Hot flashes, hormone therapy, and the science of perimenopause

MUSIC PLAYING] FLORA LICHTMAN: Hey, it’s Flora and you’re listening to Science Friday. We’re talking about a condition that affects more than 4 billion people on this planet, but historically has been pretty neglected by medicine. Any guesses? Perimenopause– the window before menopause, where hormones begin fluctuating wildly, leaving women with brain fog, hot flashes, dropping bone density, and mood changes.

Now, thanks in part to social media, perimenopause is way more in the public discourse than it used to be. But it’s not just awareness that’s blown up. It’s also this promise that you don’t have to suffer like those before you, thanks to hormone therapy. And testimonials abound.

CALLER 1: This week marks my first week being on estrogen and progesterone. In the past week, my energy levels go up, my sleep has gotten better, and I’m not as moody or crabby.

FLORA LICHTMAN: After decades of controversy over prescribing estradiol and progesterone due to concerns of increased breast cancer and heart disease risk, new research has many providers reconsidering their approach. Here to sort out the science are two pioneers of this field. They’re both running some of the biggest long-term studies on perimenopause and the effects of hormone therapy.

Dr. Nanette Santoro is a reproductive endocrinologist at the University of Colorado Anschutz. She’s the lead investigator on a three decade study following 3,000 women to better understand the menopause transition. It’s called the SWAN study. And Dr. Genevieve Neal-Perry is a neuroendocrinologist and chair of UNC OB-GYN. She’s also a co-investigator on many large studies studying the effects of hormone therapy, and she researches how the brain changes in response to perimenopause and menopause.

Welcome both of you to Science Friday. I am so excited to talk to you about this.

DR. NANETTE SANTORO: Thanks, pleasure to be here.

DR. GENEVIEVE NEAL-PERRY Absolutely.

FLORA LICHTMAN: You both have been studying this since before it was cool. Do you feel like we’re in a moment for perimenopause? And how would you describe it?

DR. NANETTE SANTORO: Well, we’re definitely in a moment. And while I think it’s wonderful that there’s this much attention being paid to this life passage, since I and Genevieve now are both survivors of perimenopause, it’s a bit of a touchy time, because we do lack information. So as you’ve said, we don’t have all the information we need to proceed. And some directions in which the field is going are a little concerning.

FLORA LICHTMAN: Let’s talk about the information we do have, just the basics. What’s happening under the hood during perimenopause?

DR. NANETTE SANTORO: Well, there’s this impression that women are just sort of like Whistler’s Mother just sitting quietly in a rocking chair while their hormones just peter out. And that’s not what’s happening. So, as you said in the beginning, hormones are up and down, so there’s a period of fluctuation. But as we’ve also learned from the SWAN study, it really is a body-wide set of changes that are dramatic for some, but for many they’re inconvenient, annoying. And there’s probably few women who don’t really notice much of anything.

FLORA LICHTMAN: You mentioned that symptoms aren’t the same for everybody. We actually– we asked listeners to call in, and we got a bunch of responses, with some people saying perimenopause totally altered their personality, and others saying they barely noticed it.

CALLER 2: I don’t like it. I don’t like it at all. I ran into my doctor’s office and literally yelled to say, please help me. I feel like I’m going to lose my mind.

CALLER 3: Never had a single symptom or problem.

CALLER 4: The thing that was so shocking to me, on top of the hot flashes, the sleep disturbances is– I wasn’t myself. I didn’t call people back. Everything seemed harder than it should be. But of course, I’m on the other side now, and I’m considered menopausal. And I would say the skies have cleared a bit, but it was really hard for a long time.

FLORA LICHTMAN: Do we know why perimenopause hits some people harder than others?

DR. NANETTE SANTORO: We have some evidence that there are some people who are a little more vulnerable than others to it. And there are some racial and ethnic differences in severity of symptoms that can erode your well-being. People with heightened symptom sensitivity, people who have more aches and pains going into the process, people who struggle financially to get by. The people who are the most socially stressed, I would say, in our current environment with the worst social determinants of health, tend to have the worst symptoms. And tragically, these are the ones who tend to be treated less.

FLORA LICHTMAN: We’re a very nerdy show, and I you’re both endocrinologists, so I want to get into the details. Let’s talk about hot flashes. How are they linked to hormone changes? What’s the mechanism? Genevieve?

DR. GENEVIEVE NEAL-PERRY Yeah. So this is actually when I become nerdy, because I am truly a neuroscientist at heart living in an OB-GYN world. What triggers hot flashes? It is related to the way changes in hormones actually affect neurons that are located in the brain, that actually regulate how we experience our environment, whether we feel hot or cold.

FLORA LICHTMAN: Do they have a name, these neurons?

