Estrogen Therapy May Help Relieve Menopausal Brain Fog, Suggests Study
USA: An estrogen hormone therapy combining estriol and progesterone may improve cognitive symptoms commonly described as “brain fog” in menopausal women, according to a small case series published in Scientific Reports.
Researchers from UCLA evaluated Pearlpak treatment in 20 menopausal women and examined its effects on specific cognitive domains. The findings suggest that hormone therapy may offer potential benefits for menopause-related cognitive complaints, although larger controlled studies are needed to confirm its effectiveness and underlying mechanisms.
The study was led by Noriko Itoh from the Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, USA, and colleagues. The researchers focused on the potential effects of estrogen on brain health, noting that estrogen has neuroprotective properties and that hormonal changes during menopause may contribute to neurological and cognitive changes.
The investigators assessed Pearlpak, a blister-pack hormone treatment containing estriol and progesterone, in a case series involving 20 menopausal women with a mean age of 53.5 years. Estriol was of particular interest because it preferentially interacts with estrogen receptor beta (ERβ), which is involved in neuroprotective pathways in the brain.
After 12 months of treatment, participants reported significant improvements across several cognitive symptoms and abilities. These included brain fog, concentration, working memory, processing speed, verbal memory, and problem-solving. The findings build on earlier research in women with multiple sclerosis, in which oral estriol was associated with improved cognitive processing speed and reduced cerebral cortical atrophy after 12 months.
To investigate potential biological mechanisms, the researchers also conducted experiments in a preclinical mouse model. Midlife female mice that had undergone ovariectomy earlier in life demonstrated cognitive impairment in the Morris Water Maze test, along with increased glial activation and loss of synapses in the dorsal hippocampus.
The study led to the following findings:
- Midlife female mice showed increased ENO1 levels in astrocytes, with higher levels linked to poorer cognitive performance.
- ERβ deletion in astrocytes reproduced cognitive impairment, glial activation, and synaptic loss similar to those seen after ovariectomy.
- One month of estriol treatment reduced ENO1 expression in hippocampal astrocytes, lowered glial activation and synaptic loss, and improved cognitive performance.
- The findings suggest that ERβ signaling and ENO1 activity in hippocampal astrocytes may contribute to estriol’s potential effects on cognitive function during menopause.
The researchers emphasized that the human findings come from a small, uncontrolled case series, meaning the results cannot establish that Pearlpak caused the observed cognitive improvements. Larger randomized and controlled studies will be needed to determine its effectiveness, safety, and mechanisms.
The study highlights a potential approach of developing organ-specific hormone therapies based on estrogen receptor activity, with the aim of maximizing benefits in tissues such as the brain while limiting unwanted effects in other organs. The authors suggested that comprehensive menopause care could help evaluate the effects of targeted treatments across multiple organ systems.
Reference:
Itoh, N., Itoh, Y., Patil, R., Till, C., Smith, M., Schwartz, J., Davis, B., Oberman, E., Romeroso, B. D., & Voskuhl, R. R. (2026). Targeting hormone treatment for the brain in menopause. Scientific Reports, 16(1), 25901. https://doi.org/10.1038/s41598-026-65603-4
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