Victor W. Henderson

Estrogen for Alzheimer’s disease in women: Randomized, double-blind, placebo-controlled trial

Background: AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder. Methods: Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks. Results: Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer’s Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences. Conclusions: Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

Postmenopausal hormone therapy: An endocrine society scientific statement

OBJECTIVE Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. EVIDENCE Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence. CONSENSUS PROCESS A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors. CONCLUSIONS The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Womens Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society

Objective:To update for both clinicians and the lay public the evidence-based position statement published by The North American Menopause Society (NAMS) in March 2007 regarding its recommendations for menopausal hormone therapy (HT) for postmenopausal women, with consideration for the therapeutic benefit-risk ratio at various times through menopause and beyond. Design:An Advisory Panel of clinicians and researchers expert in the field of womens health was enlisted to review the March 2007 NAMS position statement, evaluate new evidence through an evidence-based analysis, and reach consensus on recommendations. The Panels recommendations were reviewed and approved by the NAMS Board of Trustees as an official NAMS position statement. The document was provided to other interested organizations to seek their endorsement. Results:Current evidence supports a consensus regarding the role of HT in postmenopausal women, when potential therapeutic benefits and risks around the time of menopause are considered. This paper lists all these areas along with explanatory comments. Conclusions that vary from the 2007 position statement are highlighted. Addenda include a discussion of risk concepts, a new component not included in the 2007 paper, and a recommended list of areas for future HT research. A suggested reading list of key references is also provided. Conclusions:Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable close to menopause but decreases with aging and with time since menopause in previously untreated women.

Clinical subtypes of dementia of the Alzheimer type

Clinical subtypes of dementia of the Alzheimer type were evaluated by comparing age at onset, aphasia, family history, and motor disorder in 146 individuals with progressive dementia. Early onset was significantly associated with more prevalent and more severe language disorder. Forty-five percent of all probands had familial history of dementia, but we could not differentiate relative familial risk based on age at onset or aphasia. Independent of duration of illness, myoclonus and noniatrogenic extrapyramidal disorder were associated with greater severity of dementia.

Neuroleptic malignant syndrome A pathogenetic role for dopamine receptor blockade

The neuroleptic malignant syndrome (NMS) of extrapyramidal signs and hyperthermia is an uncommon complication of therapy with the major tranquilizers. Other manifestations are pallor, diaphoresis, blood pressure fluctuation, tachycardia, and tachypneic hypoventilation, which may necessitate respirator support. Death often occurs, but full recovery can result with prompt recognition and proper management. In a patient with Parkinson disease and a chronic psychiatric disorder treated with haloperidol, typical features of NMS appeared upon cessation of dopaminergic antiparkinsonian drugs. Manifestations of NMS are attributed to dopamine receptor blockade in the striatum, increasing thermogenesis, and in the hypothalamus, impairing heat dissipation.

Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer's disease

Objective: To examine whether estrogen replacement therapy (ERT) affects clinical and cognitive responses to tacrine in women with Alzheimers disease (AD). Design: A 30-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial of tacrine in which a subgroup of women were receiving ERT prior to randomization. Patients: Women with mild to moderate-stage AD, at least 50 years of age, who were enrolled in the previously reported trial. Interventions: Randomized assignment to placebo or to one of three ascending-dosage regimens of tacrine: maximum dosages of 80 mg/d, 120 mg/d, or 160 mg/d. Outcome measures: Alzheimers Disease Assessment Scale--Cognitive Scale (ADASc), Clinician Interview-Based Impression of change (CIBI), Mini-Mental State Examination (MMSE), Caregivers Impression of Change (CIC). Results: Of 318 women with evaluable data 14.5% were receiving ERT. Women completing the trial taking ERT and tacrine improved more than women not receiving ERT who were randomly assigned to tacrine or to placebo as assessed by the ADASc (p < 0.01), the CIBI (p = 0.02), the CIC (p = 0.006), and the MMSE (p = 0.07). They improved significantly on the ADASc (p = 0.01) using an intent-to-treat analysis. Conclusions: Prior and continuing ERT may enhance response to tacrine in women with AD. Randomized trials are needed. NEUROLOGY 1996;46: 1580-1584

