Is Hormone Replacement Therapy in Menopause Helpful or Harmful - Transcript

Dr. Mark Hyman:
Coming up on this episode of the Doctor's Farmacy, there

Dr. Cindy Geyer:
Are a whole lot of hormones in our bodies. It's not just estrogen and progesterone, which start to oscillate in the menopause transition, but all of those hormones are talking to each other.

Dr. Mark Hyman:
Well, welcome back to the doctor's Farmacy. Cindy, it's so good to have you back.

Dr. Cindy Geyer:
Thanks, mark. It's nice to be here.

Dr. Mark Hyman:
We were just chatting before and I realized we started working together in the late 1990s

Dr. Cindy Geyer:
That we go

Dr. Mark Hyman:
Way back. I'm thinking nineties was like 30 years ago almost. It's crazy. We've been doing functional medicine and this work for decades,

Dr. Cindy Geyer:
A long

Dr. Mark Hyman:
Time. And today our topic is a really important one because it confuses the heck out of most people. There's so much misinformation about it, and there's been so much back and forth in science about it that it's hard to know what to know and what to do for most, who suffer from the symptoms of menopause, who are concerned about whether hormones should be used at all for healthy aging or whether they're dangerous going to cause breast cancer, whether it protects 'em against dementia, whether it's going to cause heart attacks, or whether you need it for your bones or whether you don't, because it's going to do all these other things. And so we're going to get deep into it today, we're going to talk about some cases at the Ultrawellness Center. We've been doing this work for a long time. Before that at Kenya Ranch, we worked together.
We've been doing that for a long time, and I think we cut our teeth on this topic because the people who came to Kenya Ranch were generally women between their forties and sixties. And so basically our entire patient population was Terry and pre and postmenopausal women, which forced us to learn a lot about this, whether we liked it or not. And also it was interesting because I remember early on we were getting hints from early data that Premarin and Provera, the hormones that were being at the time were concerning. And that I remember a woman coming up to me at one of the lectures at Canyon Ranch when we were there, and she said, because I was giving a talk about menopause, and I was saying how hormones might be risky, and we still don't really have enough data and they're concerning. And she said to me, Dr. Hyman, my doctor said, if you don't prescribe Premarin and Prera, to me, it's malpractice.
And I was like, okay. And a lot of this sort of push towards these hormones for everybody came from a large study called the Nurses' Health Study, which was a population-based observational study, essentially, where they track people over time. In this case, nurses out of Harvard. And they tracked them for years and years, and they gave them questionnaires, what did you eat? How much you exercise? Did you take hormones? What did you do? And it looks for patterns in the data. Is there a correlation between smoking and heart disease or a correlation between eating low fat diets and heart attacks or between taking hormones and your risk factors and a risk of different diseases? And so they saw certain patterns in this data that were in the early seventies that showed that women who took hormones seemed to do better in every way. They had less dementia, less heart disease, less breast cancer.
They were great. And so that's when everybody piled on and was like, okay, everybody needs to take hormones. And that's where this woman's doctor was coming from was based on this data. But correlation does not mean causation. I am starting at a high level here. We're going to get into the cases and the story and what to do and all that. But I want to start set the stage here because at a very high level, this was a shit show because what happened was nobody actually studied it and actually looked at a randomized controlled human trial on whether hormones did what we thought they did or not. And every day, the sun comes up and I wake up. It doesn't mean they had anything to do with each other. It's a hundred percent correlation, but zero causation. And so what turned out to be was this healthy user effect in this nurse health state.
The women who actually took the hormones were the ones who went to the doctor and took care of themselves and had their checkoffs and exercise and ate better. Ate better. Yes. So it wasn't the hormones, it was everything else that protected them. And when they finally did the women's health study, which was a billion dollar study, like 160,000 women, I think, and we're going to get into the issues with it in a little bit. That study was commissioned by Be Healy, who was the first woman to head the NIH said, you know what? Men and women are different. We haven't studied women. How about we do that? And they did it except it was very flawed study, and it kind of led to a lot of backlash. And all of a sudden everybody went from the entire menopausal cohort of women in America taking hormones to the next day, they're going to kill you, stop them.
And all of a sudden it was mayhem and women were suffering and all these withdrawal symptoms, and it was a disaster. So we're kind of in a new era where we have a more nuanced, sophisticated view. And that's really what we do at the Ultrawellness Center in Lennox. We really take a very sophisticated deep view and analysis of people's overall health, their hormonal health, their metabolic health, their genomics, their gut microbiome, and then you call it the estrobolome, which is something you've probably never heard about, which is we'll get into, which is how your microbiome affects your hormones. And we do a really deep personalized approach and we figure out who needs them, who doesn't, which ones you should get and which ones you shouldn't get. And actually not just how to use hormones, but how to use all the other tools we have in functional medicine to optimize a woman's health trajectory through the course of their life.
So with that intro, Cindy, I want to kind of have you sort of break down the issue of menopause in our society because when we were at Canyon Ranch in, remember learning that women in Japan had no word for hot flashes. So I was like, I dunno if it's true or not, but it was kind of a myth there or something. And I was like, well, all right, well, that means not everybody's suffering from the same symptoms. So talk about this transition that happens to women. When did it start? How does it progress? Not like, okay, one day you're fine and the next day you have menopause. It's just a lot of changes happen in every cycle of a woman's life, from puberty to adolescence to twenties to thirties to forties to fifties. And so it's really about understanding all that trajectory. So take us through what happens in an optimal way and what could happen, and then what typically happens for women and why.

Dr. Cindy Geyer:
So that's a great setup, mark. And I think that a really important thing to recognize is women are not a monolith. We're not all the same. We come to this whole transition phase, which we're going to explain a little bit in a minute with different sets of expectations, different things going on in our lives, different genetics, different relational concerns, different dietary habits, et cetera. So different life

Dr. Mark Hyman:
Exposures.

Dr. Cindy Geyer:
Yes. And how a given woman is going to experience that transition is all over the map. And what we're talking about, menopause itself is a very narrow window in time. It's defined as one year past your last menstrual period. But the transition phase, that's when your hormones start to oscillate all over. The map can start as early as a decade before that last period. So that means for some women, late thirties, early forties, their bodies are giving them little clues that things are shifting. And it can be anywhere from, okay, your periods start to get a little more irregular, they get longer or they get shorter. Some women will start to experience significant hot flashes and night sweats, what we call the vasomotor symptoms of menopause. They might have more mood shifts around their periods if they're prone to having menstrual migraines, those can get worse, more intense, more frequent. So there's a lot going on. Sleep disruption starts to happen, more irritability, so there's a lot of

Dr. Mark Hyman:
Symptoms. Heavier cycles,

Dr. Cindy Geyer:
Heavier cycles or long cycles, short,

Dr. Mark Hyman:
Shorter everything goes. Kalu.

