Targeting hormone treatment for the brain in menopause.

Estrogens are neuroprotective, and menopause may contribute to neurodegeneration. Estriol preferentially binds estrogen receptor beta (ERβ) in brain to induce neuroprotection. Previously, oral estriol improved cognitive processing speed and reduced cerebral cortex atrophy at treatment month twelve in women with multiple sclerosis (MS). Here, treatment with a blisterpack designed for healthy menopausal women which contains estriol and progesterone (Pearlpak) was assessed for its effect on cognitive domain-specific symptoms in a case series of twenty menopausal women (mean age 53.5 years). At treatment month twelve, there were significant improvements in self-reported brain fog, concentration, working memory, processing speed, verbal memory, and problem solving. A preclinical model explored mechanisms. Midlife female mice (age 12-13 months), previously ovariectomized either at 2 months or at 11 months of age, exhibited cognitive deficits on Morris Water Maze, with glial activation and synaptic loss on dorsal hippocampal pathology. Astrocytes had increased levels of Enolase 1 (ENO1), a key protein in glucose utilization. Increased ENO1 correlated with worse cognitive performance. Deletion of ERβ in astrocytes in gonadally intact midlife females recapitulated deleterious effects of ovariectomy. Conversely, treatment of midlife female mice with estriol from age 11 months to age 12 months reduced ENO1 expression in hippocampal astrocytes, reduced glial activation and synaptic loss, and improved cognitive performance. This preliminary study suggests that Pearlpak treatment for cognitive symptoms of menopause warrants further investigation given the safe use of these hormones in Europe and Asia for decades to reduce other menopausal symptoms.