DR. GENEVIEVE NEAL-PERRY They do. The neurons are called KNDy neurons, and the way that I like to think about them is if you remember the hot tamales, they’re like these little hot tamales that become super active in the absence of estrogen. And these neurons increase this peptide called neurokinin. And that is what will connect with neurons that actually regulate how we sense our environment. And it’s because of these neurons become hyperactive. They stimulate the neurons who are located in the area that control heat, and then they stimulate themselves. So it’s like this kind of self-stimulation and stimulating these other areas that trigger hot flashes. And that’s what happens.

DR. NANETTE SANTORO: There’s two parts of hot flashes that are really mysterious and still remain to be understood. And how does the brain adapt? I mean, the brain adapts to so many things. It’s what makes us human. So the brain does eventually adapt for 85% to 90% of women. And there’s this 5% to 10% that their hot flashes never go away. And they’re just as bad as they were in the menopause transition.

The other part of this that’s also very fascinating is that we think of hot flashes in association with low estrogen. But during the menopause transition, estrogen is up. It’s down. It’s up, it’s down. It’s variable. And that is when hot flashes peak in a woman’s life. So that’s when they reach their highest level then and the year or so after the final menstrual period. So why they’re still happening with full force when estrogen is there is also not known. So there’s something more dynamic going on.

FLORA LICHTMAN: Nanette, on social media, I feel like so many symptoms get blamed on perimenopause. If you’re having a bad hair day, it’s perimenopause. Do you feel like some symptoms are unfairly attributed to perimenopause?

DR. NANETTE SANTORO: Absolutely, it’s very difficult to out right now looking at hormones alone. So if I were to look at your reproductive hormones as you’re entering the menopause transition, I would see very, very tiny differences between what you were maybe doing in your thirties. And sometimes we see no difference at all. So in the absence of hormone changes, it’s hard to attribute this to hormones.

It may be a variation of a PMS type of symptom or hormone intolerance. And it definitely deserves to be assessed and treated. So I don’t want to dismiss it. But when you look at the symptom experience of women in their 30, 35 plus, there’s high symptoms for many, many things. The things that really tick up with the menopause transition are hot flashes, sleep, some mood changes.

FLORA LICHTMAN: And at what age do those happen for most people?

DR. GENEVIEVE NEAL-PERRY In their mid 40s to late 40s. That’s the average person. But, we don’t want to just dismiss people who may be having symptoms earlier. And that’s where there’s such a gap in knowledge. In understanding who’s at risk for earlier symptoms, we do know that there’s some racial and ethnic differences. So we do African-American women have symptoms earlier and well before there’s evidence of menopause.

There is something that’s related to aging, in general. And in our animal models, neurons that typically respond to estrogen don’t respond the same way. So they start to become like they’re desensitized. Now whether or not that’s what’s happening in humans, we don’t know. But we do have data that that’s what we’re seeing in non-human models.

[MUSIC PLAYING]

FLORA LICHTMAN: I have to take a break, but when we come back, we have to talk about the wild ride that is hormone therapy and its history. Are you all up for that?

DR. GENEVIEVE NEAL-PERRY Absolutely.

FLORA LICHTMAN: OK, buckle up, everybody. Don’t go away.

[MUSIC PLAYING]

FLORA LICHTMAN: Prescribing hormone therapy for perimenopause has been such a huge journey over the last few decades. Genevieve, can you give me a sort of short version of why it was taboo and what’s changed in the last couple of years.

DR. GENEVIEVE NEAL-PERRY Oh, that you asked for a lot there.

[LAUGHTER]

So the Women’s Health Initiative, the WHI study was a really important study, and it was designed to help us understand whether estrogen hormone therapy was associated with breast cancer, whether we had improvement in terms of neurocognition and whether we had heart benefit. And it was designed to look at women who were older.

And it did what it was intended to do in terms of the study. And we found that it wasn’t cardioprotective, because for many years women were told even if you’ve been menopausal for 15 years should start estrogen because it’s cardioprotective. So it found that wasn’t the case. And we found that–

FLORA LICHTMAN: It wasn’t helping heart health? Estrogen wasn’t helping heart health?

DR. GENEVIEVE NEAL-PERRY And it wasn’t helping cognition in older women. And there was an increased risk for breast cancer, which, by the way, was not the first time this was demonstrated. However, what happened is that study was extrapolated to a completely different population. And so there was this conflation. That, oh, all women should never have estrogen because estrogen is bad. And it was just– it was misapplied.

The information was misapplied to a group that wasn’t studied. The concern was that there was cancer. And there was neurocognitive dysfunction in women who used it. So it was just assumed that it was bad for everyone. And that’s why there was this huge drop off. And patients, as well as, providers became afraid to give women hormone therapy for hot flashes, because they thought what they observed in WHI applied to all women who were menopausal, as well as perimenopausal.

FLORA LICHTMAN: Nanette, anything to add to that piece of the history?

DR. NANETTE SANTORO: It was known at the time of the WHI that there probably was going to be a small increase in the risk of breast cancer. That’s been known. It’s been supported.