Dr. Cindy Geyer:
That's some women. There are other women. We do see them mark regular periods like clockwork. They wake up one day, they don't have another one, and that's it. Yeah, that's right. But that's not the majority. And historically, because women were still getting periods, they weren't technically at menopause. So the hormone conversation wasn't really on the radar at the time

Dr. Mark Hyman:
Or just give 'em the pill

Dr. Cindy Geyer:
Or just take the Premarin and you'll be fine, honey. No conversation about what else is going on.

Dr. Mark Hyman:
So Cindy, how is it that women experience these transitions differently? Are there factors that are causing women to have worse menopausal symptoms and perimenopausal symptoms and other people to sail through the Japanese women who don't have a word for hot flashes? What's the deal?

Dr. Cindy Geyer:
So there can be genetic pieces to it. So for some women, we don't understand exactly why, but genetics can play a role. If your mother had a rockier course with a lot of symptoms, you might be more predisposed to that. We know that women who have a history of hormonally related symptoms, for example, P-M-S-P-M-D-D, postpartum depression may also be more likely to have the mood swings as the perimenopause transition occurs as well. So some clues from your past history. Nutrition plays a huge role. For example, coffee is a pretty notorious hot flash trigger. Alcohol is a pretty notorious hot flash trigger. Oscillations and blood sugar stress can all be hot flash triggers. So depending on a woman's,

Dr. Mark Hyman:
You're taking away all the fun coffee, sugar and alcohol. I know it's a bummer, isn't it?

Dr. Cindy Geyer:
But it means that some of the foods and substances you ingested in your twenties and thirties really can contribute to symptoms in your forties and fifties

Dr. Mark Hyman:
Or even this food you're eating. Then if you're drinking a lot and drinking a lot of coffee and having a lot of alcohol and eating a lot of sugar and refined carbs, it's going to make this whole process a lot worse for you. Right.

Dr. Cindy Geyer:
And we also know that when we think about hormones, there are a whole lot of hormones in our bodies. It's not just estrogen and progesterone which start to oscillate in the menopause transition, but all of those hormones are talking to each other. We think people talk about the hormone soup or the hormone dance because we have insulin, for example. And we know as estrogen levels start to go down, we become less sensitive to the impact of insulin. Our ability to regulate blood sugar deteriorates or can go down, that can make us more prone to those blood sugar swings, as I mentioned, that can trigger hot flashes.

Dr. Mark Hyman:
A lot of women complain about that extra weight around the middle, that they get around menopause too, which is related to what you're talking about.

Dr. Cindy Geyer:
Absolutely. Absolutely. And of course, thinking down the road, that's also setting the stage for higher risk of cardiometabolic disease, diabetes, heart disease, and cognitive issues down the road. So it's not just about symptoms.

Dr. Mark Hyman:
That's why women sort of are delayed a little bit in getting heart attacks, but it's because of the protection they had early on. Right?

Dr. Cindy Geyer:
Yeah. We know there's an interplay with cortisol stress hormones that as estrogen goes down, our body may respond more significantly to the effects of stress. We might feel it more or may have more symptoms, and we can talk some more about genetics that play a role with that. It was actually an interesting study I came across recently that found that women who had experienced adverse childhood experiences at least two or more, even if they didn't significantly have issues that they knew of in their twenties and thirties, it significantly increased the risk of a first onset of major depression in the menopause transition. So even the things that we experienced early on can have an impact on

Dr. Mark Hyman:
Western depress. It doesn't point to say we're going to put this in the show notes, but there's a questionnaire and a link to it you can take online called the ACE questionnaire, which means adverse childhood events. Meaning did your parents neglect you? Did they beat you? Was there alcoholism in the family? Was there someone in prison? What happened when you were a child that impacted your psychological state and how that impacted your biological state. So even though we think it's psychological, it's translated into our biology, as Carolyn me says, our biography becomes our biology.

Dr. Cindy Geyer:
The unmasking of that as estrogen levels go down, might not show up till a woman is in her forties or fifties. So it's important to recognize that

Dr. Mark Hyman:
There's other factors that affect this smoking. Right, exercise.

Dr. Cindy Geyer:
Exercise, absolutely. Or lack

Dr. Mark Hyman:
Of it. Or

Dr. Cindy Geyer:
Lack of. We'll talk about the importance of that. So as women go through the menopause transition, it's actually a really rich time to start paying attention to lifestyle factors that you can put into place, not only to help your symptoms, but to set you up for the second half and aging well, and some things move up in priority. For example, when you mention exercise resistance training, we can come back to that, but

Dr. Mark Hyman:
So weightlifting is more important as you get older because you lose muscle, you become fat, and then you end up needing more of that to help your metabolism. And when say, my metabolism slowed down, well, yeah, it did because you're losing muscle.

Dr. Cindy Geyer:
And another important contributor is coincident with those changes in hormones. There's a lot of life stuff that's often happening

Dr. Mark Hyman:
At the same, the sandwich generation, the

Dr. Cindy Geyer:
Sandwich generation. So your parents are getting older if you're fortunate enough to still have them, and they might be experiencing health issues and requiring more attention and care from you if you have children. I mean, mine, I hit the menopause transition. My two boys were 14, so that was a very interesting hormonal mix in my house, which brought up some challenges of its own. Or you might be having children leaving home. So you're your relationships

Dr. Mark Hyman:
And your career is probably at its peak. So you've got these triple whammy almost. Yeah.

Dr. Cindy Geyer:
You might even be looking at your partner and saying, is this the same person that I married? And where are we going with our relationship? So there's a lot of things that are happening coincidence with those hormonal shifts that play a role with our experience.

Dr. Mark Hyman:
So there's other things that also contribute like environmental toxins. Oh

Dr. Cindy Geyer:
My gosh, yes. That

Dr. Mark Hyman:
Are a huge factor, right?

