By Rhonda Voskuhl, M.D., Professor of Neurology at UCLA, Co-Founder of CleopatraRX
I have spent my career seeing patients in the neurology clinic and doing NIH-funded research on estrogen and the brain. My goal is to harness clinical and neuroscience insights to prevent cognitive decline of brain aging due to menopause.
The Unmet Need
The U.S. has an aging population, given past successes in treating many diseases. Unfortunately, aging is associated with cognitive decline. This brings a new challenge for healthcare, society, and individuals living through it. The incidence of dementia is exponentially increasing, and Alzheimer’s disease patients are mostly (two thirds) women.
How do we meet this challenge? The answer lies in what we already know:
- Estrogen protects the brain in females.
- Estrogen levels drop in menopause and are gone for a third of life.
- Menopause can accelerate biologic aging.
- “Brain fog” occurs in about 70% of menopausal women.
What menopause brain fog is and what it is not
What it is: “Brain fog” of menopause is when some aspects of thinking become difficult. Women can’t think of a word, lose their train-of-thought, or forget things from a few days ago. Mental tasks become difficult or slower, and they lose confidence. They try to compensate by making lists, taking more time, avoiding new jobs. On brain imaging, years of being menopausal aligns with changes in parts of the brain that carry out these mental tasks.
What it is not: Not all cognitive areas are affected, and there is not a decrease in IQ. Menopausal women do not all have dementia. There is not global brain atrophy or pathology on MRI.
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Cognition during acute and chronic menopause: It’s more than hot flashes
Menopause affects multiple organs: brain, heart, bone, skin, colon, the genitourinary system and breast. There are acute and chronic changes. Acutely, many women in early menopause have hot flashes, night sweats, and poor sleep. This can indirectly affect cognition. That said, hot flashes dissipate on their own in 3-7 years in most women, while cognitive issues persist and worsen after hot flashes have stopped. Other women have cognitive issues of menopause and have never had hot flashes. The direct effects of chronic menopause on the brain are due to loss of neuroprotective estrogen. Since chronic effects can begin at the same time as acute effects, early preventative treatment is critical. Non-hormonal treatments that target the thermoregulatory center of the brain to reduce hot flashes do not prevent long term effects of being estrogen deficient on other areas of the brain involved in cognition.
Why wasn’t a treatment for brain protection during menopause developed in the past?
They tried, but used the wrong estrogen. Clinical studies of the early 2000s used Premarin (conjugated equine estrogens, oral) and estradiol (oral and transdermal patch). While they reduced hot flashes, they had safety issues that made their use controversial. Next, clotting risks induced by oral estradiol were mitigated by switching estradiol as a pill to estradiol as a transdermal patch. This bypassed liver-induced production of the estradiol metabolite that caused clotting. However, a concern with both estradiol pill and estradiol patch remains: it binds strongly to the estrogen receptor (alpha) associated with breast cancer. This concern limited its use to the lowest dose, the shortest duration, and the youngest ages possible. Neither Premarin, nor estradiol, were shown to significantly improve cognition or prevent dementia. They remain FDA approved for treatment of hot flashes, not cognition. Basic research suggests some possible protective effects of estradiol on brain. But for brain protection, higher doses work better than lower doses, and long treatment duration is required. Thus, the risk:benefit ratio of estradiol makes it not clinically feasible to protect the brain from chronic effects of menopause.
Estriol is the alternative for estradiol.
Menopausal women need more than two choices: A) estradiol, or B) nothing. The alternative is C) estriol. Estriol is a different type of estrogen, one that protects the brain by binding a distinct estrogen receptor (beta) in brain cells, with weak binding to the receptor (alpha) in breast. Estriol naturally forms during pregnancy, and multiple pregnancies are beneficial for preventing later cognitive decline in healthy menopausal women. Oral estriol treatment has been used safely in Europe for over 40 years for hot flashes, vaginal dryness, and other menopausal symptoms. It is still used orally, since it cannot be converted by the liver into the metabolite that causes clotting. Evidence that estriol is brain protective can be found from neuroscience in the menopause model where it improved cognition and reduced regional brain atrophy and pathology. Further, in a case series of menopausal women taking oral estriol for 12 months in a blisterpack patented by UCLA for menopausal women (PearlPAK), there was significant improvement in the cognitive symptoms known to be affected by menopause (as measured by the Voskuhl Menopause Brain Fog AssessmentTM). [1]
As a compounded product, PearlPAK® is not FDA-approved, and has not been established as safer or more effective than FDA-approved hormone therapy. It is intended for use under the supervision of a qualified clinician.
