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In the absence of estradiol, brain glucose transport diminishes significantly. This effectively starves the brain for energy inducing severe bioenergetic deficiencies with all of the concordant neuronal damage one might expect. The reduction in glucose affects the mitochondria severely. Recall that glucose is one of the major fuel substrates of the brain, particularly where the Western diet predominates. The decline of glucose transport, therefore, is significant, and alone, without any other changes to the mitochondria, elicits a cascade of deleterious reactions. Oxidative phosphorylation and associated enzymes are downregulated, ATP production wanes, and ultimately may initiate the deformation of the very shape of the mitochondria, as observed in the research cited above. The ensuing reduction of ATP starves the brain of critical energy but also induces a state of hypoxia with the mitochondria incapable of utilizing molecular oxygen. With that hypoxia, inflammatory pathways are initiated further cementing mitochondrial death spirals and associated neuronal damage.

Interestingly, this reduction in aerobic activity coincides with the emergence of a ketogenic phenotype. That is, with the loss of one fuel substrate, ketones become the dominant source of fuel and the associated enzyme machinery is upregulated. Unfortunately, the Western diet is highly dependent upon carbohydrates and so a woman experiencing this loss of estradiol is not likely to consume sufficient fats and proteins to effectively weather this shift. Nevertheless, it does provide an opportunity for recovery. What if women who have lost the ability to produce sufficient estradiol either because of surgically (oophorectomy) or chemically (Lupron and other GnRH analogs) induced menopause adopt a ketogenic diet? Could we maximize the preferred energy source of the post-menopausal brain and reduce the neurological symptoms?

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