Dr. Cindy Geyer:
They're huge. And that also plays a role when we're working with women to have a more informed, personalized discussion about pros and cons of hormone therapy. Interactions with endocrine disrupting chemicals are also going to impact how that woman is going to respond to those hormones. And they might be more risky if she's taking hormone replacement therapy and she's exposed to pesticides and solvents and heavy metals and phalates and plastics, et cetera. So it's much richer conversation than just, do I take hormones or not?

Dr. Mark Hyman:
Yeah, I mean these even are called xenoestrogens. They're called foreign estrogens, and they're effective at very small doses to create a big effect, and they're synergistic. So one plus one doesn't equal two, it equals a hundred or a thousand. And so we're just living in a soup of these chemicals. It has a huge role. So it's complicated, and yet it's knowable. We actually are able to assess all these things, even looking at your gut microbiome and how that plays a role in your hormone metabolism. So we look at toxins and we look at hormones, we look at insulin at cortisol, thyroid, we look at your lifestyle. We look at all these variable factors that are affecting how you feel and go through the different cycles of a woman's life that can be sometimes very symptomatic. And I got very angry when I started learning about this, Cindy, I don't, how about you?
But I was like, wait a minute. All these women are suffering for no reason. This is not a normal design flaw. If you believe in God or don't believe in God, whether it's nature or God, whatever. However, it wasn't a design flaw. Something's wrong that 75% of women have PMS, right? Something's wrong that most women suffer with all the symptoms through menopause because it means that something's out of whack. And so when we look at conventional medicine and it's approach, how is it limited? What are the challenges and what is sort of the current view on this? Because it's very different than what we do in functional medicine we do with Ultrawellness Center. I just want people to have a sense of if they go to their doctor and they have these issues, what are they going to get?

Dr. Cindy Geyer:
Well, it's interesting because I think we kind of touched on this briefly. The conversation about the menopause transition really has boiled down to do I take hormones or not? And we've talked about the pendulum shifts. First, everybody takes hormones, then nobody takes hormones. And now the pendulum is shifting back. I think there was an article last year in the New York Times that says, why have women been deprived of this very effective treatment for symptoms? So the pendulum is shifting back and saying, maybe women should all be on hormones again. And again, it's missing the nuance of all the other factors that are happening because not all women are going to necessarily benefit. So how do we navigate that risk benefit equation by looking at all of the factors we just talked about?

Dr. Mark Hyman:
How does, so it's sort of binary. You either take hormones or you don't. Yes, take 'em or you don't. If you have risk factors or breast cancer, well, sorry, just suffer. We'll see you later. Right? Hopefully it'll go away in a few years or not.

Dr. Cindy Geyer:
As opposed to saying, well, how do you feel? What's going on in your life? What's working for you? What's your nutrition? What's your sleep? What's your expose zone? What else could be going on? Looking at somebody's genetics that could influence how she's going to process those hormones that she takes or makes, looking at the health of her gut, looking at her key nutrients that we know really support estrogen detoxification and metabolism.

Dr. Mark Hyman:
So that's really key. So when we see someone who comes in with hormonal dysregulation, what are the kinds of things we look at? You just mentioned estrogen and genetics. Well, I remember basically thinking there was estrogen and progesterone, testosterone, and I didn't realize they were like a million estrogen metabolites. There's no such thing as estrogen as estradiol, estro, l estro, and then all the metabolites of estrogen. It's complicated, complicated. The average person who goes to medical school never learned it. And if you're even a hormone expert, it's still kind of not really on the radar. It's shocking to me. We've been doing this for decades, Cindy, and we knew this stuff decades ago and are checking this stuff, including the microbiome, including estrogen metabolites in the urine, and being able to customize nutritional supplementation or diet or other factors. And it's stuff that we know is in the science.
It just hasn't gotten in the clinic yet. Right. Alright. So Cindy, pretend I'm like a 47-year-old perimenopausal woman, which clearly I'm not, but I'm going to, just going to pretend for a minute. I come in and I'm complaining my cycles are really heavy. I get premenstrual migraines. I've got bloating after I eat and digestive issues or bowel. I love eating my sushi all the time. I have T every day and maybe I drink a little too much. I have a cup of glass of wine every night. And I'm also, I love dairy. I just love cheese. I love my yogurt. What are you going to do with me miserable. And I can't sleep. I'm moody. My husband wants to leave me, and I am starting to get no sex drive and I don't feel right and I'm gaining weight. So help. What's the workup? How do you approach

Dr. Cindy Geyer:
Them like this? Boy, that is such a common scenario. You would not believe how many women I see that

Dr. Mark Hyman:
Literally, I just didn't just make that up out of nowhere. I can think of a designations like that.

Dr. Cindy Geyer:
So the first thing I want to say is I think the importance of setting space to acknowledge somebody's experience and just reflect back, wow, that's a lot. We're going to work together to figure out a way to help you feel better and tease out what's going on. I think that's really

Dr. Mark Hyman:
Important. So giving them hope, giving them

Dr. Cindy Geyer:
Hope, and validating their experience.

Dr. Mark Hyman:
You're not crazy. This isn't in your head. There's stuff going on and we can dissect it, understand it, and help put Humpty dumpy back together again. Yes.

Dr. Cindy Geyer:
And thinking of this as actually a wonderful window of opportunity to really take stock of where you are in the moment, what's going on with your hormones. So hearing that history, when she's got digestive issues, she's got mood changes, she's clearly having symptoms related to her periods, she's having relationship concerns as a result, how do we tease all this out? We go back and start with the basics. So we want to understand her nutrition. And you know what? The Ultrawellness Center, everybody who comes to see us also works with a nutritionist because that's such a cornerstone of health.

Dr. Mark Hyman:
Oh, food is medicine. How can I practice medicine without working

Dr. Cindy Geyer:
The nutritionist? Right, exactly. So that's going to be a big part of it. And of course what comes up for her is, all right, well, she loves her dairy and she's got a lot of digestive issues. Does she have lactose intolerance? Does she have a dairy sensitivity? So we're going to be wanting to know a little bit

Dr. Mark Hyman:
More about that and how does dairy affect hormones? So many hormones, and it can really affect women's hormones,

Dr. Cindy Geyer:
Insulin like growth factor in most dairy, which can raise estrogen levels and play a role with tissue production of estrogen. So that definitely plays a role. We want to do a deep dive into what's going on for her. So not only what's happening in the moment, but what are the things we want to start paying attention to as she moves into the second half, if you want to think of it like that. So what I'm going to want to understand for her is sometimes we can get a lot just from a family history, what runs in her family? Did everybody in her family get cardiovascular disease and dementia, or does everybody have uterine cancer, ovarian cancer? That's going to potentially set the stage towards which way we might be leaning from a hormonal standpoint, the adverse childhood experience, what her childhood was like, what stresses in her life.

