The Change Is Gonna Come: Menopause and the Brain (S2 Episode 2 Reprise)

Menopause can wreak havoc on mood and body temperature as it signals the end of fertility, but some of the biggest changes it causes are in the brain. Emily Jacobs, assistant professor in the department of psychological and brain sciences at UC Santa Barbara, explains how the precipitous decline in estrogen during the “change of life” disrupts the endocrine system, and why menopause makes some women feel like they’re going crazy while others sail through unscathed. Plus: Hear from real women describing the wide range of effects they experienced.

Phil Stieg: Hello, today, I have with me Dr. Emily Jacobs. Emily is a neuroscientist at the University of California, Santa Barbara, in psychological and brain sciences. Currently, she focuses on sex hormones and their influences on brain function, in particular brain changes that occur around menopause,
Emily, thanks so much for being with us.

Emily Jacobs: Thank you so much for having me.

Phil Stieg: How long is the typical menopause period? And as I understand it, there are specific stages in menopause. Can you describe that for me?

Emily Jacobs: Menopause is a transition. It starts with, you know, a fully reproductively capable woman with regular menstrual cycles. And we enter sort of a late reproductive stage and then perimenopause where we start to see infrequent cycles. They may grow shorter or longer in length. And this is where we get a lot of kind of turbulence, where hormone levels can have a much greater dynamic range. But eventually it starts to fall down. And by post menopause, which is defined as 12 months, one year without any cycle, ovarian hormone levels have declined by about 90 percent. That’s estrogen and progesterone from your ovaries. Those levels have really plummeted.

Phil Stieg: Can you tell me what kind of emotional and physiologic changes women experience when going through menopause, and then why do others not experience any of those at all?

Emily Jacobs: When we talk about these hormonal changes where you have this 90 percent decline in the production of ovarian hormones, those hormones are going to act on a lot of different bodily systems, not just the brain. And that’s the power of hormones. Hormones do not have targeted effects. You know, they have sweeping effects across an organism. But from a brain perspective, we know that about 40 percent of women will experience brain fog—

Phil Stieg: Permanent or temporary?

Emily Jacobs: Well, that is the question. And for most women, it’s likely temporary, that it’s driven by the perimenopausal state where these hormones are really kind of showing these large dynamic changes. But by post-menopause, you know, there are very … These are self-described cognitive changes, which are real. But when we put them, you know, when we bring women into the lab and give them a whole battery of cognitive tests, there are very few that are going to pick up these sorts of subtle cognitive differences.  It’s we know women don’t go crazy through the menopausal transition. We’ve got plenty of evidence that’s not the case. But but that’s not to say that these changes that they’re experiencing aren’t real. And one of the goals of my lab and many others who are focusing on this is to try to understand kind of what’s going on under the hood in terms of their brain structure and function that might make some women more susceptible to those cognitive changes.

Phil Stieg: Emily, I don’t think most of the population really understands how much of an endocrine organ the brain really is. Can you clarify that for us?

Emily Jacobs: Sure. When we say that the brain is an endocrine organ, we mean that in a couple of different ways. So the brain, and particularly a region called the hypothalamus, which sits right at the base of your brain, produces hormones. It guides the production of hormones from other organs, other peripheral endocrine glands in your body. So there’s this tightly coordinated, what we call a neuroendocrine cascade, where your brain, through the production of hormones in the brain itself, can guide the production of hormones in places like your testes or your ovaries.  And then the loop comes back full circle where those hormones, like estrogens and progesterone and testosterone that are produced by these endocrine glands, travel through your bloodstream and those hormones can bind to receptors that are also in your brain.

Documentary Voice: A lot of my friends who’ve never experienced menopause symptoms have asked me what it feels like and the only thing I can compare it to is like being in on a Coney Island roller coaster. So my brain and body feels like it’s climbing towards some sort of the top of something. And then the heat is the ride down.
(music out)

Phil Stieg: So I don’t think we touched clearly upon why some women have brain fog and others don’t.

Emily Jacobs: You know, the spectrum goes through from women who experience no symptoms whatsoever. In fact, don’t even kw that they’ve gone through menopause. If you know they’re not tracking their cycles, I mean, really, truly just sail through to women who become debilitated and experience, you know, what can be quite severe forms of perimenopausal depression, severe vasomotor hot flashes, brain fog. And it is a complete spectrum from one end to the other. Most women will not experience these sort of severe outcomes, but some will, and we need to be able to speak to the entire population and understand what may be driving those individual differences. And, of course, consider these women, you know, in a nuanced way that appreciates that full spectrum.

