GLP-1 & PCOS Breakthroughs: How Ozempic is Changing Women’s Health | Dr. Melanie Cree

Dr. Gabrielle Lyon: 00:00

Music, PCOS affects millions of women, yet most still struggle to get real answers. If you're dealing with irregular periods, weight gain, fertility issues or hormonal imbalances, this episode, friends is for you. Today. We're sitting down with Dr Melanie Cree, a leading pediatric endocrinologist and one of the top researchers in PCOS treatment. The

Dr. Melanie Cree: 00:25

other side of PCO really seems to be related to type two diabetes. The primary therapy for PCOS is lifestyle changes.

Dr. Gabrielle Lyon: 00:36

Today, she'll be breaking down the latest breakthroughs in managing PCOS. If you've ever been told that PCOS is just about losing weight or taking birth control, this conversation will change the way you think about it. Dr Melanie Cree, welcome to the show. Thank you. And I have to tell you, you're an MD, PhD. You are a physician scientist, and I just have to read this, because we look for the best of the best, and you have an extraordinary track record for somebody so young, so just incredible. You are a pediatric endocrinologist, Associate Professor at the University of Colorado and Children's Hospital. You have a clinical practice, yes, still focused on treating adolescents polycystic ovarian syndrome. You founded and direct the Children's Hospital Colorado. It's a multi disciplinary PCOS clinic. You are really a world leading expert, and we are just so happy to have you. Thank

Dr. Melanie Cree: 01:49

you. Thank you. I'm happy to talk about my work. We cannot wait.

Dr. Gabrielle Lyon: 01:53

And before you do, I want to know, why do you do

Dr. Melanie Cree: 01:59

what you do? I think in part, I'm a third generation physician, and really watched my father a lot as a child, and he's a family physician, and he would take me on house calls, and I just really saw how when you take the time and the extra step, you can really make a difference in people's lives. And then I'm very passionate about women's health. I went to Bryn Mawr College. It's an all women's college, and kind of, through my career, have worked towards providing better care for women, in part for what I've seen in my friends, in part for the errors or misdiagnoses and things that have happened in my own life. So really kind of working towards improving women's health. And so, you know, it's one of the Texas phrases, get her done. So love that.

Dr. Gabrielle Lyon: 02:56

Yeah, pretty extraordinary. And your research focuses on how insulin works in youth with polycystic ovarian syndrome. Yes. For diabetes, I would love to talk about the spectrum of the work that you're doing and really where you're focused right now. Yeah.

Dr. Melanie Cree: 03:12

So for PCOS, I'm pretty much the entire human spectrum. So I'm good friends with the head and founder of PCOS challenge, which is the biggest patient organization within the United States, and so do a lot of patient advocacy and education. So we went to Capitol, Capitol Hill in DC, one year with one of my patients, and met with all our representatives, working on patient education materials, patient facing, trying to get funding there, running clinical trials, so, testing existing medicines to see if they help with PCOS, and then getting more into metabolism, so using special chemicals called stable isotope tracers to understand how the liver works and how muscle works and how fat tissue works, and developing methods to measure how different things work in the liver, so we found a new pathway in mammals that had Never been described before. No big deal. No, no biggie.

Dr. Gabrielle Lyon: 04:22

And what is that pathway that's crazy?

Dr. Melanie Cree: 04:25

So we found that so within the liver, when we have extra fat, we burn it, and when we burn that, we make reactive oxygen species, and that leads to fibrosis and liver disease. Essentially, fatty liver. Yes, exactly, so that so you've got all the extra fat, and then you get the fibrosis, and there's a compound called glutathione that we make, and so glutathione kind of mops up those reactive oxygen species, so if you have enough glutathione, you don't get fibrosis in the liver. So we found that. Glycerol, which is the backbone in fat, actually can be turned into glutathione. So our and that was the new path. That's fascinating. So our hypothesis is that when you have extra weight, or we're eating fatty foods, that you've got free fatty acids, and then you've got the glycerol, and they're both in excess. So the free fatty acids go into fat, and then they get burned, and the glycerol comes to make the glutathione to balance out the reactive oxygen species when the fat from the free fatty acids is burned, wow. So that that's our hypothesis, but we didn't know that glycerol turned into glutathione. Because

