For three decades, Dr. Rhonda Voskuhl has studied how estrogen protects the brain — and what its loss in menopause does to memory and focus. That work began with her multiple sclerosis patients, whose cognitive symptoms eased during pregnancy, and led to the estriol research behind PearlPAK®. The studies below trace it, from the earliest findings to the newest UCLA research.
Translational Medicine
2002-2018, Estriol treatment in MS women anti-inflammatory, reduced brain lesions and improved cognition.
2016-2022: Estriol treatment improved cognition, reduced brain atrophy, reduced blood biomarker in MS.
R2023: Menopause mouse model: ERβ target for better cognition, less brain atrophy, less pathology at midlife.
2023-2026: Estriol treatment (PearlPAK®) in healthy menopausal women improved cognition.
Decades of research have examined how estriol influences the brain, immune system, and cognition. Select a topic to see the studies behind it.
“Targeting hormone treatment for the brain in menopause.”
Twenty menopausal women treated with PearlPAK® for twelve months showed significant improvement in brain fog, concentration, memory, and processing speed — the oral first published study of estriol treatment in healthy menopausal women.
“Estrogen receptor β in astrocytes modulates cognitive function in mid-age female mice.”
In midlife female mice, the loss of ovarian hormones led to shrinkage in the hippocampus and measurable cognitive decline, while younger mice were spared. The protective factor was estrogen receptor beta (ERβ) in the brain’s support cells — the same receptor estriol is built to target.
“The X Factor in Neurodegeneration.”
In this review, Dr. Voskuhl explains how sex chromosomes and declining hormones make neurodegeneration different in women — and why brain-protective treatment should be designed for female biology rather than borrowed from studies of men.
“Neuroprotection in cerebral cortex induced by the pregnancy hormone estriol.”
Estriol — the estrogen the body produces in pregnancy, and the active ingredient in PearlPAK® — preserved neurons and the connections between them in preclinical models, supporting its role in maintaining cognition.
“Estriol-mediated neuroprotection in multiple sclerosis localized by voxel-based morphometry.”
Imaging revealed that estriol treatment protected gray matter in specific regions of the cortex, and that the protection tracked with better scores on cognitive testing.
“Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis.”
In preclinical models, estriol treatment limited gray matter loss — the kind of protective effect that underpins its potential for preserving cognition.
“Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease.”
Estriol helped maintain signaling in the hippocampus — the seat of memory and word retrieval — under conditions that would otherwise disrupt it.
“Oestrogen receptor β-ligand acts on CD11c⁺ cells to mediate protection in experimental autoimmune encephalomyelitis.”
This work traced the specific immune cells estriol acts on to reduce inflammation and protect brain tissue — the mechanism behind the clinical results.
“Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis.”
By mapping how brain cells rebuild their protective coating, the team identified cholesterol regulation as a promising target for restoring damaged tissue.
“Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles.”
Researchers identified an X-chromosome gene that helps explain why women are more likely to develop multiple sclerosis — part of the larger effort to understand how sex shapes brain health.
“Treatment of multiple sclerosis with the pregnancy hormone estriol.”
Twenty years ago, Dr. Voskuhl reported that estriol — the hormone that had eased her patients’ symptoms during pregnancy — could be a safe and effective treatment. It laid the groundwork for everything that followed.
“Estriol combined with glatiramer acetate for relapsing-remitting multiple sclerosis: a randomized, placebo-controlled phase 2 trial.”
In a placebo-controlled phase 2 trial, adding estriol to standard treatment reduced disease activity over the long term — clinical confirmation that estriol reaches the brain and does something measurable there.
“Decreased neurofilament light chain levels in estriol-treated multiple sclerosis.”
Women treated with estriol showed a significant drop in neurofilament light chain — a blood marker of nerve injury — compared with placebo, direct evidence that estriol protects the nervous system.
From clinical trials in multiple sclerosis to the molecular pathways of midlife memory, each chapter has moved the same question forward.
Dr. Voskuhl’s approach has always been bench to bedside. She’s a rare number of physician-scientists who run a continuously funded research program while still seeing patients every week in her own clinic — a finding in the lab isn’t where the work ends, it’s the reason to ask what it means for the woman in front of her. That combination is what carried a small 2002 pilot study all the way to the research behind PearlPAK today.
6 cognitive domains · 12 months · 100% reported improvement
The Neurologist behind it all
Long before the clinical trials included women, and long before studying sex differences considered worth researching, Dr. Voskuhl was asking why women’s brains respond to disease differently than men’s. Professor of Neurology at UCLA and Director of the UCLA MS Program, her research is the reason PearlPAK® targets the female brain specifically, rather than starting from treatments designed around men.
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PearlPAK® is designed to target the brain for women in menopause. See the product.
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