Menopausal women with cognitive decline reported improvements in cognitive symptoms during 12 months of estriol-based hormone treatment.
In a case series, researchers included 20 menopausal women with a mean age of 53.5 years who were treated as part of standard patient care. The participants received oral estriol once daily for 12 months, while progesterone was prescribed according to clinical need. Estriol doses were 2 mg (n = 10), 4 mg (n = 7), and 8 mg (n = 3). Progesterone doses were 100 mg (n = 15), 200 mg (n = 2), and 0 mg (n = 3). There was no randomization, placebo group, or comparator treatment.
Cognitive symptoms were assessed at baseline and month 12 using the Voskuhl Menopause Brain Fog Assessment, a questionnaire designed to quantify self-reported brain fog, concentration, working memory, processing speed, verbal memory, and problem solving in menopausal women.
Scores showed statistically significant improvements across all 6 cognitive domains. In subgroup analyses examining age, education, recent systemic estradiol use, and estriol dose, all subgroups showed improvement, with no statistically significant differences in the degree of change between paired subgroups. The only baseline difference was less severe working memory difficulty among women with more than 16 years of education compared with those with 16 years.
The researchers conducted preclinical assessments in midlife female mice and found that ovariectomized mice developed cognitive deficits accompanied by glial activation, synaptic loss in the dorsal hippocampus, and increased expression of the ENO1 protein in astrocytes. Higher ENO1 expression was associated with poorer cognitive performance. Deleting estrogen receptor beta in astrocytes produced similar changes in gonadally intact mice.
Conversely, estriol treatment in the mice reduced ENO1 expression in hippocampal astrocytes, decreased glial activation and synaptic loss, and improved cognitive performance, suggesting that estrogen receptor beta signaling in astrocytes may contribute to estriol's effects on cognition.
The researchers noted that estriol could potentially affect cognition directly through estrogen receptor beta signaling in brain cells or indirectly through improvements in vasomotor symptoms and sleep. While not all women in the case series had vasomotor symptoms, all reported cognitive improvement.
The findings should be interpreted with caution. The clinical component included just 20 women, lacked randomization and comparison group, and used individualized hormone doses. Cognitive changes were measured using self-reported symptoms rather than objective neuropsychological testing. The researchers therefore could not establish causality or determine how much of the change was attributable to estriol, progesterone, or other factors.
“This preliminary study suggests that [estriol-based] treatment for cognitive symptoms of menopause warrants further investigation,” wrote lead study author Noriko Itoh, of the Department of Neurology at the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues.
Full disclosures of the study authors can be found in the study.
Source: Scientific Reports