Dr. Mark Hyman:
We have a 32 page questionnaire at the center that's really helpful, and then we ask another 400 questions. So we do a very deep history way more than you'd get when you go to a traditional doctor. We take the time, and that teaches us a lot about your whole timeline, the risk factors, where to look, what the issues are. And so once we've done that whole deep history and we've kind of picked up the clues, what do we do diagnostically? A lot of testing that we do there is it's different. And that helps us understand what may be really going on underneath the surface.

Dr. Cindy Geyer:
So from a conventional standpoint, we still want to look at those, looking at her levels of hormones, we want to know her progesterone, her estrogen, her DHEA, her cortisol and in depth thyroid, her insulin. So we want to know the whole hormonal melia, even vitamin D, which is a hormone. So we want to look at that piece, really want to understand, which

Dr. Mark Hyman:
Often don't get looked at properly. Even when you go to the regular doctor,

Dr. Cindy Geyer:
Nobody measures an insulin. We'll look at a glucose

Dr. Mark Hyman:
Or they won't measure your full thyroid panel. They'll just look at TSH or they don't measure cortisol or cortisol saliva testing. So they don't look at all your hormones and they don't look at the timing necessarily of them. So it all matters.

Dr. Cindy Geyer:
And I actually do neutrogene genetic testing in most people because I think it actually sets the stage for a more personalized approach to diet and lifestyle. What did you come into the world with that's going to be modulated or influenced by what you're eating and what you're exposed to? And it can really help us personalize the conversation in a much better way than I can just from asking about family history. And we can come back to that, but that's really helpful.

Dr. Mark Hyman:
That's important.

Dr. Cindy Geyer:
Looking at the advanced cardiometabolic markers, not just knowing the insulin and glucose and A1C, but cholesterol particle size and number, the inflammation related markers. I think that's also important because as we know, cardiovascular events start to creep up for women in their fifties and beyond. So we kind of want a baseline. We want to know some of those key nutrient markers, their B vitamin status, magnesium status, I think you mentioned she likes a lot of fish, want to know her mercury levels. So the things that aren't typically looked at, omega fatty acid levels. So we can do some specific nutritionally related markers. We can look at those estrogen metabolites. Is she processing estrogen? Whatever she's making right now, is she processing it along these pathways that we know have more of a potential risk from a tissue effect, more breast stimulation, for example. So we can do urine and blood levels of those estrogen metabolites, which are really

Dr. Mark Hyman:
Helpful. Yeah, it's important. And I think it's something that was sort of shocking to me when I started learning about this. I'm like, wait, wait. It's not just estrogen. There's all this other stuff that's going on and what regulates these things. So you can actually see the different patterns of the breakdown products of estrogen. And some of them are hardly carcinogenic and toxic, and some of them are highly protective. So there's ones that are called like two hydroxy, they're protective and 16 hydroxy estrogens that are toxic. And then we can look at patterns of methylation, the four methoxy estrogen, so we can see all these different kinds of estrogen metabolites, and then we can look at genetics, we can tie it together. We can understand then how to give them the right supplements or the right diet or the right lifestyle interventions to actually regulate these things.

Dr. Cindy Geyer:
And I think that part is really important. It's not just about looking at the metabolites themselves. They have an action step. There are things we can do to shift those metabolites to support detoxification and really help a woman with her symptoms and to reduce risk if she does choose to take hormones.

Dr. Mark Hyman:
The other thing that sort of seems weird is that we look at the gut, right? Yes. And you talked about something called the and the microbiome and how that relates to estrogen. Can you talk about that a little? I think it's sort of novel, and we actually look at that in our practice, the UltraWellness Center.

Dr. Cindy Geyer:
Yeah. So one of the things that we know is that when we package up and detoxify estrogen, one of the primary routes of excretion is in the gut. So what's going on in your gut can influence how efficiently you can clear estrogen metabolize out of your system. We also know that your gut microbes can make hormones themselves. So depending on the balance of your gut microbes, you might have more or less circulating hormones. Who knew? That's really been seen in women who have polycystic ovarian syndrome, for example, that the gut microbiome influences the level of the androgens, the more male hormone like metabolites.

Dr. Mark Hyman:
Yeah. There's a whole thing called the entero hepatic circulation, which is from the gut to the liver and back. And usually when you finish with your hormones, you poop. You go through your liver, they go through your bile, they go into your gut and you poop 'em out. But sometimes they don't all get out and they get reabsorbed. Can you talk about that and why that's a problem?

Dr. Cindy Geyer:
Yeah. So one example of something we would see on a stool test that we would do is an enzyme called beta glucuronidase. And beta glucuronidase is produced when we have an imbalanced gut microbiome. So certain microbes will produce this enzyme. Why is that important? Well, we've talked about methylation of estrogen, but glucoronidation is another pathway by which we kind of package up those estrogen metabolites and stress hormones and some toxins to allow them to get excreted in the stool. Well, if you have a microbiome that's secreting high amounts of this enzyme, beta glucuronidase, guess what? Kind of unpackages everything and allows recirculation of estrogen stress hormones and toxins. So it adds more burden to the detoxification systems.

Dr. Mark Hyman:
And what's so amazing when you start to pay attention and you watch this, and we've done this again, we've done this for decades, you see someone with a high beta, you see someone who's got a higher circulation of recirculation and absorption of estrogens. You see that they're symptomatic from it, meaning they have estrogen dominant symptoms of breast tenderness, fluid retention, migraines, heavy bleeding clots, all that stuff. And when you treat the gut and you clear out the bad bugs that are causing this enzyme to be produced, what bacteria do they produce? Molecules and metabolites and enzymes, and there's millions of 'em in there, billions, trillions, probably like 40 trillion bacteria. And they're all doing that. And so some of these are bad, some of them are good. And when it does that, it kind of causes more problems. And we can actually treat the gut as a way of treating hormonal dysregulation

Dr. Cindy Geyer:
That's so important. Who would've thought? Right?

