What Exactly Happens Inside a Woman’s Brain After Menopause? This Groundbreaking Study Has the New, Exciting Answers

For years, Lisa Mosconi, MD, has been shouting from the rooftops that menopause doesn’t just impact our ovaries, it reshapes our brains. And this week, the neuroscientist published a new, groundbreaking study that offers more proof that the dip in estrogen during the menopause transition literally changes the female brain.

For the first time ever, Dr. Mosconi and her colleagues measured estrogen activity in the brain, showing us exactly what happens as the hormone starts to wane. It’s giving them some new ideas about what that might mean for women’s brain health. 

Dr. Mosconi has been working tirelessly on this research for the last five years. First, she had to develop a molecule that would trace estrogen activity in the brain during PET scan imaging—something that had never been done before. Then, she had to recruit premenopausal, perimenopausal, and post-menopausal women to join the study, and have them take this experimental estrogen tracer before undergoing brain imaging. But once the study was under way, what Dr. Mosconi found was jaw-dropping: Estrogen receptors in the female brain don’t shut down after menopause, as previously thought. Instead, the female brain makes more estrogen receptors in the perimenopause and postmenopausal periods, indicating the female brain is hungry for estrogen during this big hormonal transition—eager to sop up as much estrogen as possible. 

In an interview with The Sunday Paper, Dr. Mosconi shares more details about the results of her game-changing study and what it could mean in our quest to better understand women’s brain health as we age.

A CONVERSATION WITH DR. LISA MOSCONI

Tell us a bit about how this study came to be.

I’ve been looking at women’s brains for a long time, but we were always looking at menopause in terms of the distal effects of something that we believe to be the cause of the effects: Estrogen withdraws, and we know that estrogen is protective for brain health. So, the assumption is that the changes in estrogen concentrations in the brain are leading to the changes in gray matter volume, changes in connectivity, changes in brain energy levels, and changes in Alzheimer's plaques.

But this is this is just an idea based on animal models. However, mice don't go through menopause—certainly not the way that women do. And mice don't develop Alzheimer's either. I really wanted to see what happened in women.

So, in 2019, I went to my radio chemistry department at Weill Cornell—which is one of the best in the world—and I told the chief of radiochemistry, “I need a tracer for brain estrogen.” And he said to me, “Well, good luck with that!” Nobody had developed it. There are tracers for estrogens from the neck down, which we use to study estrogen-dependent cancers. But it’s very hard to get a tracer inside your brain and get a measurable signal. 

I thought, “This is unacceptable.” If you think about it, 151 million American women on are on hormonal birth control. Another 14 million or more are taking hormones for menopause. Hundreds of thousands of women start hormonal therapy for cancer every single year. And we have no clue what any of these treatments do to your brain other than what women report, which nobody believes.

So, you made the tracer that enabled you to study estrogen in women’s brains in a way that had never been done before?

Yes! It's not easy to make a tracer. You need to really understand the biology of estrogen and how it works, and especially the way that estrogen works together with its receptors. 

Hormones alone don’t matter; they’re just the message carriers. You need this information hormones carry to be read, and the reader—the decoder of the messages hormones carry—is the hormone receptor.

What really matters is the way that estrogen binds to the receptor, how long it stays with the receptor, and how strongly it's connected. And then that whole thing becomes a unit that travels inside brain cells, all the way to the nucleus of the cell, to communicate information: I need more neuroplasticity. I need more energy. I need more blood flow. I need more immunity. I need more connectivity.

We needed to find the right tracer that was close enough to the estrogen our bodies make, to really tell us how our estrogen—especially estradiol—actually works in the brain.

Once you found the tracer, you were able to start measuring estrogen activity in the human brain for the first time. What did you find?

First, it’s important to know that estrogen receptors are not just permanent features on brain cells. They must be constantly made. Your brain essentially says, I need more estrogen, how do get it? Either estrogen is coming at the brain and it makes estrogen receptors in response. Or, the brain starts making estrogen receptors so that it can capture every available bit of estrogen when estrogen concentrations are low.

We previously had this idea that the brain stopped making estrogen receptors after menopause. We thought the brain was simply saying, I don't need estrogen. But what our study showed is exactly the opposite: We looked at women from age 40 to age 65, and what we found is that these estrogen receptors are being actively made for many years after menopause. And we saw that this estrogen receptor density predicts the presence of menopausal symptoms.

This is a big difference in the way we understand what women's brains want. What we see with these brain scans, in my opinion, are brains that are hungry for estrogen. There's no other reason to have all these receptors, which are metabolically expensive for the body to make and a lot of work for the brain. It’s not something the body would just do casually.

