Does Postmenopausal Estrogen Use Confer Neuroprotection?
Does Postmenopausal Estrogen Use Confer Neuroprotection?
Sex steroids modulate brain function at all developmental stages of life. This article focuses on the role of sex steroids after menopause with the intent of addressing the question whether or to what extent sex steroids, particularly estrogenic agents, are neuroprotective for the aging brain of women. The rationale for delving into this complicated topic is that the information and perspective so acquired will aid physicians in counseling surgically and naturally menopausal women about their therapeutic options. Whereas we review and synthesize relevant data from monkey, other animal, cellular, and molecular studies, the emphasis is on human studies and reconciling the disparate evidence. Although the knowledge gaps are considerable, available evidence suggests that extended use of non-oral estradiol is a reasonable course of action if the woman to be treated has a relatively low risk for cardiovascular disease and venous thromboembolism or a high concern about developing dementia. It is important to emphasize that estradiol may negatively impact an already unhealthy individual and yet synergize other health-promoting behaviors such as good nutrition, exercise, and stress reduction in a relatively healthy individual.
Sex steroids both organize the brain, causing and amplifying sexual dimorphism, and activate the already imprinted and sexually dimorphic brain, leading to sex-specific hormone actions and behaviors. The role of sex steroids in gating traditional reproductive behaviors such as sexual behavior, lactation, and maternal attention has been extensively chronicled in animal, including monkey, models. The complexity and multiplicity of determinants underlying human behavior make it difficult to appreciate the exact contribution of sex steroids. Indeed, an interactive model may be best for understanding the impact of sex steroids as modulators of brain health. However, commonplace symptoms that accompany the menopause transition, namely, hot flashes, sleep disturbances, and irritability, suggest that parts of the brain subserving functions other than solely reproductive ones are critically impacted by the presence or absence of sex steroids. Sex steroids modulate synaptic density, neuronal and glial viability, and neurotransmitter systems that underpin cognitive, emotional, and motor functions. A wealth of molecular, cellular, and physiologic investigations, clinical observations and trials, and epidemiologic studies support the notion that postmenopausal hormone use, directly and indirectly, preserves cognitive function and protects from dementia and clinical conditions such as depression that heighten the risk for cognitive impairment. The interpretation of cellular and molecular data in animals is relatively straightforward and consistent with neuroprotection. Clinical and epidemiologic studies have yielded conflicting results, which are ascribed to (1) timing of exposure; (2) type, dose, duration, and route of administration; and (3) interactions with host genetics, health, lifestyle, and prior hormonal exposures, including reproductive events. Herein we briefly review current concepts and controversies surrounding the neuroprotective role of postmenopausal hormone treatment, particularly estrogen. Discrepancies between cellular and clinical data argue against premature dogmatism and for refined notions about the roles of sex steroids in aging women. The possibility remains that a proper dose of the right estrogen given by an appropriate route of administration and initiated during the perimenopause for a sufficient duration in a healthy host will confer neuroprotection.
Abstract and Introduction
Abstract
Sex steroids modulate brain function at all developmental stages of life. This article focuses on the role of sex steroids after menopause with the intent of addressing the question whether or to what extent sex steroids, particularly estrogenic agents, are neuroprotective for the aging brain of women. The rationale for delving into this complicated topic is that the information and perspective so acquired will aid physicians in counseling surgically and naturally menopausal women about their therapeutic options. Whereas we review and synthesize relevant data from monkey, other animal, cellular, and molecular studies, the emphasis is on human studies and reconciling the disparate evidence. Although the knowledge gaps are considerable, available evidence suggests that extended use of non-oral estradiol is a reasonable course of action if the woman to be treated has a relatively low risk for cardiovascular disease and venous thromboembolism or a high concern about developing dementia. It is important to emphasize that estradiol may negatively impact an already unhealthy individual and yet synergize other health-promoting behaviors such as good nutrition, exercise, and stress reduction in a relatively healthy individual.
Introduction
Sex steroids both organize the brain, causing and amplifying sexual dimorphism, and activate the already imprinted and sexually dimorphic brain, leading to sex-specific hormone actions and behaviors. The role of sex steroids in gating traditional reproductive behaviors such as sexual behavior, lactation, and maternal attention has been extensively chronicled in animal, including monkey, models. The complexity and multiplicity of determinants underlying human behavior make it difficult to appreciate the exact contribution of sex steroids. Indeed, an interactive model may be best for understanding the impact of sex steroids as modulators of brain health. However, commonplace symptoms that accompany the menopause transition, namely, hot flashes, sleep disturbances, and irritability, suggest that parts of the brain subserving functions other than solely reproductive ones are critically impacted by the presence or absence of sex steroids. Sex steroids modulate synaptic density, neuronal and glial viability, and neurotransmitter systems that underpin cognitive, emotional, and motor functions. A wealth of molecular, cellular, and physiologic investigations, clinical observations and trials, and epidemiologic studies support the notion that postmenopausal hormone use, directly and indirectly, preserves cognitive function and protects from dementia and clinical conditions such as depression that heighten the risk for cognitive impairment. The interpretation of cellular and molecular data in animals is relatively straightforward and consistent with neuroprotection. Clinical and epidemiologic studies have yielded conflicting results, which are ascribed to (1) timing of exposure; (2) type, dose, duration, and route of administration; and (3) interactions with host genetics, health, lifestyle, and prior hormonal exposures, including reproductive events. Herein we briefly review current concepts and controversies surrounding the neuroprotective role of postmenopausal hormone treatment, particularly estrogen. Discrepancies between cellular and clinical data argue against premature dogmatism and for refined notions about the roles of sex steroids in aging women. The possibility remains that a proper dose of the right estrogen given by an appropriate route of administration and initiated during the perimenopause for a sufficient duration in a healthy host will confer neuroprotection.
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