Dr. Mark Hyman:
And that's the kind of stuff you're not getting when you go to your gynecologist. It's really the things that we're doing are not eat your wheatgrass and get a coffee enema and everything can be fine. This is deep science we're talking about. It's not stuff that's not in the National Library of Medicine, pub Med. It's not evidence-based. We talk about evidence-based medicine. We don't have evidence-based medicine. We have reimbursement based medicine. And what we're doing is taking a look at the literature and trying to close that gap of 20 or 30 or something, 50 years from when we know something to when we do it. And so we've been seeing the clinical results of this for decades in these cohorts of women, and it's revolutionized our care and their lives and their health. And I think it's so important. So you're talking about Cindy is really a very methodical way of unpacking a personalized map of each person's life history, their psychology, their biology, their genetics, their microbiome, their toxin levels, their nutritional status, all of it.
And that gives us then direction about what to do and where to go with these people and how to understand how to take the right steps to create the balance that leads to the resolution of symptoms. So we're not necessarily treating a disease per se, we're treating dysfunction or balance. Having a high baby gluc is not a disease, but it, it's a deviation from optimal function. And so we can kind of get people back towards that. And then hormones start to regulate. And I think it's amazing when you start to fix all the other things, hormones kind of go back into line. They often go back into line without needing to take hormones or take drugs. And it's not that they're bad or we don't use them, and we're going to talk about how we use them, but often you kind of start with all that stuff first and then you see where you are. Right.

Dr. Cindy Geyer:
I think another hormone that's really, really important, if you had, I probably shouldn't say this. If you had to pick one to really focus on insulin,

Dr. Mark Hyman:
I would agree. I read about five 10 books on that one. Yeah,

Dr. Cindy Geyer:
I mean, I think insulin and estrogen will regulate to some degree if we really focus on insulin.

Dr. Mark Hyman:
So how do we do that?

Dr. Cindy Geyer:
All the things you just talked about. So again, there are genetics. Some of us are going to be more predisposed to have insulin resistance than others, but lifestyle really moves up in priority there. So we're of course going to limit or avoid the foods that give you a quick bump in blood sugar and then a decrease in blood sugar. So processed carbohydrates, sugars, ultra processed foods really drive that whole thing, which

Dr. Mark Hyman:
Is about 65% of our diet. It

Dr. Cindy Geyer:
Is, unfortunately. Unfortunately.

Dr. Mark Hyman:
Yeah, diet's a huge factor,

Dr. Cindy Geyer:
But stress also impacts insulin. Sleep impacts insulin with sleep. You and I have talked about this before, but it's quality, quantity, and timing of sleep also influence our insulin regulation. And we haven't really touched on this yet, but sleep disruption can often be huge in the menopause transition

Dr. Mark Hyman:
As a cause or as a consequence.

Dr. Cindy Geyer:
It's both. Yeah, it's actually both. So as we talked about the vasomotor symptoms of menopause, so as the hormonal shifts, hot flashes, hot flashes and night sweats. So for some women it's waking up at night and throwing the covers off and sweating and then putting 'em back on and then throwing 'em off and then putting 'em back on. You can wake up pretty grumpy and tired if that's happening.

Dr. Mark Hyman:
All sounds like you're pretty familiar with that, Cindy.

Dr. Cindy Geyer:
Oh yeah.
You talk about what you know, right? So as somebody who's been through that, absolutely. But there's another thing that starts to emerge. We know that estrogen affects other tissues and it affects the connective tissue and elasticity. So this sounds like the depressing part, but what women often notice on the outside with wrinkles is happening on the inside with our airway. So the airway can become more collapsible and sleep disordered breathing, upper airway resistance, snoring, sleep apnea goes up, fourfold in the menopause transition. We don't want to miss sleep disordered breathing or sleep apnea as a contributor to insulin resistance, mood swings, weight gain, irritability, loss of sex drive, because it's both cause and effect with the menopause transition. And we don't want to just blame it on the hot flashes and the night sweats. There might be more going on.

Dr. Mark Hyman:
Yeah. So yeah, it sounds like we call ourselves holistic doctors. We take care of people with a whole list of problems. And so this is really what we specialize in. I had love you to talk about this case that you shared a little bit earlier with me about this 52-year-old woman who had allergies, migraines, weight gain over eight years, lost her parents. And it's a really great case. Talks about how we think about people going through this phase of life differently. And by the way, before you do, I just want to say it doesn't matter what phase of life you're in as a woman, whether you're a teenager going through hormonal changes in your twenties, thirties, forties, fifties, sixties and beyond. We take care of all of it. We're just sort of focusing a little bit on menopause now. But this applies across the board. And we have different issues at different ages, but looking at the life cycles of women is really a core part of what we do.

Dr. Cindy Geyer:
I agree. And I think as I mentioned before, it's a window of opportunity. It's often the symptoms that bring you to talk to the functional medicine practitioner, but it opens the door for a conversation about everything, which is really important. I'm going to look back on this. So this is somebody who didn't come to me initially for menopause, but she happened to be in the menopause transition. She was 52, I think her last menstrual period was about six months before she came to see me. And she had this history of allergies and migraines. So just so you know, I'm going to talk as I go through this. One of the things that comes up for me with allergies and migraines is thinking about the role of histamine in some of her symptomatology the last eight years. So as she's entered the menopause transition, her weight's been going up and she had what's a very common occurrence.
She lost both of her parents. Unfortunately, her partner had a serious health issue. So there's been a lot of added stress and face it, mortality was right in front of her. So that can bring up a lot of things about, oh my gosh, what does it mean to be getting older and what's going to happen for me? She had also noticed in the last three years, she was starting to have some hot flashes and sleep disruption, brain fog, which she in particular linked to more sugar and carbohydrate intake. And at the same time, she was craving more of those foods as she was more stressed, a little bit of a vicious cycle. And we started her really on a nutrition plan while we were gathering some of the data. And her original nutrition plan was kind of what we talked about, whole food plant-based diet, minimizing those processed carbohydrates, even trying a low histamine diet to see if we could sort of clear the decks and what would happen with her allergies.
And her migraines recommended doing a sleep study, some breath based practices, which we know have shown some evidence for reducing the hot flashes. It just helping support her with all the stuff that she's been dealing with. And then when we got her labs back, her estrogen was not measurable. So she's not making any at all. Some women will make a little bit, she had some yeast overgrowth in her gut. We had some elevated markers. And it also showed up in her stool test. And she had intestinal methane overgrowth as well, which was probably playing a big role with some of her digestive issues and this strobe alone that we talked about. And she was showing some evidence of increased intestinal permeability. Her LDL particles were higher than we wanted to see it.

