Frontiers proposal. National Institute on Aging “bench to bedside: estrogen as a case study”

Asthana, Sanjay; Brinton, Roberta Dı́az; Henderson, Victor W.; McEwen, Bruce S.; Morrison, John H.; Schmidt, Peter J.

doi:10.1007/s11357-009-9087-2

Cited by 24 publications

(15 citation statements)

References 59 publications

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“…Given the need for large sample sizes and lengthy follow-up, and given recognized health risks of hormone therapy, it is difficult to envision primary prevention trials for Alzheimer’s disease that begin in midlife. Well-designed cohort studies, convergent findings from appropriate laboratory models, and long-term clinical trials using surrogate biomarkers of brain function and neural pathology could help provide less ambiguous answers to vexing questions that remain [104]. …”

Section: Discussionmentioning

confidence: 99%

Alzheimer's disease: Review of hormone therapy trials and implications for treatment and prevention after menopause

Henderson

2014

The Journal of Steroid Biochemistry and Molecular Biology

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139

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Hormonal changes associated with the menopausal transition and postmenopause have the potential to influence processes linked to Alzheimer’s disease symptoms and pathogenesis, but effects of menopause on Alzheimer risk can be addressed only indirectly. Nine randomized clinical trials of estrogen-containing hormone therapy in Alzheimer’s disease patients were identified by a systematic literature search. Findings suggest that hormone therapy does not improve cognitive symptoms of women with Alzheimer’s disease. No clinical trials of hormone therapy address Alzheimer prevention, but one clinical trial provides moderate evidence that continuous, combined estrogen plus progestogen initiated at age 65 years or older increases the risk of dementia. The timing, or critical window, hypothesis suggests that hormone therapy initiated at a younger age in closer temporal proximity to menopause may reduce the risk of Alzheimer’s disease. This hypothesis is supported by observational research but is not addressed by clinical trial data. Unrecognized confounding is of concern in interpreting observational results, and research that helps resolve this issue will have important public health implications. Well-designed cohort studies, convergent evidence from appropriate laboratory models, and long-term clinical trials using surrogate biomarkers of brain function and neural pathology could provide relevant answers. Other estrogenic compounds are of theoretical interest with respect to Alzheimer treatment and risk. Effects of selective estrogen receptor modulators such as raloxifene may differ from those of estrogens; potential effects of phytoestrogens are not well studied.

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Section: Discussionmentioning

confidence: 99%

Alzheimer's disease: Review of hormone therapy trials and implications for treatment and prevention after menopause

Henderson

2014

The Journal of Steroid Biochemistry and Molecular Biology

Self Cite

139

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“…In all cases, the role of the progestin in the effects of hormone replacement therapy must not be underestimated [69].…”

Section: The Effects Of Sex Steroids On Cognitionmentioning

confidence: 99%

Brain health and cognitive and mood disorders in ageing women

Silva¹,

Naftolin²

2013

Best Practice & Research Clinical Obstetrics & Gynaecol

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“…As suggested by participants in a National Institute on Aging workshop on estrogen and the aging female brain (Asthana et al, 2009), there remains pressing need for preclinical and clinical research on the relation between the menopausal transition and midlife exposures to estrogens, progestagens and related compounds, and on risks for age-associated cognitive disorders such as Alzheimer’s disease. Research needs include better predictors of adverse cognitive outcomes, biomarkers for risks associated with hormone therapy, and tools for monitoring brain function and disease progression.…”

Section: Inferences and Conclusionmentioning

confidence: 99%

Menopause and Mitochondria

Henderson

Brinton

2010

Progress in Brain Research

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Metabolic derangements and oxidative stress are early events in Alzheimer’s disease pathogenesis. Multifaceted effects of estrogens include improved cerebral metabolic profile and reduced oxidative stress through actions on mitochondria, suggesting that a woman’s endogenous and exogenous estrogen exposures during midlife and in the late postmenopause might favorably influence Alzheimer risk and symptoms. This prediction finds partial support in the clinical literature. As expected, early menopause induced by oophorectomy may increase cognitive vulnerability; however, there is no clear link between age at menopause and Alzheimer risk in other settings, or between natural menopause and memory loss. Further, among older postmenopausal women, initiating estrogen-containing hormone therapy increases dementia risk and probably does not improve Alzheimer’s disease symptoms. As suggested by the “critical window” or “healthy cell” hypothesis, better outcomes might be expected from earlier estrogen exposures. Some observational results imply that effects of hormone therapy on Alzheimer risk are indeed modified by age at initiation, temporal proximity to menopause, or a woman’s health. However, potential methodological biases warrant caution in interpreting observational findings. Anticipated results from large, ongoing clinical trials (Early versus Late Intervention Trial with Estradiol [ELITE]; Kronos Early Estrogen Prevention Study [KEEPS]) will help settle whether midlife estrogen therapy improves midlife cognitive skills but not whether midlife estrogen exposures modify late life Alzheimer risk. Estrogen effects on mitochondria adumbrate the potential relevance of estrogens to Alzheimer’s disease. However, laboratory models are inexact embodiments of Alzheimer pathogenesis and progression, making it difficult to surmise net effects of estrogen exposures. Research needs include better predictors of adverse cognitive outcomes, biomarkers for risks associated with hormone therapy, and tools for monitoring brain function and disease progression.

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Frontiers proposal. National Institute on Aging “bench to bedside: estrogen as a case study”

Cited by 24 publications

References 59 publications

Alzheimer's disease: Review of hormone therapy trials and implications for treatment and prevention after menopause

Alzheimer's disease: Review of hormone therapy trials and implications for treatment and prevention after menopause

Brain health and cognitive and mood disorders in ageing women

Menopause and Mitochondria

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