another important consideration in future studies evaluating the cognitive effects of HT may be the specific cognitive domain under investigation. Some clinical studies suggest that spatial memory might improve with HT regardless of age at initiation19-21. Measures of spatial memory were not included in the four trials described above. However, older women (mean age 65 years) showed enhanced spatial memory following 3 weeks of transdermal estradiol in a placebocontrolled randomized clinical trial19. Similarly, in a longitudinal observational study, older women who initiated HT showed no decrease in spatial memory over a 5-year interval whereas controls matched on age and score at pretreatment baseline showed longitudinal decline on this measure" . Similar findings were reported in a study of older long-term HT users . Notably, a recent study in older ovariectomized monkeys found improved performance on a spatial working memory task following treatment with cyclical estrogen and progesterone . Thus the neuroprotective effects may depend on timing of initiation, type of treatment and type of cognitive ability.

BIOLOGICAL PLAUSIBILITY

Basic science studies in rats suggest that the mechanisms by which estrogen exerts neuroprotection are age-dependent. In the hippocampus, a brain area critical to memory functioning, estrogen exerts direct effects on morphology and connectivity. Specifically, dendritic spine density in the hippocampus fluctuates with circulating estradiol over the estrous cycle and increases with estradiol treatment 4. These enhancements are accompanied by an increase in synapses 5. /V-methyl-D-aspartate (NMlDA) receptors appear to be critical mediators of the neuroprotective effects of estrogen and play a central role in memory formation 6. The mechanisms by which estradiol induces increases in hippocampal spine density are age-dependent; older female rats do not mount the same neuroprotective response 7. Moreover, NMDA receptor expression decreases with longer periods of estrogen deprivation and increasing age . Certain types of progesterone can block neuroprotective effects of estrogen. For example, MPA blocks the protective effects of estrogen against excitotoxicity "' . Clinical studies do not show a reliable detrimental effect of MPA on cognitive function, although this was observed in one clinical study' . In contrast to rats, aged female rhesus monkeys retain the capacity for spine induction in response to cyclical estrogen' '. They also show enhanced cognitive performance in response to cyclical estrogen. Whether a similar regimen in elderly women would lead to similar benefits is unknown.

SUMMARY

In summary, WHIMS provided important insights into the cognitive risks of CEE/MPA in women initiating treatment after the age of 64. However, important questions about the potential neuroprotective effects of HT remain. Those questions, which WHIMS was not designed to assess, center around issues pertaining to timing of initiation and type of regimen (cyclical versus continuous combined and type of progesterone). These questions have profound implications for clinicians. In particular, there is a need for clinical studies examining the effects of HT on cognition among groups of women excluded from WHIMS but for whom HT remains an indication. These include midlife women with moderate to severe menopausal symptoms who must weigh the potential benefits and drawbacks of HT to cognition and brain function.

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P. M. Maki

Departments of Psychiatry and Psychology, University of Illinois at Chicago, Chicago, Illinois, USA

Correspondence: Dr V. M. Maki, Neuropsychiatrie Institute, University of Illinois at Chicago, 912 S Wood St. MC913, Chicago, IL 60612, USA

Copyright CRC Press Dec 2004

Source: Gynecological Endocrinology

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