Dr. Mark Hyman:
So she had bad bugs growing in her gut. Too much cheese, too many bugs in the wrong spot. She got bloating and she had leaky gut, and all these things were causing allergies, inflammation, and making everything worse.

Dr. Cindy Geyer:
So it wasn't just the hormones. Yeah, and I think that's a really important piece to pay attention.

Dr. Mark Hyman:
But I don't want to ask you this, your experience too, Cindy, but what I found is that if I start with all these other things, the hormones often get in the line that actually the hormones are often screwed up as a downstream consequence of other upstream causes. Yes. It's not usually the hormones themselves or issue. Think about it. We all have hormones. They all should be working. Why aren't they working? It's not if you have a toxin like mercury, that's a bad thing. If you have a parasite, that's something that's an upstream cause. But if you have screwed up hormones, it's usually the consequence of something else that's screwing 'em up. It's not a primary thing. It can be. It can be. It can be. It can be. But you're going to have an and producing insulin as a tumor. Or you could have, I dunno what else. You could have a lot of things. You'd have a cortisol producing tumor and have Cushing. So there's a lot of things that obviously aren't what you're doing, but for the most part, a lot of it I see as downstream. Is that your experience?

Dr. Cindy Geyer:
It is. And I will say with the exception of menopause, because while a lot of women get better, there's still a subset that the estrogen itself being so low can be playing a role with some of the symptoms, a documented change in those hormone levels. But

Dr. Mark Hyman:
85 year women are not having hot flashes. True. And they have low estrogen. True. Right. So what's going on?

Dr. Cindy Geyer:
Well, that's true. That's true. Actually, about 15% of them will continue to have that. Oh boy. So we don't know what's going on with those women. But oh, and one other thing that showed up for her, she had some common nutrient deficiencies. Her B12 was low, her vitamin D was low, and we mentioned about vitamin D playing a role as actually a hormone as well. So we targeted all those things and she was feeling better, especially the brain fog and fatigue. So that responded really well to the nutrition approaches in addressing her gut.

Dr. Mark Hyman:
So you basically fixed your gut, got an elimination diet and healed the microbiome, which is a core part of what we do in functional medicine and whatever you've got, it usually plays a role, whether it's heart disease or diabetes or cancer or allergies or autoimmune disease or autism or a DD or hormonal issues, we really have to look at the gut as a central feature. And so you're saying just by getting rid of the bad bugs, getting rid of the bad foods, put her on foods that healed her gut and things that healed her leaky gut, she improved

Dr. Cindy Geyer:
And supporting her nutritionally? Absolutely. And her

Dr. Mark Hyman:
Migraines got better, her allergies got

Dr. Cindy Geyer:
Better, migraines got better, migraines got better, allergies got better.

Dr. Mark Hyman:
So Cindy, we did all these things. You did all these incredible things. You diagnosed her with all these imbalances, we corrected them. And we do this kind of work at the Ultrawellness Center. We do deep dives. We find all these things that need to get corrected, we correct them, and people's health just dramatically improves. But sometimes with the hormone issue, you need to use hormones. And it's not that they're bad or good. And I think we get into this binary thinking in medicine, it's good, it's bad, it's good, it's bad. And the truth is it's got to be personalized and it's different for everybody. And there are some rules and principles that I think we follow in functional medicine around prescribing hormones, which I want to get into. But tell us the rest of the story with this woman. You got her mostly better, but then she was still having very low estrogen. What did you do? She

Dr. Cindy Geyer:
Came back in about three months later and articulated that she was feeling better. The brain fog, the fatigue, her migraines, her allergies, they were all better. But it's interesting, the hot flashes were continuing and her sleep was being more affected. So she now came back saying, you know what? I think I do want to try hormones. We had this conversation back and forth, and of course you're going to do your due diligence before prescribing hormones. You want to make sure that she's up to date with her mammogram and there's no concern there that she hasn't had any dysfunctional bleeding, that it raises a red flag and you want to make sure that there's no hyperplasia or anything going

Dr. Mark Hyman:
On there. Heavy bleeding in the perimenopausal area where you get pre-cancer stuff in the uterus, and you can check that with a vaginal ultrasound.

Dr. Cindy Geyer:
And she didn't have any of that. So we

Dr. Mark Hyman:
Decided now we have something really cool we do is a liquid biopsy, which we didn't have years ago, which is essentially ability to track cancers through a blood test that looks at fragments of cell-free DNA, where we can actually see og, well, maybe we should screen and see not just where the mammogram, which misses a lot, but actually a gallery test which looks at liquid biopsy. And then you can go, gee, I'm pretty comfortable this person is not having some latent cancer and I'm going to throw some estro on it and give her a problem.

Dr. Cindy Geyer:
So we decided to try hormones. And my general thinking about hormones, that term bioidentical, I created a lot of confusion back in the day, but my favorite way to do it is to use a patch which has a lot of customizable doses. And it's an estradiol that is pharmacologically exactly the same as what your own ovaries would've produced before menopause. I like it. It's convenient. You put it on twice a week, it gives you a steady amount of estrogen. And like I said, there's a range of doses because she's symptomatic. I'm going to start with a mid-level dose. We started with a mid-level dose for her, because she has her uterus, she does need progesterone because progesterone's going to protect overstimulation or over thickening of that lining of the uterus. And we can also take advantage of progesterone because it has some calming sedating effects and give it at night. So it might also help her

Dr. Mark Hyman:
Sleep like the body's natural Valium. Yeah,

Dr. Cindy Geyer:
Yeah, yeah, absolutely. So that's what we did. We started her on a

Dr. Mark Hyman:
Patch. And was that an oral progesterone or

Dr. Cindy Geyer:
The progesterone is oral for her? It was.

Dr. Mark Hyman:
And it's not just the progesterone that we used to prescribe Provera. And my joke with that one, it's called progesterone. It makes women fat, hairy and depressed. Of course. And it does. It's horrible. In fact, it makes people eat more. They use it during cancer treatment to get people to eat more. Right. And so when cancer patients are starving, they're losing weight because they give 'em, this increased their appetite. Right.

