Rhonda Voskuhl, MD, on estriol for cognitive symptoms of menopause

An estriol-and-progesterone regimen was associated with improvements in self-reported cognition over 12 months in a small case series of menopausal women, according to Rhonda Voskuhl, MD, of the department of neurology at the University of California, Los Angeles. The work, presented at The Menopause Society Annual Meeting, repurposes an approach Voskuhl’s group developed in multiple sclerosis (MS) to healthy women with cognitive symptoms of menopause.¹

The strategy centers on estriol, which binds primarily to estrogen receptor (ER) beta in the brain while binding weakly to ER alpha in the breast, Voskuhl said

From MS to menopause

Estriol is neuroprotective in MS models through ERβ, and prior oral estriol treatment in women with MS improved cognitive processing speed and reduced cerebral cortex atrophy at 12 months.¹ Repurposing that approach, investigators treated 20 menopausal women (mean age, 53.5 years) with an estriol-and-progesterone blisterpack and assessed them with the Voskuhl Menopause Brain Fog Assessment at baseline and 12 months.¹

At 12 months, participants reported significant improvements in brain fog, concentration, working memory, processing speed, verbal memory, and problem solving.¹

“It was only 20 women, but they all improved from month zero to month 12 of treatment,” Voskuhl said.

In a parallel mouse model, ovariectomized midlife females showed cognitive deficits, glial activation, and hippocampal synaptic loss, along with increased astrocyte Enolase 1 (ENO1), a protein central to glucose use; higher ENO1 tracked with worse cognition.¹ Deleting ERβ from astrocytes reproduced the effects of ovariectomy, while an ERβ ligand or estriol lowered ENO1 and improved cognition.¹

Limitations and next steps

Voskuhl was candid about the study’s main weakness, the absence of a placebo group.

“The problem with it is there was no placebo treatment. Everybody got drugged,” Voskuhl said. “You just don’t know until you have a placebo control.”

She noted that her group faced the same question in MS, where an early uncontrolled finding, published in Annals of Neurology, was later confirmed in a placebo-controlled trial in The Lancet Neurology that showed cognitive benefit and reduced brain atrophy at 1 year.

Voskuhl called for a comparative, controlled, multicenter trial in healthy women with cognitive symptoms of menopause, using cognition and brain imaging as endpoints.

“It'll probably take several years, but that's where we are. And I think there's a lot of promise,” she said. “I'm just very hopeful because I think the field is finally emerging… Women’s brains matter. They can’t cap out at age 50 and get insecure about their brain.”

Reference:

Voskuhl R. Itoh N, Itoh Y, et al. Targeting hormone treatment for the brain in menopause. Presented at: The Menopause Society Annual Meeting. October 20-24, 2026. San Diego, California.