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Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention
After advanced age, female sex is the major risk factor for late-onset Alzheimer’s disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected....
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959926/ https://www.ncbi.nlm.nih.gov/pubmed/35356299 http://dx.doi.org/10.3389/fnagi.2022.831807 |
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author | Jett, Steven Malviya, Niharika Schelbaum, Eva Jang, Grace Jahan, Eva Clancy, Katherine Hristov, Hollie Pahlajani, Silky Niotis, Kellyann Loeb-Zeitlin, Susan Havryliuk, Yelena Isaacson, Richard Brinton, Roberta Diaz Mosconi, Lisa |
author_facet | Jett, Steven Malviya, Niharika Schelbaum, Eva Jang, Grace Jahan, Eva Clancy, Katherine Hristov, Hollie Pahlajani, Silky Niotis, Kellyann Loeb-Zeitlin, Susan Havryliuk, Yelena Isaacson, Richard Brinton, Roberta Diaz Mosconi, Lisa |
author_sort | Jett, Steven |
collection | PubMed |
description | After advanced age, female sex is the major risk factor for late-onset Alzheimer’s disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected. While most research has focused on gender-combined risk, emerging data indicate sex and gender differences in AD pathophysiology, onset, and progression, which may help account for the higher prevalence in women. Notably, AD-related brain changes develop during a 10–20 year prodromal phase originating in midlife, thus proximate with the hormonal transitions of endocrine aging characteristic of the menopause transition in women. Preclinical evidence for neuroprotective effects of gonadal sex steroid hormones, especially 17β-estradiol, strongly argue for associations between female fertility, reproductive history, and AD risk. The level of gonadal hormones to which the female brain is exposed changes considerably across the lifespan, with relevance to AD risk. However, the neurobiological consequences of hormonal fluctuations, as well as that of hormone therapies, are yet to be fully understood. Epidemiological studies have yielded contrasting results of protective, deleterious and null effects of estrogen exposure on dementia risk. In contrast, brain imaging studies provide encouraging evidence for positive associations between greater cumulative lifetime estrogen exposure and lower AD risk in women, whereas estrogen deprivation is associated with negative consequences on brain structure, function, and biochemistry. Herein, we review the existing literature and evaluate the strength of observed associations between female-specific reproductive health factors and AD risk in women, with a focus on the role of endogenous and exogenous estrogen exposures as a key underlying mechanism. Chief among these variables are reproductive lifespan, menopause status, type of menopause (spontaneous vs. induced), number of pregnancies, and exposure to hormonal therapy, including hormonal contraceptives, hormonal therapy for menopause, and anti-estrogen treatment. As aging is the greatest risk factor for AD followed by female sex, understanding sex-specific biological pathways through which reproductive history modulates brain aging is crucial to inform preventative and therapeutic strategies for AD. |
format | Online Article Text |
id | pubmed-8959926 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89599262022-03-29 Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention Jett, Steven Malviya, Niharika Schelbaum, Eva Jang, Grace Jahan, Eva Clancy, Katherine Hristov, Hollie Pahlajani, Silky Niotis, Kellyann Loeb-Zeitlin, Susan Havryliuk, Yelena Isaacson, Richard Brinton, Roberta Diaz Mosconi, Lisa Front Aging Neurosci Neuroscience After advanced age, female sex is the major risk factor for late-onset Alzheimer’s disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected. While most research has focused on gender-combined risk, emerging data indicate sex and gender differences in AD pathophysiology, onset, and progression, which may help account for the higher prevalence in women. Notably, AD-related brain changes develop during a 10–20 year prodromal phase originating in midlife, thus proximate with the hormonal transitions of endocrine aging characteristic of the menopause transition in women. Preclinical evidence for neuroprotective effects of gonadal sex steroid hormones, especially 17β-estradiol, strongly argue for associations between female fertility, reproductive history, and AD risk. The level of gonadal hormones to which the female brain is exposed changes considerably across the lifespan, with relevance to AD risk. However, the neurobiological consequences of hormonal fluctuations, as well as that of hormone therapies, are yet to be fully understood. Epidemiological studies have yielded contrasting results of protective, deleterious and null effects of estrogen exposure on dementia risk. In contrast, brain imaging studies provide encouraging evidence for positive associations between greater cumulative lifetime estrogen exposure and lower AD risk in women, whereas estrogen deprivation is associated with negative consequences on brain structure, function, and biochemistry. Herein, we review the existing literature and evaluate the strength of observed associations between female-specific reproductive health factors and AD risk in women, with a focus on the role of endogenous and exogenous estrogen exposures as a key underlying mechanism. Chief among these variables are reproductive lifespan, menopause status, type of menopause (spontaneous vs. induced), number of pregnancies, and exposure to hormonal therapy, including hormonal contraceptives, hormonal therapy for menopause, and anti-estrogen treatment. As aging is the greatest risk factor for AD followed by female sex, understanding sex-specific biological pathways through which reproductive history modulates brain aging is crucial to inform preventative and therapeutic strategies for AD. Frontiers Media S.A. 2022-03-09 /pmc/articles/PMC8959926/ /pubmed/35356299 http://dx.doi.org/10.3389/fnagi.2022.831807 Text en Copyright © 2022 Jett, Malviya, Schelbaum, Jang, Jahan, Clancy, Hristov, Pahlajani, Niotis, Loeb-Zeitlin, Havryliuk, Isaacson, Brinton and Mosconi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Jett, Steven Malviya, Niharika Schelbaum, Eva Jang, Grace Jahan, Eva Clancy, Katherine Hristov, Hollie Pahlajani, Silky Niotis, Kellyann Loeb-Zeitlin, Susan Havryliuk, Yelena Isaacson, Richard Brinton, Roberta Diaz Mosconi, Lisa Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention |
title | Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention |
title_full | Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention |
title_fullStr | Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention |
title_full_unstemmed | Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention |
title_short | Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention |
title_sort | endogenous and exogenous estrogen exposures: how women’s reproductive health can drive brain aging and inform alzheimer’s prevention |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959926/ https://www.ncbi.nlm.nih.gov/pubmed/35356299 http://dx.doi.org/10.3389/fnagi.2022.831807 |
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