Dr. Cindy Geyer:
And we can talk about that because I think the Women's health Initiative, which prompted everybody to throw their hormones in the garbage, one of the downsides of it, or one of the potential flaws of it, two of them actually most of the women were in their sixties. So they're a decade past the average age of menopause. And physiologically, women are in a different place than they might not get the same tissue responsiveness to estrogen. And they used Premarin, which is conjugated equine estrogens,

Dr. Mark Hyman:
Horse estrogen,

Dr. Cindy Geyer:
Horse estrogen.

Dr. Mark Hyman:
But it means pregnant mares urine. Yes, Premarin, that's actually how they got the name. It's get it from pregnant mares and then they concentrated and it's horse, which is very different than ours, and it's very inflammatory and quite toxic.

Dr. Cindy Geyer:
And when it's given by mouth, it goes through the liver and creates higher C-reactive protein, inflammation markers, higher clotting factors, worse insulin resistance instead of better insulin resistance,

Dr. Mark Hyman:
Triglycerides,

Dr. Cindy Geyer:
Higher triglycerides. So all of the things that were blamed on estrogen and hormones may have been more a function of the older age group of the women when they started and the formulation in the route of administration.

Dr. Mark Hyman:
So they used basically the wrong kind of estrogen and the wrong kind of progesterone

Dr. Cindy Geyer:
And the wrong route of administration

Dr. Mark Hyman:
And the wrong route of administration. So yeah, sort of the philosophy we use basically is use as little as possible for a short time as possible for the hormone that's same as your body makes and give it by bypassing the liver through your skin hopefully, or under the tongue or there's a million ways to do it. But basically it's doing it mostly trying to mimic nature and not overdoing it. And not underdoing it. Right.

Dr. Cindy Geyer:
So that brings up another point, right? It is not common practice once you put somebody on hormones to follow up blood levels.

Dr. Mark Hyman:
Amazing.

Dr. Cindy Geyer:
And for me,

Dr. Mark Hyman:
It's like giving a person a blood pressure pill and not checking their blood pressure. Exactly. Or giving someone a cholesterol pill and not checking their cholesterol.

Dr. Cindy Geyer:
So we want to see does it help the symptoms, but we also want to see, well, what is your blood level? Because that can help you gauge. For example, if I started a given dose of a patch and she comes back and she's still having hot flashes, how well is she absorbing that patch? Is it enough to get a measurable rise in her estrogen or not? Because then that can guide the dosing. I also just from trying to thread the needle of risk and benefit, I don't believe in supplementing somebody's estrogen to the level it was when she was in her twenties. We're trying to get the benefits but not really drive too much estrogen. So we mitigate risk.

Dr. Mark Hyman:
And I dunno if you do this, Cindy, but I often will check estrogen metabolites on women who are taking hormones. So I can assess whether or not they're producing toxic estrogens. I will often look at their genetics. You mentioned genetic testing, and there's genetics around estrogen metabolism, and we can look at like COMT and other hormones, methylation hormones, methylation pathways like mt HFR. And basically in English, that means we can check various enzymes that are involved in detoxifying estrogen and whether they're working well or not. And then we can use science to find the right co-factor for that enzyme, which is a nutrient, right? And so we can start to build a very scientific way of personalizing cure, and this is where all medicine is going. We're all going to be doing this. And right now, sadly, very few people get this. And it's really why we do the work we do at the Ultrawellness Center to give people the chance to get access to the future of medicine now.
And the good news is people get better. It's just amazing to see these stories that you're telling. You're so satisfying because people have all these symptoms, not just menopause like allergies, migraines, gut issues like this woman had, and you were able to get all that sorted and then get her back on track and people can come back and basically have a resolution. A lot of these really difficult problems that we don't have good solutions for in traditional medicine. So the issue around the hormones, I want to dive into a little bit more because you sort of brought it up with this woman. The Woman's Health Initiative you mentioned was problematic for a lot of reasons. They used the wrong forms of hormones, the wrong dose of hormones, the age group they gave him was problematic. But the data was kind of a little bit mixed in a way. And there's been more data that actually shows that. So the right use of hormones using bioidentical hormones may not have the same risks. Can you talk about that there is a risk like a breast cancer and other risk factors?

Dr. Cindy Geyer:
Yes. So what emerged after the Women's health initiative, and I remember us having conversations about this, is this timing hypothesis, could you potentially, is there a window of opportunity when the body still has upregulated estrogen receptors that if we introduce the bioidentical forms through the skin, so you're not going to have those other effects, that there might be a delay in the onset of some of the organ system effects that start to happen after menopause? We touched on it briefly, but we know that insulin resistance goes up, weights shifts to be more around the middle, and women start to accelerate loss of muscle mass and bone mass. There's endothelial dysfunction. The arteries become less elastic and more reactive and plaque can start to form. And what's really a big concern, and I think this is where some of the research has been interesting, is risk for cognitive decline.
We know unfortunately, that Alzheimer's disease disproportionately affects women and women who've gone through menopause early are at a much higher risk. So there's also been this real interest in, well do hormones play a role in delaying the onset of cognitive changes? Because estrogen does a lot of things in the brain that should be protective. It reduces neuroinflammation, it helps artery elasticity, it reduces amyloid plaque accumulation. And more recently, there has been research. So a couple of studies came out after the Women's health Initiative looking at that timing hypothesis, and they found that introducing hormones within the five year window of the last menstrual period, five to 10 year window of the last menstrual period in most women, again, we're back to the monolith, but most women, the benefits actually seem to outweigh the risks. So that's great. It was support for what we suspected, but then we got some data to show that. So the keeps trial in the elite trial were two of the ones that showed that. And more recently, within the last couple of years, there's actually been a segregation with looking at cognitive protection for hormones. And the evidence is suggesting that particularly for women who carry an A POE four allele, which is one of the genetic predictors of higher risk of Alzheimer's disease,

Dr. Mark Hyman:
Which we check,

Dr. Cindy Geyer:
Which we check that estrogen therapy is associated with more preserved cognition, higher volume in the parts of the brain that are involved in memory like the hippocampus. So it's as long as it's introduced within that critical window, that perimenopausal

Dr. Mark Hyman:
Window. It is just so essential what you're saying, Cindy, because it just speaks to the way we think in functional medicine, which is fundamentally different. And it's about personalization. It's not one size fits all, and it's understanding each person's unique risks, their genetics, their other risk factors. And like you said, someone's got a high risk factor for Alzheimer's with this a OE gene, this APOE four allele, they're benefiting from hormone therapy,

Dr. Cindy Geyer:
Right? Potentially. Yes.