One of my favorite statistics, is that in the prefrontal cortex, 50 percent of your neurons pyramidal three neurons, 50 percent of them contain estrogen receptors. Half of the neurons in your frontal lobe express estrogen receptors—

Phil Stieg: Men and women?

Emily Jacobs: To the best of our knowledge.  And this suggests that this hormonal signal of estrogen is like a major organizing principle of how this region of the brain operates.  So a critical question is for women. When you go through menopause and you lose ovarian production of this hormone, how do these regions of the brain respond? And that is exactly the question that my lab is trying to answer.

Phil Stieg: As I was listening to you, I was thinking about, you know my Mother. She   was going through menopause and she had a hysterectomy. That’s the way they treated it back then. They put them on hormonal replacement.

Emily Jacobs: Estradiol, the major form of estrogen in mammals is neuroprotective. And you can do you can—remove the animal’s ovaries and show that it causes havoc on these regions of the brain that contain estrogen receptors. You give estrogen back and you know, all is right with the world… in a sort of simplistic way.

Phil Stieg: Mm hmm.

Emily Jacobs: So, the first female director of the NIH was Bernadine Healy. And her major initiative was something called the Women’s Health Initiative. And just to give you insight into the thinking at the time, this is going to be the gold standard – a randomized clinical controlled trial on a huge population, the first one  to really test in women whether HRT was neuroprotective,

Phil Stieg: HRT?

Emily Jacobs: Hormone Replacement Therapy.  And the Institute of Medicine at the time came out with a position statement that said, we think running this randomized clinical trial is unethical because the benefits of estrogen are so obvious. OK, so that’s just to clue you into thinking. At the time, they didn’t want to run the study. Fast forward several years later and that clinical trial ended early because of the opposite effects — adverse effects on stroke and in other outcomes. So, you know, the field, you could just hear the screech brakes, right, of people of doctors around the world taking women off HRT.   The number of prescriptions for hormone replacement therapy plummeted in the months after that report came out. The is that they threw the baby out with the bathwater. That study enrolled women who were on average age 75. Right? Decades after they’ve gone through the menopausal transition! And the brain is going to be different.  And you’re suddenly reintroducing this now foreign hormone to a brain that has gotten used to being without it. So it was not answering the question of whether hormone replacement therapy in sort of a critical window of this transition state might be beneficial. And we’re really kind of still trying to pick up the pieces and understand the potential utility of hormone therapy.

Phil Stieg: So It’s amazing. In 2021, we’re still in kind of a primitive level in terms of understanding all of this stuff.

Emily Jacobs: We really are.



Voice 1: When I was in menopause, I would wake up every night at four o’clock in the morning, stressed and  anxious, stare out my window and not be able to fall back to sleep. But the good news is it doesn’t last forever.

Voice 2: Couldn’t sleep, couldn’t think. Head in a fog the whole time. It was like an endless hangover with no liquor.

Voice 3: I love menopause because I stopped having migraine headaches. I wasn’t having to plan my life around monthly migraines.

Voice 4: Actually, the biggest changes were…all of a sudden, I’m putting on weight in places where I never have before.  I am I am much rounder and squishier without changing anything else about my diet or habits.

Voice 5: Hot flashes interrupt my sleep. And so I’ll wake up several times at night and … that affects how I am during the day. I’m groggy I can’t remember things. I’m not top of my game at all.

Voice 6: Perhaps because my periods were difficult and intense when menopause hit, I felt a burst of creative energy and alertness in my body and mind.

Voice 7: I went to see so many different doctors and gynecologists because…this was really something that was actually pretty debilitating during certain stages. And it’s I guess what frustrates me the most or strikes me the most is how varied and inconsistent medical response is.

Part 2
Phil Stieg: What can women do, you know, when they’re 30 to ease the impact of menopause?