FLORA LICHTMAN: There was nothing new. There was no new risk uncovered.

DR. NANETTE SANTORO: Exactly, exactly. So if you were prescribing it for heart disease, you needed to stop. Breast cancer risk doesn’t go away. The blood clot risk doesn’t go away. But these are small, and they were never balanced or meant to be balanced in the Women’s Health Initiative against the benefit of making your symptoms go away. So doctors and prescribers were left with nothing, because that was our only– that was the only tool in the toolbox. So the furore that came out over this is just– was such a honking mess.

FLORA LICHTMAN: Now doctors are prescribing hormone therapy again. And of course, it’s like all the buzz on social media. What has changed?

DR. NANETTE SANTORO: Sure. Well, for me, as the Women’s Health Initiative was followed up– there was 10 year follow up, there was 18 year follow up– and as you saw the follow up of these women who took it for about six to seven years, what you saw was a nothing burger. You saw no net change in mortality. People were not dying. There was no huge change in disease risks on any– there were some tiny differences.

And then when you broke it down by age, you saw something that looked a little more favorable for women ages 50 to 60, which is the prime hot flash years. So it became far less scary. Although I would pose it that it really never should have been anywhere near as scary as it was. To see hormone therapy dropped from 25% to 2.5% and never recover was just craziness.

FLORA LICHTMAN: You know, Nanette, you said at the top you had some concerns about where the field is going. What do you mean?

DR. NANETTE SANTORO: I have concern about hormones being the answer to everything. Much as I love hormones–

[LAUGHTER]

–and have dedicated my life to studying them, they’re not the answer to everything. So we need to really keep our toolkit– keep as many things as you can available to help your patient. And some of the influences that are happening in the social media world, there’s a lot of commercialization.

Midlife women have now been recognized as a fantastic market to sell stuff to. So lots of stuff is being sold to women. They’re being bombarded with information, and that makes it difficult to partner with my patient, to work through her symptoms and use all of the modalities at hand, if the promised, fantastic treatment of hormone therapy isn’t the answer for her.

DR. GENEVIEVE NEAL-PERRY I want to just add to that, because I am concerned like Nanette. And I’m concerned because I feel that women are being taken advantage of. This is a very vulnerable time. You’re tired because you’re waking up at night, right, from sleep disruption. You’re not feeling your best, and you’re looking for things to help them feel better. And there are people who are taking advantage of this and selling women things where there is absolutely no evidence to support it.

FLORA LICHTMAN: Such as?

DR. GENEVIEVE NEAL-PERRY Such as some of the peptide stuff. There is in evidence that bioidentical are better than our standard hormone therapy, where we know that there’s been an appropriate testing in terms of the dosing and safety. Women are being told estrogen is the fountain of youth. If you use estrogen and hormone therapy, you’re going to stay younger. It feels like we’re back in the 50s and early 60s when women were told you need estrogen to stay young.

And there is just– it’s the data isn’t there. There are things that just happen as we get older. And estrogen is not going to change that.

DR. NANETTE SANTORO: I like to tell my patients, you know, your estrogen was very low when you were nine years old. Your estrogen was 9 and your skin was really great. Right?

[LAUGHTER]

So there are some beliefs that are very hard to shake. I call them zombie ideas. We’re also at a time where I think there’s a virtual craze on for testosterone as being an incredible, fantastic treatment. And again, data just aren’t there to support it. And it isn’t that there’s no data. There’s actually negative data. There’s data that studies– some studies have been done and do not support some of the indications that my patients will bring in saying, I must have testosterone for X, Y, Z.

DR. GENEVIEVE NEAL-PERRY And I think one thing that’s misconstrued is that there’s this idea that testosterone levels are so low as you get older. And actually, if you look at the ratio of estrogen to testosterone, it’s actually higher in the postmenopause. And people don’t recognize that. And I tell my patients, I’m like, look are concerned about hair growth on your face now, what do you think is going to happen if I give you androgens. So I think it’s so important for people to be really– if it sounds too good to be true, it is.

FLORA LICHTMAN: It is. It always is.

[MUSIC PLAYING]

This has been such an informative conversation. Thank you both for walking us through it today.

DR. NANETTE SANTORO: It’s our pleasure. Could talk about it all day.

DR. GENEVIEVE NEAL-PERRY Thank you.

FLORA LICHTMAN: Dr. Nanette Santoro is a reproductive endocrinologist and President of the Endocrine Society. And Dr. Genevieve Neal-Perry is a reproductive endocrinologist and department chair of UNC OB-GYN.

[MUSIC PLAYING]

This episode was produced by Dee Peterschmidt. Thanks to everyone who called in for this, and you can always call us. We’re here. We’re listening. 877-4-SCIFRI is our number. Thank you for listening. I’m Flora Lichtman.

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