While we tend to think of menopause as a strictly genitourinary condition, the truth is much more complex. Menopause also affects a woman’s bones, skin, colon, heart — and perhaps most surprisingly, her brain.
Women spend roughly a third of their lives as estrogen deficient, and the effects of that deficiency can be both acute and chronic. Many women in perimenopause experience hot flashes, night sweats, and sleep disruption, which can indirectly affect cognition. (It’s hard to think straight when you’ve been tossing and turning all night.)
But not every cognitive symptom can be explained by poor sleep. While hot flashes generally dissipate after three to seven years, cognitive issues can persist and even worsen after those hot spells end. Some women experience cognitive symptoms without ever dealing with hot flashes at all. Brain MRIs also show more abnormalities in regions associated with cognition — the hippocampus and prefrontal cortex — in women who have been menopausal for longer.
And while non-hormonal treatments (such as Veozah) can target the thermoregulatory center of the brain (the hypothalamus) to reduce hot flashes, they don't protect the brain's cognitive regions from the long-term effects of estrogen deficiency.
Why the most commonly prescribed estrogen doesn’t help with brain fog
Clinical studies conducted in the early 2000s focused on the use of conjugated equine estrogens and estradiol, and while these were shown to reduce hot flashes, safety issues made their use controversial.
One concern with oral estradiol was that it was converted to a metabolite that caused clotting, and a transdermal patch was made to mitigate this risk. However, the estradiol patch still binds strongly to an estrogen receptor (alpha) associated with breast cancer, so doctors limit its use to the lowest dose and shortest duration possible.
In 30 years of research, estradiol treatment has never been shown to improve cognition or prevent dementia, which is why the estradiol patch is FDA approved for hot flashes, not for help with reduced cognition.
An alternative for estradiol
Menopausal women with brain fog need more than the two choices they currently have, which are estradiol and, well, nothing.
One potential alternative is estriol. It's a different type of estrogen, one that protects the brain by binding a distinct estrogen receptor (beta) in brain cells, with only weak binding to the estrogen receptor (alpha) in breasts. Oral estriol treatment has been used safely in Europe for over 40 years for hot flashes, vaginal dryness, and other menopausal symptoms. It's still used orally, since it cannot be converted to a metabolite that causes clotting. When estriol is taken orally, it goes into the blood, then into the brain to bind to receptors on brain cells.
Estriol naturally forms during pregnancy, and multiple pregnancies have been shown to be beneficial for preventing later cognitive decline in healthy menopausal women. Through NIH-funded research at UCLA, my group showed that estriol treatment at midlife improves cognition and reduces regional brain atrophy and pathology in the menopause mouse model — a typical first step in uncovering drugs that will also help human beings.
Repurposing treatment from one condition to another
When a new treatment is needed, doctors often repurpose a drug that has already shown efficacy in one condition for use in another. The reasons why are clear: We already know how it works, and it has a proven safety record.
My research team first showed that estriol treatment binds to an estrogen receptor (beta) in brain cells to improve cognitive function and reduce regional brain atrophy and pathology in multiple sclerosis (MS) mice models. Next, we conducted two clinical trials in women with MS who took 12 months of oral estriol. They showed improved cognitive processing speed, decreased regional brain atrophy, and reduced levels of a neurodegenerative biomarker in the blood. This was not a mere slowing of decline in cognitive testing over months. It was a significant improvement compared to what we saw in women who took placebo pills. The potential application to menopause-related brain fog is clear.
Recently, we published results in Scientific Reports: "Targeting Hormone Therapy for the Brain in Menopause" was a case series of otherwise healthy menopausal women who took a tailored combination of oral estriol and progesterone for 12 months in a blisterpack (PearlPAK) patented by UCLA. They experienced significant improvement in brain fog, concentration, working memory, processing speed, verbal memory, and problem solving — all symptoms known to be affected by menopause, as measured by the Voskuhl Menopause Brain Fog Assessment. (If you’re wondering if you have menopause-related brain fog, you can take your own cognitive assessment here.)
Does menopausal brain fog increase risk for Alzheimer’s disease?
Two-thirds of Alzheimer’s patients are women, and early preventive treatment is key.
Mild Cognitive Impairment starts a decade before Alzheimer’s disease, presenting with subtle cognitive deficits. Whether menopause-induced cognitive issues represent an even earlier phase of the disease is under worldwide investigation. Around 60 to 70 percent of menopausal women report cognitive symptoms, but of course not all of them go on to develop Alzheimer’s. Other factors, such as genetics and lifestyle, also play a role.
Even if some time in the future cognitive issues of menopause are shown to correlate with increased risk of eventual Alzheimer’s disease, it will not be proof of causality, but only of an association. Proof of causality requires both the development of a treatment targeting cognitive issues of menopause and the ability to show that this treatment decreases later risk. Now is the time to develop that treatment.
The funding challenge in women’s health
Preclinical research in both MS and in menopause models, as well as in clinical trials in women with MS and a clinical case series in healthy menopausal women, have all shown brain-protective effects of oral estriol treatment at 12 months. These are converging lines of evidence that suggest that more research is warranted in menopausal women, including placebo-controlled clinical trials that include cognitive testing, brain imaging, and blood biomarkers similar to trials conducted on women with MS.
However, for FDA approval, two pivotal Phase 3 clinical trials in thousands of women are required. The cost for such research is likely to be over $50 million, and it will take at least eight years to complete. Many in big pharma are resistant to investing in a treatment like oral estriol and tailored progesterone in a blisterpack, because these are not new compounds — meaning they cannot charge $10,000 to$20,000 per year per patient.
Women can’t afford to wait
For now, however, we have a distinct type of estrogen — estriol — that has shown great promise for brain protection. I started a telehealth company, CleopatraRX, to bring this treatment not only to women who come to UCLA, but also to others who live in rural communities or inner cities across the United States. FDA approval is a future goal.
But as has been the case for over 20 years, the National Institutes of Health and other philanthropic organizations will likely continue to fund this research. Yes, many women need a solution now. But the good news is that we are making progress in addressing this unmet need, one step at a time.
Rhonda Voskuhl, M.D., is a professor at the University of California, Los Angeles. She is also the founding neurologist of the UCLA Comprehensive Menopause Program and the co-founder of CleopatraRx.