Did these results surprise you?

Yes! I was expecting to find more estrogen receptors in the brains of the premenopausal women, which is when a woman still has a lot of circulating estrogen. Instead, I stood in the lab looking at brain scans of postmenopausal women and saw more estrogen receptor activity in their brains. And I was like, “What is going on here?” I worried something was wrong. But no, we weren’t doing anything wrong. Rather, the theories that we had were wrong because they didn’t look at what was actually happening in women’s brains.

Wow. How might we be able to use this type of testing in the future to help women in midlife?

We are looking at this now, with phase two and phase three of the research. I really want to map out the window of opportunity for women when it comes to using menopausal hormone therapy. We currently don't know when the window opens and closes. I think we now know from this study that it opens during perimenopause, because we find the density of estrogen receptors increase in perimenopause, suggesting it would potentially be helpful to start treatment in some women before the final menstrual period. 

But we don’t know when the window closes, considering estrogen receptor activity is still high at age 65. I think we may have a wider window of opportunity to intervene, maybe even as long as these estrogen receptors are active.

Right now, there's a tendency to discourage women who are older than 60 or 65 from going on hormones. But the rationale is based on clinical observations, not biology. If we have the biology—if we can see the density of estrogen receptors in a woman’s brain—we can make treatment options more personalized: If your brain wants the hormones and you have the symptoms, why not give you hormones? If your brain doesn't look like it needs hormones, then maybe we don't give them to you. 

And we are also looking at how this research can be used to gauge Alzheimer’s risk—something Maria Shriver and I have been talking about for so long. We know that estrogen is a neuroprotective hormone. As we lose it after menopause, women’s brains may start to show Alzheimer’s plaques. This is a theory based on animal models, and nobody’s been able to do it in vivo [in a living organism]. So that’s another way we’re hoping to use this research.

You are such a force when it comes to reminding women of the power and strength of our brains. How does this research further prove this point?

I think this research really shows us that the human brain—and especially women's brains—are very plastic. There’s this notion that the brain is relatively fixed after adolescence. But what we are learning is that women's brains have their own agenda! And we know so little about what our brains are and aren’t doing.

What we think is happening with this estrogen receptor activity is that it’s a compensatory reaction: Our brains are actively making a choice. And to me, that suggests that we should give our brains more credit than we do. We're always making fun of our brains—we blame our brains or get frustrated with our brains instead of remembering all the incredible things we can do even as we go through a hard time, like menopause.

I am pro-information and anti-suffering. I think that the more information we can provide and the more clarity we can help women achieve, the better we will feel as a society about going through menopause. This transition is nothing to be ashamed of. It's a neurophysiological process; it’s supposed to happen! It would be wonderful if we could go through it with no glitches—no symptoms—but unfortunately those symptoms do happen. And in that case, there are quite a few things that one can do to feel better and find relief while also supporting our brains.

What are the key takeaways for women right now? What can every woman before, during, and after the menopause transition do to protect her brain?

The menopause brain is a brain in transition. There’s a reason for the transition; it needs to happen. And the brain needs to adapt the same way that your body is adapting to this change. So, do not be scared. Consider this a transition phase where self-care and healthcare become really important.

One thing that always strikes me women talk to me about menopause is there’s never a sense of achievement. You go through puberty and think, “OK, parts of this aren’t great but I'm a woman now!” Then, you get pregnant, and it's a difficult process—there are hot flashes, sleeplessness, brain fog—but there’s a baby, right? You look forward to the outcome. But with menopause, nobody cares! It’s time we give ourselves some credit.

When I go through menopause, I want a party.

Ten years from now, what do you hope this research will have enabled us to do in terms of women’s brain health?

I hope we’ll have midlife clinics that specialize in women’s health needs that include our brains in the diagnostic workups.

I hope our research will help us come up with better treatment plans and interventions that actually work and also address the stigma—not just around menopause, but around menopause care.

We are still dealing with a combination of ageism, sexism, and menopause-ism—and it’s not doing us any favors. Ten years from now, I hope more of us will understand what’s happening to our brains in menopause, know there’s nothing mysterious or pathological going on, and then say, “Wonderful, good to know, now how can I feel better?”

Dr. Lisa Mosconi is the director of the Weill Cornell Women’s Brain Initiative and the author of "The Menopause Brain: New Science Empowers Women to Navigate the Pivotal Transition with Knowledge and Confidence."