Estrogen is often compared to Meryl Streep due to its remarkable versatility, as noted by researchers. It is not only crucial for sexual and reproductive health, but also enhances bone strength, maintains skin elasticity, regulates blood sugar, boosts circulation, reduces inflammation, and supports the central nervous system.
“You name an organ, and it aids its health,” states Roberta Brinton, a neuroscientist and director of the Center for Innovation in Brain Science at the University of Arizona.
However, the broader significance of estrogen has taken time to be acknowledged. Since its discovery in 1923, it has primarily been labeled as the “female sex hormone,” limiting its perceived importance to a single dimension.
The term “estrogen” derives from the Greek word “oestrus,” which refers to the frenzied state of animals in heat. Scientifically, estrus describes the time in some mammals’ reproductive cycles when females are fertile and sexually active.
Women experience menstruation instead of estrus. Nonetheless, when estrogen was named, its roles were narrowly defined: inciting excitement and aiding female sexual health. Presently, estrogen is being recognized for its pivotal role in brain function.
Research indicates that estrogen is essential for healthy brain development, but it is also implicated in conditions such as multiple sclerosis and Alzheimer’s. Fluctuations in estrogen levels—whether due to menstrual cycles or other influences—can worsen migraines, seizures, and various neurological issues.
“Many neurological disorders can be influenced by fluctuations in sex hormones,” asserted Dr. Hyman Schipper, a neurologist at McGill University, who identified a dozen such conditions in a recent journal article. “Numerous reproductive therapies could be adapted for these neurological disorders.”
The growing recognition that sex hormones influence brain health is shifting how healthcare providers manage brain conditions—allowing them to tailor treatments, prevent negative interactions, and create new hormone-based therapies.
In women, estrogen is primarily produced in the ovaries, along with contributions from adrenal glands and fat tissues. Men, on the other hand, convert testosterone into estrogen in their testes, where it is essential for sperm production, bone health, liver function, fat metabolism, and other processes.
However, both men and women’s brains also generate estrogen, highlighting its importance in neuroscience. “The brain functions as a sort of endocrine organ,” explains Lisa Mosconi, a neuroscientist leading the Women’s Brain Initiative at Weill Cornell Medicine.
The brain has numerous estrogen receptors that activate and deactivate over a person’s lifetime. Initially thought to be confined to areas involved in reproduction like the pituitary and hypothalamus, these receptors are actually spread throughout the brain, according to Dr. Mosconi, who developed a PET-scanning method to visualize them in living brains. “We couldn’t find any brain region without them,” she noted.
Estrogen can attach directly to receptors in neurons and other cells, initiating a chain reaction of biological activities. It can also be metabolized into neurosteroids, which have their own wide-ranging effects.
Some neurosteroids are already utilized in therapies; for instance, Allopregnanolone, a progesterone metabolite, is used to treat certain epilepsy types. This same metabolite is under clinical investigation as a potential regenerative treatment for Alzheimer’s.
During pregnancy, a mother’s estrogen is critical for organizing the embryo’s neural pathways, directing brain cell production, and promoting the growth of various brain regions. At significant life stages such as puberty, pregnancy, and menopause, estrogen aids in remodeling and refining the brain.
Yet researchers now understand that estrogen influences brain development throughout life. It can affect neuron activity, lessen inflammation, promote brain plasticity, convert glucose to energy, prevent plaque accumulation, and enhance cerebral blood flow.
Not every effect is beneficial; Dr. Schipper has observed that prolonged estrogen use in rodents can age certain brain regions. “No hormone solely performs one function,” he remarked.
Pregnancy and the brain
Historically, neuroscientists understood that estrogen had effects beyond reproductive functions, yet they tended to overlook them. Before 2016, female animals were generally excluded from studies to avoid dealing with hormonal variations and their associated behavioral and physiological differences.
“How can we discover if estrogens are neuroprotective if we never study females?” questioned Dr. Rhonda Voskuhl, a neurologist at UCLA’s Comprehensive Menopause Program. “It’s ridiculous.”
In 1998, Dr. Voskuhl was looking for a molecule that could shield the brain from multiple sclerosis, an illness that causes the immune system to attack nerve cells, damaging their protective sheath. This condition affects around one million Americans, predominantly women.
While existing drugs help reduce inflammation and prevent further nerve damage, they are limited. “We need something that directly targets the brain,” Dr. Voskuhl stated.
Her investigation began with a clinical observation: Pregnancy was known to alleviate M.S. symptoms. During the third trimester, relapse rates drop significantly; pregnancy offers protection akin to the best treatments. Unfortunately, this protective effect is temporary, with relapse rates soaring after childbirth.
She realized that the immune system calms down during pregnancy, likely to safeguard the developing embryo, but she believed there was more at play. “It stands to reason that the mother would produce something that is both anti-inflammatory and neuroprotective,” she theorized.
This protective substance was found to be estriol, a type of estrogen mainly created by the placenta. In a 2016 randomized clinical trial involving 164 women, Dr. Voskuhl demonstrated that estriol treatment over two years led to a notable decrease in M.S. relapses, along with improvements in cognitive function and reduced gray matter loss.
Estriol has been deemed safe, with menopausal women in Europe using it for many years. Unlike estradiol, it does not bind significantly to breast receptors, reducing its long-term breast cancer risk. Dr. Voskuhl mentioned that it might also have applications for men, calling it “a gift to scientists.”
Currently, Dr. Voskuhl is investigating whether this finding applies to all women going through menopause, not just those with M.S. She has created a hormone therapy named PearlPAK, which includes estriol and is marketed by CleopatraRX, where she serves as a medical advisor.
