Abstract
The impacts of menopause on neurodegenerative diseases, especially the changes in steroid hormones, have been well described in cell models, animal models, and humans. However, the therapeutic effects of hormone replacement therapy on postmenopausal women with neurodegenerative diseases remain controversial. The steroid hormones, steroid hormone receptors, and downstream signal pathways in the brain change with aging and contribute to disease progression. Estrogen and progesterone are two steroid hormones which decline in circulation and the brain during menopause. Insulin-like growth factor 1 (IGF-1), which plays an import role in neuroprotection, is rapidly decreased in serum after menopause. Here, we summarize the actions of estrogen, progesterone, and IGF-1 and their signaling pathways in the brain. Since the incidence of Alzheimer’s disease (AD) is higher in women than in men, the associations of steroid hormone changes and AD are emphasized. The signaling pathways and cellular mechanisms for how steroid hormones and IGF-1 provide neuroprotection are also addressed. Finally, the molecular mechanisms of potential estrogen modulation on N-methyl-d-aspartic acid receptors (NMDARs) are also addressed. We provide the viewpoint of why hormone therapy has inconclusive results based on signaling pathways considering their complex response to aging and hormone treatments. Nonetheless, while diagnosable AD may not be treatable by hormone therapy, its preceding stage of mild cognitive impairment may very well be treatable by hormone therapy.
Highlights
Neurodegenerative diseases include movement, cognitive, and behavioral disorders which are caused along the process of neurodegeneration
These results show that changes in sex steroid hormones did affect the intestinal microecological environment, which might contribute to neurodegenerative diseases
The activated estrogen receptor (ER) translocate to the nucleus and bind to estrogen response elements (EREs) on specific genes [206]. This ERE binding facilitates the recruitment of other transcription factors, leading to an increase or decrease in target genes’ expression, such as brain-derived neurotrophic factor (BDNF) and glial cell-line-derived neurotrophic factor (GDNF) [171,207], which are important in neural protection
Summary
Neurodegenerative diseases include movement, cognitive, and behavioral disorders which are caused along the process of neurodegeneration. Lack of definitive diagnosis tools, and complex pathophysiology make these neurodegenerative diseases, especially AD, difficult to treat. In these neurodegenerative diseases, increases in neuronal loss are found with disease progression [4,5,6]. Endocrine dyscrasia by menopause and andropause is correlated to neuronal dysfunction, cell death, and cognitive decline [8]. In addition to incidence and prevalence, the disease progression and treatment responses are different according to gender [11]. We first present evidence showing the sex differences, especially the impacts of menopause, in major neurodegenerative diseases. We present details on what is known about the molecular pathways through which menopause contributes to neurodegenerative diseases
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