Menopause Brain Fog Study: New Research on Estriol

By CleopatraRX | Medically Reviewed by Manasa Murthy, PharmD | Updated July 2026

The Symptom That Gets Explained Away

For decades, women have described the same thing in Dr. Rhonda Voskuhl’s clinic. A name that will not come. A meeting once run from memory, now run from notes. Most had already been told it was stress, poor sleep, or simply their age. This month, Dr. Voskuhl and her colleagues are published a study that speaks directly to what those women were describing: the cognitive symptoms of menopause, and what happens when they are treated at their source.

Brain Fog Has a Biology

Before the study itself, two facts deserve naming. First, the “brain fog” of menopause is common, and it is not vague. It occurs in roughly 62% of menopausal women, and it shows up as measurable problems in specific cognitive domains: verbal memory, working memory, concentration, and processing speed. Second, these changes track with the loss of estrogen acting in the brain, including in the memory region (the hippocampus), which can show abnormalities on MRI during this transition. Brain fog has a biology. That is where Dr. Voskuhl says any honest treatment has to begin.

It Began With Multiple Sclerosis

Dr. Voskuhl’s work on estrogen and the brain did not begin in menopause. It began in multiple sclerosis. Two thirds of patients with MS are women, and many report that their disease quiets during pregnancy, then worsens in the months after delivery. The hormone that rises most in pregnancy is estriol, an estrogen the body makes in quantity only when a woman is carrying a child. In clinical trials, women with MS treated for twelve months with oral estriol showed improved processing speed and reduced atrophy of the cerebral cortex on MRI, and basic research in MS models identified the brain cell and the estrogen receptor responsible. The through-line, from the beginning, was estriol.

Two Estrogens, Two Receptors

Estrogen does not act through a single door. It works through receptors, and two of them matter most here. Estradiol, the estrogen of the menstrual cycle, binds strongly to estrogen receptor alpha (ERα), which is concentrated in breast tissue. Estriol binds primarily to estrogen receptor beta (ERβ), which is concentrated in the brain and which a number of research groups have found to play a protective role during aging. Dr. Voskuhl’s research has focused on receptor beta specifically for its possible role in brain health. How differences in receptor binding relate to other outcomes, including breast tissue effects, remains an active area of study, not a settled comparison between the two hormones.

That distinction is also why Dr. Voskuhl reads the major hormone-cognition trials differently than the field has tended to. The KEEPS cognitive study and the Women’s Health Initiative — both widely cited as evidence that hormone therapy doesn’t help cognition — tested transdermal estradiol or conjugated equine estrogens, not estriol. Neither found a cognitive benefit. But neither tested a therapy selective for the brain-associated receptor, either. Whether that distinction explains the difference is a hypothesis her research is built to test, not a claim she considers settled — and it isn’t a basis for comparing estriol’s effectiveness or safety against FDA-approved therapies, which has not been established in head-to-head trials.

Inside the Study: From Mice to Women

The study has two parts. In the first, researchers returned to the laboratory. Midlife female mice whose estrogen was removed developed cognitive deficits, along with inflammation, a loss of the connections between neurons, and a rise in a specific protein in the brain’s support cells (ENO1, in astrocytes). When treated with estriol, or with a compound selective for estrogen receptor beta, that protein fell and the deficits reversed.

In the second part, researchers treated women. This was a case series of twenty menopausal patients, mean age 53.5, given tailored estriol in the morning and progesterone at night for twelve months. Over that year, the women reported significant improvement across six cognitive domains: brain fog, concentration, working memory, processing speed, verbal memory, and problem solving. The improvements held regardless of a woman’s age, her education, or whether she had used hormone therapy before.

What It Proves, and What It Doesn’t

This is a case series, not a placebo-controlled trial, and the cognitive improvements were reported by the women themselves. Every participant also had a college degree or more, so how far these results extend to the broader population is still an open question. Dr. Voskuhl doesn’t call it the final word, and larger controlled studies are the necessary next step. Still, this is the first time this specific approach has been documented across a full year, and the direction is consistent with three decades of work behind it. The study is published this month in Scientific Reports.^[1]

Why Twenty Women Matter to Millions

Each woman will be estrogen deficient for roughly a third of her life, from her early 50s to her early 80s. The average chief executive is hired at 54 — about the same age the average American woman reaches menopause. The years when the brain is asked to do the most are the same years it is quietly losing the estrogen it was built to run on. Menopause has long been discussed mainly through hot flashes. For a great many women, Dr. Voskuhl argues, the cognitive symptoms are the more consequential story, and they deserve to be measured.

Two thirds of Alzheimer’s patients are women, and while no one has shown that the cognitive symptoms of menopause lead to Alzheimer’s, a longitudinal study is now following the same women for years to ask whether the domain-specific changes seen at menopause raise that later risk. This is a short-term result, not a promise about Alzheimer’s, and Dr. Voskuhl is careful not to frame it as one.

She believes menopause treatment needs to move toward estrogen receptor–specific targeting, the way pharmaceuticals for other conditions already have — larger studies, and the same rigor for the female brain that’s long been extended to every other organ. It’s also why she didn’t wait for someone else to do it. Her research is the foundation for PearlPAK®, a compounded estriol and progesterone protocol available nationwide through CleopatraRX telemedicine. As a compounded product, PearlPAK® is not FDA-approved. It is intended for use under the supervision of a qualified clinician.

Reference

[1] Scientific Reports, DOI: 10.1038/s41598-026-65603-4

---