The company claims that PearlPAK can help with “memory and cognitive health problems associated with menopause.” However, Dr. Voskuhl is conducting annual cognitive tests on women using PearlPAK to verify this claim. She believes it’s crucial for women to have answers without having to wait for the unlikely prospect of funding from the N.I.H. or a pharmaceutical company for a randomized clinical trial. “I’m just trying to apply the methods used in M.S. research to menopause,” she explained.
A complicated legacy
This isn’t the first time therapeutic estrogen has been promoted as a panacea for cognitive ailments in menopausal women. “Before 2000, estrogen seemed like a miracle solution,” said Dr. Schipper.
At that time, estrogen was believed to protect the aging brain from strokes and Alzheimer’s, a notion bolstered by several animal studies and a few human observational studies.
That perspective shifted in 2003. The Women’s Health Initiative Memory Study, a pivotal clinical trial that examined the long-term effects of hormone therapy in postmenopausal women, discovered that older women on estrogen — as opposed to those taking estrogen with progesterone — faced double the risk of dementia compared to those on a placebo.
As a result, physicians shifted away from prescribing estrogen to postmenopausal women, and women began to avoid it out of concern. The prevailing sentiment among many researchers became: “Why bother studying it? No one will take estrogen anymore, so there’s no point,” remarked Margaret McCarthy, a neuroscientist at the University of Maryland. “It was detrimental to research.”
Subsequently, it became evident that this heightened risk applied mainly to women who initiated estrogen therapy at 65 years or older, more than a decade after their last menstrual cycle. A meta-analysis revealed that for women aged 50 to 55, the impact of estrogen on dementia risk was neutral. Younger women were not part of the Women’s Health Initiative.
“Timing is crucial,” stated Dr. JoAnn Manson, a W.H.I. researcher and neuroendocrinologist at Brigham and Women’s Hospital who led the meta-analysis. “Evidence is mounting that there’s a critical exposure window for estrogen with respect to potential cognitive advantages.”
Researchers had to move beyond the simplistic view of estrogen as a protector for the brain, delving into more intricate questions: When and how does this hormone safeguard cognitive function?
Investigating Alzheimer’s origins
The significance of estrogen in brain health is particularly clear during menopause, where its decline can lead to cognitive symptoms that many midlife women experience and dislike—such as hot flashes, disrupted sleep, and mental fog. Some neuroscientists assert that the drop in estrogen levels is a key factor in why Alzheimer’s disease affects women at nearly double the rate of men.
As estrogen diminishes, the brain’s metabolic processes change. Prior to menopause, the brain primarily uses glucose, a function aided by estrogen, but after menopause, it begins to utilize alternative energy sources, even deriving energy from its own white matter, as found in animal studies by Dr. Brinton.
“It’s like a starvation response,” she explained. “This isn’t tied to reproductive abilities, but rather signifies a transformative phase in the brain.”
This transition could indicate the onset of vulnerability to Alzheimer’s — and, in theory, it’s when estrogen therapy or other treatments might help stave off cognitive decline. However, Dr. Brinton couldn’t visualize this process in a human brain. In 2014, she sought assistance from Dr. Mosconi, a neuroimaging specialist.
At that time, doctors could only measure estrogen levels in the bloodstream. But Dr. Mosconi realized that millions of people were undergoing some form of estrogen therapy, and no one knew its effects on brain function. “It’s absurd,” she remarked. To address this, she devised an imaging technique to visualize estrogen receptors in the brain, adapting a tracer used to detect similar receptors in breast cancer.
In 2024, she and Dr. Brinton were astonished to find that after menopause, the quantity of estrogen receptors in the brain seemingly surged, likely to capture more of this hormone. However, intriguingly, a greater number of estrogen receptors correlated with poorer memory and cognitive performance.
In February, Dr. Mosconi initiated a $50 million research initiative funded by Wellcome Leap named Cutting Alzheimer’s Risk Through Endocrinology. She aims to identify women at the highest risk for Alzheimer’s due to estrogen-related brain changes and determine whether hormone therapy during a critical time could mitigate their risk.
The solution might not be straightforward, as understanding when to apply estrogen patches is just the start. “There’s a complex system that needs further exploration before we interfere,” she warned.
Bridging a neurological gap
As scientists enhance their understanding of how sex hormones influence the brain, some doctors are concerned that this critical information isn’t making its way into clinical practice quickly enough. “It significantly impacts my work,” said Dr. Schipper. “Every neurologist’s practice should be influenced by it.”
For instance, Dr. Schipper might increase a patient’s epilepsy medication during the late luteal phase of her menstrual cycle, when estrogen spikes raise the likelihood of seizures.
He would also steer clear of prescribing Dilantin, a well-known anticonvulsant, as many neurologists overlook its effect of accelerating liver metabolism, which can lead to the breakdown of hormones in birth control. This could result in unplanned pregnancies, which Dr. Schipper notes often go unconsidered.
Similarly, Dr. Jelena Pavlovic, a neurologist from the Albert Einstein College of Medicine in New York City, discovered that women prone to menstrual migraines are especially sensitive to headaches immediately after their uterine lining sheds, when estrogen levels drop sharply. Recognizing this relationship allows her to offer preventive treatment at the most effective times.
“We need to incorporate women’s health concerns into neurology,” emphasized Dr. Pavlovic, one of the few neurologists with expertise in headache disorders and sex hormones.
Dr. Voskuhl, whose work intersects both gynecology and neurology, concurred. She highlighted that when doctors treating neurological issues fail to share insights with those managing hormonal health— and vice versa—patients ultimately bear the brunt of it.
“The solutions are present,” she stated. “If these specialists would communicate, the answers are there.”