Repurposing treatment from one condition to another.
Thinking outside the box: When a new treatment is needed for a given condition, neurologists repurpose a drug that is known to be effective in one condition for use in another. That’s because a lot is known about how it works and its safety. Estriol has been investigated in women with multiple sclerosis (MS) for decades. MS affects women three times more often than men, MS gets better during pregnancy when estriol levels are high, and multiple pregnancies are protective from long term disability. Cognitive decline also occurs in MS. Several peer reviewed, high impact, science publications have provided evidence that estriol is neuroprotective. This included the MS model showing brain protection by estriol binding to estrogen receptor (beta) in brain cells to improve cognitive function and reduce regional brain atrophy and pathology. Two clinical trials in women with MS showed that estriol treatment reduced inflammation in brain and decreased regional brain atrophy by MRI, improved cognitive processing speed testing, and reduced levels of a disease biomarker in blood. These benefits in women were observed after taking oral estriol treatment for 12 months, with results significant as compared to placebo control treatment.
Does brain fog of menopause today increase risk for Alzheimer’s disease later?
Two thirds of Alzheimer’s patients are women. Early preventive treatment of Alzheimer’s disease is better than later treatment. Mild Cognitive Impairment is the condition that starts a decade before Alzheimer’s disease, when there are subtle cognitive deficits. Whether menopause induced cognitive issues represent an even earlier phase, one preceding Mild Cognitive Impairment, is unknown and under investigation world-wide. Since around 70% of menopausal women report cognitive symptoms, not all go on to develop Alzheimer’s disease. Other factors such as genetics and lifestyle also play a role. Looking ahead, even if cognitive issues of menopause are eventually shown to correlate with development of Mild Cognitive Impairment and Alzheimer’s disease 10-15 years later, that will not be proof of causality. It would only be an association across time. Proof requires 1) development of a treatment targeting cognitive issues of menopause, then 2) showing that preventative treatment decreases later risk. Now is the time to develop that treatment, one designed to improve cognitive symptoms of menopause.
My Vision for the Future
Estrogen deficiency has acute and chronic effects. There are chronic effects of being menopausal not only for the brain, but also for the genitourinary system, bone, heart, metabolism, colon, and skin. Comprehensive menopause clinics manage both acute and chronic symptoms, which are not mutually exclusive. They start as acute effects, are overlaid by chronic effects, and have overlap. Early, preventative treatment is key. My goal is to disentangle mechanisms underlying chronic effects of estrogen deficiency on cognition, so we can prevent them using treatments targeting specific estrogen receptors that protect the brain, with minimal binding to estrogen receptors in other organs than confer toxicity (like breast). Estrogen receptor specific treatments are the window of opportunity for optimally tailored MHTs of the future. This estrogen receptor based strategy can be applied to each menopause symptom to discover optimally tailored MHT for each woman’s primary health concern.
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References
[1] Itoh N, et al. Targeting hormone treatment for the brain in menopause. Scientific Reports. 2026;16:25901. https://www.nature.com/articles/s41598-026-65603-4
[2] Voskuhl RR, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurology. 2016;15(1):35–46.
[3] Sicotte NL, et al. Treatment of multiple sclerosis with the pregnancy hormone estriol. Annals of Neurology. 2002;52(4):421–428.
[4] Itoh N, et al. Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice. Nature Communications. 2023;14:6044.
[5] Voskuhl R, et al. Decreased neurofilament light chain levels in estriol-treated multiple sclerosis. Annals of Clinical and Translational Neurology. 2022;9:1316–1320.
[6] Ziehn MO, et al. Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease. Laboratory Investigation. 2012;92(8):1234–1245