Treatment with an ER-β ligand reversed hippocampal neuropathology in mid-aged mice may offer a new therapy for menopause-related cognitive issues, according to new research presented at the ACOG Annual Clinical & Scientific Meeting in San Francisco.
Researchers focused on the role of estrogen receptor-β (ERβ) in astrocytes. Cognitive deficits and hippocampal atrophy in aging female mice were linked to synaptic loss and increased glial activation when ovarian hormones were depleted at midlife.
“Other studies have shown that stimulation of estrogen receptor beta in the brain is protective. This [study] shows for the first time the brain cell type and region where this protection occurs and does it in a natural aging model,” said lead author Dr. Rhonda R. Voskuhl in an interview with Conexiant. “The concept that both estrogen loss and midlife aging are synergistically deleterious is also new.”
Advanced RNA sequencing and pathway analysis of gene expression in hippocampal astrocytes from midlife female astrocyte-ERβ conditional knockout mice revealed differentially expressed pathways, including Gluconeogenesis I and Glycolysis I.
“The abnormal expression of the glucose metabolism gene found in mice was also found in humans,” said Dr. Voskuhl, as this study also included analysis in women comparing ages before versus after menopause.
Treatment with an ERβ ligand at midlife reversed dorsal hippocampal neuropathology in mice, underscoring the therapeutic potential of targeting ERβ in astrocytes.
“Treatment during menopause using a distinct estrogen that targets estrogen receptor beta could be used to improve cognitive deficits and prevent abnormalities in brain regions aligning with these cognitive functions,” Dr. Voskuhl said. “Notably, this estrogen (estriol) binds weakly to estrogen receptor alpha in breast, and it has been used widely in Europe for 40 years.”
Regarding limitations, Dr. Voskuhl said, “A clinical trial in women with multiple sclerosis has been done, with neuroprotection shown, as cited. However, this trial has not yet been done in menopausal women. When estriol was used for menopause widely in Europe, there was no assessment of whether there was improvement in cognition in a registry. Also, consistent and optimal estriol and progesterone doses were not used previously in humans, thereby creating variability.”
Dr. Rhonda R. Voskuhl holds a consulting role and shares in CleopatraRX, and Dr. Cassandra E. Meyer is employed by Genentech; other authors reported no conflicts.