Alzheimer’s Disease and Other Neurological Disorders

By Henderson, V W

ABSTRACT Menopausal status and estrogen-containing hormone therapy may influence several neurological disorders, including Alzheimer’s disease, epilepsy, migraine headache, multiple sclerosis, Parkinson’s disease, sleep disorders, and stroke. For most of these illnesses, evidence on hormone therapy is insufficient to guide practice decisions. For stroke, clinical trial evidence indicates that hormone therapy increases risk of cerebral infarction. For women with Alzheimer’s disease, estrogen treatment trials have tended to be small and of short duration. Most suggest that estrogen started after the onset of dementia symptoms does not meaningfully improve cognition or slow disease progression. Hormone therapy initiated after age 64 increased all-cause dementia in the Women’s Health Initiative Memory Study. Many observational studies, however, report protective associations between hormone use and Alzheimer risk. Apparent risk reduction may represent a bias toward hormone therapy, since hormones are more often prescribed to healthier women. However, when compared to the Women’s Health Initiative Memory Study, estrogen exposures in many observational studies reflect hormone initiation at a younger age, closer to the time of menopause. One intriguing hypothesis is that hormone therapy initiated or used during an early critical window may reduce later Alzheimer incidence. Public health implications of this hypothesis are important, but current data are inadequate to decide the issue.

Key words: ALZHEIMER’S DISEASE, NEUROLOGICAL DISORDERS, PARKINSON’S DISEASE, EPILEPSY, STROKE, HORMONE THERAPY

INTRODUCTION

During development and adulthood, the human brain is a target for estrogen and other steroid hormones. Estrogen influences neural function and neurological disease directly, through effects on neurons and glia, and indirectly, through effects on the cerebral vasculature and immune system. Neuronal effects occur through interactions with intracellular estrogen receptors (ERa, ERbeta) that function as ligand-activated transcription factors, and through other mechanisms. Estrogen production by the ovarian follicles ceases close to the time of natural menopause and, by inference, reproductive stages and estrogen-containing hormone therapy (HT) are thus relevant to a number of neurological disorders. In 2004, the Executive Committee of the International Menopause Society (IMS) issued guidelines for hormonal treatment of women in the menopause transition and beyond1. At that point, potential effects of HT on neurological disease were acknowledged, but little could be firmly concluded. The following text describes recognized effects of estrogen and HT on Alzheimer’s disease and provides summary information for effects on Parkinson’s disease, stroke and epilepsy.

ALZHEIMER’S DISEASE

In most regions of the world, Alzheimer’s disease is the most common cause of dementia among the elderly2. About twice as many women suffer from Alzheimer’s disease as men. This sex difference is due in large part to the fact that life expectancy is longer for women, but some studies also suggest higher incidence rates, particularly in late old age2. Neuroprotective actions and effects of estrogen on basal forebrain cholinergic neurons, beta-amyloid formation, and the vasculature appear relevant to treatment and prevention of Alzheimer’s disease.

Preclinical research suggesting that estrogen might improve symptoms of Alzheimer’s disease has found little clinical trial support, including a 12-month US study of 120 hysterectomized women, where the randomized intervention was unopposed conjugated equine estrogens3, and a 28-week French study of 117 women where the active intervention was transdermal estradiol and oral micronized progesterone4.

Initial results of the Women’s Health Initiative Memory Study (WHIMS) were published in 2003 and 2004(5,6). The primary endpoint was incident dementia. Participants were relatively – but not optimally – healthy US women aged 65-79 years, who were randomly assigned to receive conjugated equine estrogens or placebo. Women with a uterus allocated to active treatment also received medroxyprogesterone acetate in a combined formulation. The number of new dementia cases was relatively small during mean follow-up periods of 4-5 years (61 cases among 4532 women with a uterus, 47 cases among 2947 women without a uterus). Fifty percent of cases were diagnosed as Alzheimer’s disease, but results for Alzheimer’s disease were not reported separately because of small numbers. The hazard ratio (HR) for dementia was doubled for women assigned to estrogen plus progestogen (HR 2.05, 95% confidence interval (CI) 1.21-3.48)5 and increased by half for women assigned to estrogen alone (HR 1.49, 95% CI 0.83-3.66)6. Women who had used HT in the past were less likely to develop dementia during the WHIMS trials, but prior use did not significantly modify the dementia risk of on- trial HT.