Emily Jacobs: First, let’s just normalize menopause instead of making this taboo topic, let’s talk about it even just from a sort of cultural perspective, because a lot of women will experience these brain fog changes and be terrified that this means they’re on the route to Alzheimer’s disease. And in most cases, that’s not true. So what we can do as scientists is to try to help figure out what each of those sort of subpopulation of women is vulnerable. And we’re not there yet.  We don’t have the answer. But let’s start by investing in women’s health research from a national federal funding perspective, because these questions should have answers already – and they don’t. You know, one of the benefits that just happened a few years ago was just getting a taxonomy of menopause, and so there was something of a stages of reproductive aging workshop which convened endocrinologists to get together so that we could have a  working definition of menopause.

Phil Stieg: And you’re telling me this is recent?

Emily Jacobs: Probably in the last 10 years.

Phil Stieg: Really? That amazes me that it took that long.

Emily Jacobs: It is. You know, it is an insight into how often women’s health is just swept under the rug, which we can get into later…


Phil Stieg: What do we know about a woman that has one child versus a woman that has six children? Does that have an impact on menopause?

Emily Jacobs: That’s an interesting question. So a friend and colleague of mine, Anne-Marie Delonge, who’s in Europe, she just published a really interesting paper.  And she shows that the more that have more children actually show younger brain age post menopause. So there does seem to be this kind of protective role of maybe because of the brain has been bathed in estrogen during each of those pregnancies to kind of create these more neuroprotective effects. We don’t know the mechanism.

Phil Stieg: People that have more babies. Do they have more of these estrogen receptors in their brain that’s beneficial?

Emily Jacobs: We don’t know. We do not know at the receptor level. But she used data from 12,000 middle aged women and found that women who had multiple children showed younger looking brains relative to women who didn’t have children.

Phil Stieg: What’s a younger looking brain mean?

Emily Jacobs: So these are sort of a great question. And these are kind of statistical tricks where we can anticipate what—so she’s using brain structure.

Phil Stieg: She’s looking at cell counts and…

Emily Jacobs: Well, sure – volume of different regions. And we would expect a certain amount of, say, atrophy or changes. And in women that had given birth many times, they showed they were sort of behind the curve. They they showed less of these brain aging biomarkers than women who had not ever given birth.

Phil Stieg: I just want to be really clear so that those listening walk away with the right message. So what you are saying is; that having multiple children may be protective from a menopause standpoint and also from the onset of dementia standpoint?

Emily Jacobs: That is what this this one study has shown. Now, that shouldn’t be a reason why people should feel bad about not having children. But understand why that association was found is now the critical question. Does it have to do with the hormonal changes experienced in pregnancy or, you know, what is it about that link that’s causal?  And we don’t know yet?

Phil Stieg: What I do want the listeners to be able to walk away with is what are your recommendations from an endocrine health standpoint?

Emily Jacobs: Well, use your voice when you go into your primary care physician because you have severe cramps or because you want to go on birth control for reproductive reasons, ask what are the side effects of these medications? And read the literature, you know, read the popular press, educate yourself if your doctor won’t do it for you. For most women going on estrogen replacement therapy early in the menopausal transition. So in perimenopause, in early post menopause is is not going to have severe it’s it’s not the scary monster that we thought it was. There is now good evidence to suggest that for most women, this can be a really safe option. You certainly should have this conversation with your doctor about when to start it, about how long to stay on it. I think the official recommendation from what we call what’s called the North American Menopause Society is that using it for five years is is fine. And for many women, it can relieve symptoms of hot flashes, vaginal dryness, of brain fog.  And it shouldn’t be it should be a  tool that you consider using.

Phil Stieg: It seems to me that the other message would be that we need to transform this from a, you know, psychological problem.

Emily Jacobs: Absolutely.

Phil Stieg: And and people need to understand that this is not, you know, just something that happens willy-nilly.

Emily Jacobs: I mean, it’s it’s not. Yes, it is. It is biological. We can point to something physical in the brain, but for some women is changing. On the other hand, it is worth noting, as you’ve said, that some women go through menopause and are just fine and that’s great. But there are individual differences and variability. And so talk to your doctor about potential changes. If you are one of the women that is experiencing side effects, there are options for you.

Phil Stieg: Emily Jacobs, you are clearly passionate, clearly driven. And clearly focused on menopause and female health issues. God willing you’ll win a Nobel Prize.  But even if you don’t, I know you’re going to help many women understand their own biology. Thank you for being with us.

Emily Jacobs: Thank you so much.

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