Dr. Mark Hyman:
So that's really interesting. Of course it helps bones, it helps skin. I want to talk about sex for a minute. I think a lot of women complain of vaginal dryness, low libido and all these things that happen, and they're not just inevitable parts of getting older. I had one woman who was like 85, came to see me and she's like, I got a new boyfriend. I wanted you to help me out. I'm like, oh, okay. So how do you think about getting a woman through the menopause transition and using hormones to help her deal with some of the challenges that happen with menopause and sexuality?

Dr. Cindy Geyer:
I think that's a great question, and I'm going to unpack it a little bit as well, because I think for women, libido and sex drive is incredibly complicated. Hormones play a role, and we're going to talk about vaginal health in a minute, but it's also important to recognize that for women, if they're not comfortable with what's happening in their bodies and they don't like the way they look, and they're exhausted and they're are taking care of their parents and taking care of their kids, frankly, it's a triage theory. It it's the last on the list. So I want to really acknowledge that, that it's not just hormonal, but we also know that the vaginal tissues and the urethra of that little tube bleeding from the bladder to the outside has estrogen receptors. So what happens is estrogen levels go down, is those tissues get thinner, they get drier, the urethra shortens the pH of the vagina, changes the microbiome with the vagina changes.
So what does that lead to? Burning irritation, pain with intercourse, dryness, urinary tract infections, yeast infections. So really things that can affect quality of life. And here's where even if a woman comes in and decides she doesn't want to do systemic hormone therapy, there's still a real role for vaginal hormones because they don't get systemically absorbed or very little get systemically absorbed. They can really allow those tissues to epithelial, get stronger and healthier and more resilient, improve the pH, help with sex drive indirectly because it's not painful anymore, or you're not getting a bladder infection every time you have intercourse. So I think there's a real good role there. And both estradiol, even compounded estriol and DHEA, that precursor of estrogen and testosterone have all been shown to help improve the tissue integrity, reduce urinary tract infections and help with albido.

Dr. Mark Hyman:
Yeah, I've seen the data on that Intravaginal, DHEA, which is something that I hadn't really heard about years ago, is sort of a new approach to helping with some of these vaginal dryness issues. So I think a topical vaginal estro is important because it helps revitalize the tissues, and it also helps prevent the thinning between the bladder and the vagina, which leads to all these frequent urination problems and coughing and sneezing and peeing, and also problems with urinary tract infections after sex and so forth. So it is not just a for sexuality, it's really for overall health. What about testosterone because that's a male hormone? Do we look at it? Do we treat it? What do we do with it?

Dr. Cindy Geyer:
It's interesting because I have actually gone back and forth with testosterone. I used to use it more of it than I do now. If I use testosterone, I tend to use it mostly for women who have either low levels or no sex drive, no libido, and it's not related to the quality of the relationship. It really feels like there's a physiologic component. So I've used topical, very low dose topical drops,

Dr. Mark Hyman:
Like on the skin.

Dr. Cindy Geyer:
On the clitoris?

Dr. Mark Hyman:
Yeah, on the clitoris. Yeah. I found that to be of the greatest hacks of all time. I learned about it years ago, and we have a compounded and a compounding Farmacy and two drops every night on the clitoris. Seems to have a profound impact. And I know because women keep calling back for refills. So I think it works, and I've heard many anecdotal stories. So I think there's ways to sort of get around some of these issues as women age. And it's really got to be personalized. We've got to do a deep dive into each woman's biology and their health. We take a very different approach at the UltraWellness Center than traditional gynecologists or hormone or endocrinologists, specialists, and we look at everything like you said, we look at everything from nutritional lifestyle to toxic load, to the gut microbiome, to metabolomics, to genetics of estrogen metabolism, to yearning, metabolites of estrogen.
I mean, the list goes on and on. So we really do a very detailed view and that allows us to really help so many people where they're stuck. So we both worked at Kenya Ranch, which is a health resort, and I always jokingly say we were resort doctors that doctors have last resort. And so I think, Cindy, it's been so great to work with you for these last decades and I continue to learn from you and you bringing so much good energy and science and kindness to your patients, and I really appreciate what you do for us at the Ultra One Center. And I just think these stories today were so enlightening. And I also think that the whole unpacking of what happens and how we deal with it and what to do about it, it can give hope to a lot of people who are really struggling. So if you're listening to this and you're miserable, you don't have to be, come see us at the Ultrawellness Center. You can check it out@ultrawellnesscenter.com and hopefully we'll see you there. And Cindy, thanks again for being on the podcast. Thanks

Dr. Cindy Geyer:
For having me, mark. Always a pleasure.

Dr. Mark Hyman:
Thanks for listening today. If you love this podcast, please share it with your friends and family. We'd love to hear your comments and your questions, and please leave us a rating and review and of course, subscribe wherever you get your podcasts. You can find me on all social media channels at Dr. Mark Hyman, and you can also subscribe to my YouTube channel at Dr. Mark Hyman. I'm always getting questions about my favorite books, podcasts, gadgets, supplements, recipes, and lots more. And now you can have access to all of this information by signing up for my free Marx Picks newsletter@drhyman.com slash Marx picks. I promise I'll only email you once a week on Fridays and I'll never share your email address or send you anything else besides my recommendations. These are the things that have helped me on my health journey and I hope they'll help you too. Again, that's dr hyman.com/marks pics. Thank you again and we'll see you next time on The Doctor's Farmacy.
This podcast is separate from my clinical practice at the Ultrawellness Center and my work at Cleveland Clinic and Function Health, where I'm the Chief Medical Officer. This podcast represents my opinions and my guest opinions, and neither myself nor the podcast endorse the views or statements of my guests. This podcast is for educational purposes only. This podcast is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. Now, if you're looking for your help in your journey, seek out a qualified medical practitioner. You can come see us at the Ultrawellness Center in Lennox, Massachusetts. Just go to Ultrawellness Center.com. If you're looking for a functional medicine practitioner near you, you can visit ifn.org and search. Find a practitioner database. It's important that you have someone in your corner who is trained, who is a licensed healthcare practitioner, and can help you make changes, especially when it comes to your health. Keeping this podcast free is part of my mission to bring practical ways of improving health to the general public and keeping with that theme, I'd like to express gratitude to the sponsors that made today's podcast possible.