The epidemiology of estrogen replacement therapy and Alzheimer's disease

Article abstract-The burden of Alzheimers disease (AD) falls more heavily on women than men. It is hypothesized that plummeting levels of circulating estrogens after the menopause increase a womans risk for this disorder and, conversely, that estrogen replacement therapy may lower the risk for dementia due to AD. A number of estrogenic properties support the biological credibility of this hypothesis. Estrogen interacts with neurotrophins and neurotransmitter systems relevant to AD and in some model systems estrogen modulates synaptic plasticity. Effects on beta-amyloid and apolipoprotein E may be especially germane to putative protective effects. Estrogen also may blunt neurotoxic consequences of the stress response mediated by the hypothalamic-pituitary-adrenal axis, augment cerebral glucose utilization, and enhance cerebral blood flow. Clinical studies of postmenopausal women suggest beneficial estrogen effects on specific cognitive skills, and small preliminary trials of estrogen replacement in women with AD support claims of clinically meaningful efficacy. Consistent with the estrogen hypothesis, cross-sectional studies imply that postmenopausal estrogen use could be associated with a lower risk for AD. Several recent epidemiologic studies in which information on estrogen replacement therapy was collected prospectively further support this contention, with a dose-response relation evident in some reports. Because estrogen users tend to differ from nonusers in a number of lifestyle characteristics, convincing demonstration of putative protective effects could best come from randomized, placebo-controlled, primary intervention trials. For the present, however, the issue of estrogen efficacy in lowering a womans risk for AD remains unsettled. NEUROLOGY 1997;48(Suppl 7): S27-S35

Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health

MediClinic Panorama and Department of Obstetrics and Gynecology, Stellenbosch University, Cape Town, South Africa; * Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; † Queen Charlotte ’ s & Chelsea Hospital, and Chelsea and Westminster Hospital, London, UK; ‡ Department of Obstetrics and Gynecology, Pisa University Hospital, Pisa, Italy; * * Jones Institute, Eastern Virginia Medical School, Norfolk, VA, USA; † † Sydney Medical School, The University of Sydney, NSW, Australia; ‡ ‡ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; * * * UF de Gyn e cologie, Universit e Paris Descartes, AP-HP, H o tel-Dieu, Paris, France; † † † Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA; ‡ ‡ ‡ Associate Dean for Clinical and Translational Research and Professor of Family Medicine-Las Vegas, University of Nevada School of Medicine, Las Vegas, NV, USA; * * * * Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA; † † † † Unit e de Gyn e cologie M e dicale, H o tel Dieu, Paris, France; ‡ ‡ ‡ ‡ Heart of England NHS Foundation Trust, Solihull Hospital, Birmingham, UK

Cognitive skills associated with estrogen replacement in women with Alzheimer's disease.

To delineate putative cognitive effects of estrogen in women with Alzheimers disease, we compared neuropsychological performances in three groups of patients with clinically diagnosed Alzheimers disease: women receiving estrogen replacement therapy (n = 9), women not receiving replacement therapy (n = 27), and men (n = 26). Untreated women and men were matched by age, education, and duration of dementia symptoms to women receiving estrogen replacement. We hypothesized that treated women would have better scores on neuropsychological tasks. Results showed that women receiving hormonal therapy performed significantly better than other women on some, but not all, tasks; on no task did women receiving estrogen score significantly worse. The largest group difference was on the Boston Naming Test, a semantic memory task previously shown to be more impaired in women with Alzheimers disease than in men with this diagnosis. Of tests considered in a discriminant analysis, the naming task was the only neuropsychological variable to distinguish between the two womens groups. Mean differences between estrogen-treated women and men were small and were not statistically significant. Findings support the hypothesis that estrogen therapy for women with Alzheimers disease is associated with better cognitive skills and that previously noted gender-associated differences in Alzheimers disease may reflect a state of acquired estrogen deficiency among women with this disorder.

Estrogen, Cognition, and a Woman’s Risk of Alzheimer’s Disease

Alzheimers disease affects women more often than men, and women with this form of dementia show greater naming (semantic memory) deficits during the course of their illness. Gonadal steroids exert organizational and activational effects on central nervous system neurons and influence brain function in other important ways. Several estrogenic actions are potentially relevant to Alzheimers disease, and it is hypothesized that one consequence of estrogen deprivation after the menopause is a higher risk of this dementing disorder. In healthy women without dementia, estrogen may enhance cognitive performance, especially in the domain of verbal memory, although the magnitude of such effects is small. Several small treatment trials of estrogen replacement in women with Alzheimers disease, however, suggest that estrogens effects on cognition could be larger in this population and may be most apparent on tasks of semantic memory. Analyses in voluntary cohorts associate postmenopausal estrogen replacement therapy with a lower risk of subsequent Alzheimers disease. In 3 recent epidemiologic studies, information on postmenopausal estrogen use was collected prospectively; while inconclusive, findings raise the possibility that postmenopausal estrogen replacement reduces a womans risk of subsequent dementia. New information from basic research and from large randomized treatment studies, cohort studies, and case-control studies is needed to resolve important unanswered clinical issues.