In observational studies, where HT exposure has usually been in the form of conjugated equine estrogens, HT use is associated with about a 40% reduction in the risk of Alzheimer’s disease7. One possibility for the apparent discrepancy between the WHIMS results and observational findings is systematic bias or confounding in observational studies; for example, the tendency for HT users to engage in healthier lifestyle practices than non-users8. Another possibility is that the WHIMS results do not generalize to women younger than age 65, who by design were excluded from the WHIMS trials8. Most HT exposure in observational studies began during the menopausal transition or early postmenopause and ended before age 65. Thus, there might be a critical window of opportunity for younger women during which HT could reduce subsequent risk of Alzheimer’s disease, whereas HT would elevate risk when used by older women9. The mechanism for this theoretical distinction is unknown but might involve competing estrogen effects in cascades involved in coagulation, thrombosis and fibrinolysis, or deleterious estrogen effects on stability of complicated atheromatous plaques. Few clinical data address the critical window hypothesis directly. In Cache County, Utah, risk of Alzheimer’s disease appeared to be reduced for women who had used HT in the past (HR 0.3, 95% CI 0.2- 0.7) but not women who were current users (HR 1.1, 95% CI 0.6- 1.9)10. In the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) study, the association between HT and risk of Alzheimer’s disease was modified by age; for women in the youngest age tertile (50-63 years), the relative risk was significantly reduced (0.35, 95% CI 0.19-0.66), but, for women in the two older tertiles, relative risks were 0.9 (95% CI 0.5-1.5) and 1.0 (95% CI 0.6-1.6)11.

OTHER NEUROLOGICAL DISORDERS

Parkinson’s disease

Cardinal signs of Parkinson’s disease are bradykinesia, rigidity, rest tremor and gait instability. It is a common age-associated neurodegenerative disorder, second in prevalence only to Alzheimer’s disease, and it affects men more often than women12. Most symptoms are attributed to the loss of dopamine-containing neurons whose cell bodies are in the midbrain substantia nigra. Estrogen reduces the extent of dopamine depletion induced by the selective neurotoxin 1- methylphenyl-1,2,3,6-tetrahydropyridine (MPTP)13, and, in non-human primates, ovariectomy reduces the number of dopaminergic neurons14. Observational studies provide conflicting evidence regarding the association between HT and Parkinson’s dis ease incidence, showing, for example, no association15, decreased risk from HT use16, or increased risk from HT use after hysterectomy but no association with HT after natural menopause17. In one small 8-week clinical trial, postmenopausal women with Parkinson’s disease randomized to conjugated equine estrogens showed improvement in motor symptoms and reductions in symptom fluctuation when compared women receiving placebo18.

Epilepsy

Epilepsy is a prevalent neurological disorder defined by the tendency to have seizures. There is a complicated relation between epilepsy and hormonal factors. For many women with epilepsy, seizures are more apt to occur during a particular phase of the menstrual cycle, an observation that implies a role for sex steroids in modifying seizure frequency. The threshold for experimental seizures is lowered by estrogen and raised by progesterone, and small open-label trials suggest that progestogens might reduce seizure frequency in women with epilepsy. In a small 3-month randomized trial, postmenopausal women with epilepsy who received conjugated equine estrogens and medroxyprogesterone acetate experienced more seizures than women who received placebo19.

Stroke

The incidence of stroke, which rises sharply with age, is higher in men. The mean age of women who experience a stroke is 75 years; for men the mean age is 70 years20. Estrogen effects on clotting, atherosclerosis and the vascular endothelium are potentially important in stroke pathogenesis. Experimentally, estrogen reduces infarct size after ischemic brain injury21. Several randomized clinical trials have examined HT effects on stroke incidence. Results suggest that HT has no significant effect on hemorrhagic stroke risk22. For ischemic stroke, HT may have no effect (two secondary prevention trials23,24) or may increase risk (Women’s Health Initiative trials25,26) (Table 1). In the latter, risks appeared to pertain both to younger and older postmenopausal women, but there was limited power to detect interactions based on age of HT use27. Table 1 Stroke risk in randomized, placebo-controlled trials of hormone therapy

SUMMARY AND KEY POINTS

* With menopause, the cessation of ovarian estrogen production and the initiation of HT have the potential to influence central nervous system processes relevant to a variety of neurological disorders.

* For women with Alzheimer’s disease, limited clinical trial evidence indicates that HT does not improve symptoms or slow disease progression.

* There is limited clinical trial evidence that HT increases dementia risk when initiated after age 64 years.

* Observational evidence implies that HT used by younger women around the time of menopause is associated with lower risk of Alzheimer’s disease. However, findings may be biased, and further research is needed to determine whether there might exist an early window during which HT effects on Alzheimer’s disease risk are beneficial rather than harmful.

* Potential effects of HT on Parkinson’s disease incidence or symptoms are largely unknown.

* Based on evidence from a single clinical trial, combined HT may increase seizure frequency in postmenopausal women with epilepsy.

* Clinical trial data indicate that HT increases the risk of ischemic stroke. HT probably has no important impact on the secondary prevention of stroke in women with established coronary heart disease or a history of stroke.

Conflict of interest Nil.

Source of funding NIH AG023038.

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V. W. Henderson

Departments of Health Research and Policy, and of Neurology and Neurological Sciences, Stanford University, Stanford, California, United States

Correspondence: Professor V. W. Henderson, Stanford University, 259 Campus Drive, HRP Redwood Building, Stanford, CA 94305-5405, USA

Copyright Taylor & Francis Ltd. Oct 2007

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