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Estrogen-mediated regulation of the bioenergetic system: estrogen signalling supports and sustains glucose metabolism in the brain by regulating expression of glucose transporters, which results in increased glucose uptake, and by stimulating glucose metabolism, mitochondrial oxidative phosphorylation and ATP generation—collectively referred to as aerobic glycolysis. Glucose (1) is the primary metabolic fuel for the brain. Estrogen regulates the bioenergetic system in brain the through the estrogen receptors, GPER, ER-α and ER-β, and their activation of PI3K and downstream Akt and MAPK–ERK signalling pathways. When the glucose pathway is compromised, for example, during starvation, acetyl-CoA can be generated from ketone bodies via ketogenesis in the liver and transported through the blood to the brain through monocarboxylate transporters (2) or from fatty acid via β-oxidation (3).

During the perimenopausal transition, neuronal levels of glucose transporters decline, which is co-incident with the appearance of hypometabolism in the brain. The brain adapts to this decline in glucose availability by increasing reliance on ketone bodies as an alternative fuel to generate acetyl-CoA required for entry to the TCA cycle (4) and ultimately generation of ATP via complexes of the mitochondrial redox carriers (5).

Initially, ketone bodies are derived from the periphery by lipid metabolism in the liver. Depletion of peripheral sources of ketone bodies can result in metabolism of brain-derived fatty acids to generate ketone bodies via β-oxidation in glia cells (3).

Hot Flushes

Increasing evidence also indicates an association of the hot flush with altered glucose metabolism. Preclinical studies of bioenergetics using animal models of the female brain during perimenopause indicate that the rise in skin temperature is co-incident with the onset of reproductive variability and senescence. Levels of glucose metabolism in the brain also decline. Furthermore, glucose tolerance is compromised in the periphery (which is indicative of insulin resistance) and increased use of ketone bodies and fatty acid metabolism occurs. Consistent with these preclinical findings, analysis in humans using 18F-FDG-PET indicate a decline in brain glucose metabolism in the brain occurs during late perimenopause and continues into postmenopause.

In the SWAN study, hot flushes or night sweats were strongly associated with dysregulation in glucose metabolism, which was indicated by considerably increased levels of fasting blood glucose and raised HOMA scores. The relationship between estrogen receptors and insulin receptors in the brain is well established and provides additional evidence for the contribution of decline in estrogen levels to dysregulated glucose metabolism.

Moreover, an association between impairment of the adipokine profile and occurrence of hot flushes early in the perimenopausal transition has been described, which also supports a link between metabolic dysregulation and hot flushes. Decreased adiponectin and increased leptin levels were associated with increased risk of hot flushes in early, but not late, stages of the perimenopause transition. This altered adipokine profile parallels BMI measurements of women with stage-dependent risk of hot flashes, such that a high BMI was associated with increased risk of hot flushes in early, but not late, in the perimenopausal transition. Increased serum levels of inflammatory cytokine monocyte chemotactic protein 1 (also known as C-C motif chemokine 2) were associated with an increased risk of night sweats, regardless of menopause stage.

Collectively, these data indicate a strong association between hot flushes and impaired glucose homeostasis in both the brain and the periphery of women undergoing perimenopause.

Cognition

Glucose metabolism in the brain is established as being critical to neurological function and that evidence of hypometabolism is apparent several decades before diagnosis of neurodegenerative diseases such as Alzheimer disease. Depression Increased risk of depression in perimenopausal women is supported by evidence from several longitudinal studies that have documented odds ratios ranging from 1.8 to 2.9 of increased risk compared with women in premenopause.

During perimenopause, both hot flushes and depression can occur early in the transition in women with no previous history of these symptoms although depression was more likely to precede hot flushes. In perimenopausal women who had depression, short-term 17β-estradiol treatment had antidepressant efficacy.

Increased risk of major depression has been linked to variants of ER-α. For example, in one study, women homozygous for the ESR1 rs9340799 variant G had a 1.6-fold increased lifetime risk of major depressive disorder. Glucose metabolism in brain regions that regulate depression and anxiety is complex, with different metabolic phenotypes in the pons (where the serotonergic raphe nucleus and locus coeruleus adrenergic systems originate) and frontal cortices.

Compared with women in postmenopause without depression, those with depression have hypometabolism in the pons and hypermetabolism in the middle and inferior (Broca’s) frontal gyrus. In women in postmenopause aged >65 years without depression, regional cerebral blood flow was increased in the left pons, which suggests a link to metabolism in the pons and an absence of depressive symptoms.

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