Hot flashes and hormone therapy: the science of perimenopause

Understanding Perimenopause Basics

0:00Hey, 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

0:34than 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. This week marks my first week being on estrogen and progesterone. In the past week, my energy levels go up, my sleep's gotten better, and I'm not as moody or crabby. 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

1:11the 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 OBGYN.

1:41She'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. Thanks. Pleasure to be here. Absolutely. 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? Well, we're definitely in a moment. And while I think it's wonderful that there's this much

2:16attention 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, you know, we don't have all the information we need to proceed. And some directions in which the field is going are a little concerning.

Hormone Changes and Brain Mechanics

2:37Let's talk about the information we do have. Just the basics. What's happening under the hood during perimenopause? Well, there's this impression that, you know, 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, you know, hormones are up and down. So there's a period of fluctuation. But as we've also learned from the SWAN study, really is a body-wide set of changes that are dramatic for some. But for many, they're inconvenient, annoying. And there's

3:15probably few women who don't really notice much of anything. You mentioned that symptoms aren't the same for everybody. We actually, we asked listeners to call Lynn. And we got a bunch of responses with some people saying perimenopause totally altered their personality and others saying they barely noticed it. 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. Never had a single symptom or problem.

3:48The 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, you know, 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. Do we know why perimenopause hits some people harder than others?

4:21We 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

4:54treated less.

4:57We're a very nerdy show. And I know 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? Yeah. So this is actually when I become nerdy because I am truly a neuroscientist at heart living, you know, in an OBGYN 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

5:34our environment, like whether we feel hot or cold. Do they have a name, these neurons? They do. The neurons are called candy neurons, you know, and the way that I like to think about them is if you remember the hot tamales, they're like these old 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

6:06these 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. There's two parts of hot flashes that are really sort of mysterious and still remain to be understood. And how does the brain adapt? I mean, we know the brain adapts to so many things. It's what makes us human. So the brain does eventually adapt for 85 to 90 percent of women. And there's this 5 to 10

6:42percent 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

7:12still happening with full force when estrogen is there is also not known. So there's something more dynamic going on. You know, Nanette, on social media, I feel like so many symptoms get blamed on perimenopause. Like if you're having a bad hair day, it's perimenopause. Do you feel like some symptoms are unfairly attributed to perimenopause? Absolutely. You know, there's, it's very difficult to sort out right now looking at hormones alone. So if I were to look at your reproductive hormones as you're entering

7:47the menopause transition, I would see very, very tiny differences between what you are 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 sort of a PMS type of symptom or a hormone intolerance. And it definitely deserves to be, you know, 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

8:17high symptoms for many, many things. The things that really tick up with the menopause transition are hot flashes, sleep, some mood changes. And at what age do those happen for most people? In their mid forties to late forties, 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, right? In understanding who's at risk for earlier symptoms. We do know that there's some racial and

8:49ethnic differences. So we do know African-American women have symptoms earlier and well before there's evidence of menopause. There's 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, you know, 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.

9:21I 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? Absolutely. Okay, buckle up, everybody. Don't go away. Prescribing hormone therapy for perimenopause has been such a huge journey over the last few

History of Hormone Therapy

9:54decades. 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? Oh, that's you. You asked for a lot there. So, you know, 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

10:26terms of neurocognition, and whether we had a heart benefit. And it was designed to look at women who were older, right? And it did what it was intended to do in terms of the study. And, you know, we found that it wasn't cardioprotective because for many years, women were told, even if you, you know, you've been menopausal for 15 years, you should start estrogen because it's cardioprotective. So I found that that wasn't the case. And, you know, we found that... It wasn't helping heart health.

10:58Estrogen wasn't helping heart health. Yeah. And it wasn't helping cognition in older women. And, you know, 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 that study was extrapolated to a completely different population. And so there was this conflation, right? That, oh, all women are not, should never have estrogen because estrogen is bad. And it was just, it was misapplied. The information

11:30was misapplied to a group that wasn't studied. The concern was that there was cancer and, you know, 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.

12:01Nanette, anything to add to that piece of the history? 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. There was nothing new. There was no new risk uncovered. Exactly. Exactly. So if you were prescribing it for heart disease, you needed to stop. The 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

12:32against the benefit of making your symptoms go away. So doctors and prescribers were left with nothing because that was the only tool in the toolbox. So the furor that came out over this is just was such a honking mess. You know, now doctors are prescribing hormone therapy again. And of course, it's like all the buzz on social media. What has changed? Sure. Well, for me, as as the Women's Health Initiative was followed up, there was 10 year

13:03follow 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's a little more favorable for women ages 50 to 60, which is the prime hot flash years. So it became far less scary,

13:36although I would I would pose it that it really never should have been anywhere near as scary as it was to see, you know, hormone therapy drop from 25 percent to 2.5 percent and never recover was just craziness. You know, you said at the top you had some concerns

Current Trends and Commercialization

13:53about how where the field is going. What do you mean? I have concern about hormones being the answer to everything, much as I love hormones and have dedicated my life to studying them. They're not the answer to everything. So we need to really keep our toolkit, you know, keep as many things as you can available to help your patient. And some of the influences that are happening in the social

14:24media 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, you know, fantastic treatment of hormone therapy isn't the answer for her. I want to just add to that because I am concerned, like Nanette, and I'm concerned because I feel that women

15:00are being taken advantage of, right? This is a very vulnerable time. You're tired because you're waking up at night, right? From sleep disruption. You know, you're not feeling your best and they're looking for things to help them feel better. And there are people who are taking advantage of this and selling women things that where there's absolutely no evidence to support it. Such as? Such as some of the peptide stuff, right? You know, there is an evidence that bioidenticals are better

15:33than our standard hormone therapy where we know that there's been an appropriate testing in terms of the dosing and safety, right? Women are being told, you know, that estrogen is the fountain of youth, right? 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.

16:03And there is just, you know, it's the data isn't there. You know, there are things that just happen as we get older. And estrogen is not going to change that. I like to tell my patients, you know, your estrogen was very low when you were nine years old. Your estrogen was nine and your skin was really great, right? 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

16:38incredible, 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, you know, I must have testosterone for X, Y, Z. And I think one thing that's misconstrued is that there's this idea that, you know, testosterone levels are so low as you get older. And actually, if you look at the

17:09ratio of estrogen to testosterone, it's actually higher in the post-menopause. And people, you know, don't recognize that. And, you know, I tell my patients, I'm like, look, you know, you you're concerned about hair growth on your face. Now, what do you think is going to happen if I give you androgens? So, you know, I think it's so important for people to be really, if it sounds too good to be true. It is. It is. It always is. This has been such an informative conversation. Thank you both

17:47for walking us through today. It's our pleasure. Could talk about it all day. Thank you. 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 OBGYN.

18:06This episode was produced by D. Peter Schmidt. Thanks to everyone who called in for this. And you can always call us. We're here. We're listening. 877-4-CYPHY is our number. Thank you for listening. I'm Flora Lichtman.