Dr. Gabrielle Lyon: 05:46

traditionally, we think about amino acids. We think about methionine, yes, as a precursor for glutathione production, which is one of the reasons why, you know, you also worked with Bob Wolf. You do work with Bob Wolf, which is truly the OG and we think about literally writes the textbook. He was on the show. We got to have him back. But, you know, we are going to talk about muscle tissue. And one of the things that I think makes you so unique, beyond your clinical experience and just the multiple papers and collaborations that you've had is that you have a really good understanding of muscle Yes, and intramuscular adipose tissue, which I have never seen a physician who is practicing, who is also doing the research and doing muscle biopsies and looking at it under ultrasound, which, you know, when I was doing muscle biopsies, we weren't using ultrasound, yeah, and I'd love you to talk about what PCOS. PCOS is. PCOS is why we should care about it, and just the ultimate impact that it has. Because it seems as if we've been trying to treat polycystic ovarian syndrome forever as one of the leading causes of infertility.

Dr. Melanie Cree: 07:03

Yes, yep, exactly. So PCOS. So first of all, you don't have cysts in your ovaries. So the name is wrong. Why did they do that? Screw that one up. I don't know. We're actually working on changing the name. What should it be called? Oh, gosh, we came up with a name last year at Rotterdam. It's going to be something along the lines of, well, we couldn't do metabolic reproductive syndrome because that has some issues in certain countries. For those women, they would be stigmatized against. So we but it's something along with metabolic and then it was something different for reproductive that that wouldn't cause the stigma so well, we'll get there

Dr. Gabrielle Lyon: 07:44

with you on their team. I am sure of it. Tell us what, yeah, tell us about PCOS, and if it's a lifelong condition, and why and how it affects fertility. Yeah. So

Dr. Melanie Cree: 07:53

we do think that there's probably two separate conditions that we're calling PCOS, because what PCOS looks like is so broad, and so that's part of the problem in making the diagnosis. So there are people who have the more what we call reproductive phenotype, and we know that this is coming through the brain, and normally women have more follicle stimulating hormone than luteinizing hormone, but in individuals with PCOS, that is switched, so women with PCOS have more LH secreted, and LH in particular, affects the fecal cells in the ovary to release testosterone. So there's definitely a genetic component to it, and we think that part of that is this brain and this excess LH, the other side of PCO really seems to be related to type two diabetes, and essentially the same fecal cells that make testosterone respond to insulin. So when you have excess insulin, you can then get excess testosterone. Now that doesn't happen to everybody. So again, there's got to be some aspect of that where the ovary is more sensitive to the insulin, but that is why the primary therapy for PCOS is lifestyle changes, because if you eat less sugar, and in particular liquid calories, if you eat less sugar, you release less insulin. If you exercise, you make insulin work better, and then you have less insulin. So one of the things that you see a lot in the literature is patients very frustrated, feeling like doctors are being dismissive. Oh, just go lose weight, and it's the right thing with the

Dr. Gabrielle Lyon: 09:53

wrong message. It's the right thing with the wrong message. So

Dr. Melanie Cree: 09:57

that's, you know, I feel like. When you explain to people, well, it's the insulin that's causing the testosterone, so we need to decrease the insulin. And so then the medication that is typically used is Metformin. Metformin makes insulin work better, so then you don't have to release extra insulin, and then your testosterone goes down. So in terms of the scope of of and

Dr. Gabrielle Lyon: 10:23

how long is Metformin, sorry to interrupt. How long has Metformin been used in the treatment of so do we call it PCOS, or do we can call it PC? What are we calling it? What are we calling it? PC, something. Yes. Okay. From so the use of metformin, which has been used for a long time. How long has that been utilized as a treatment? Because you and I were talking about throughout your career, now we have the use of GLP ones, which, right? That totally changes the game. Yep, yeah. When did they initially start using Metformin and how effective has it been? So

Dr. Melanie Cree: 11:00

PCOS was originally called Stein Leventhal syndrome, and it was discovered in the early 1900s PCOS as a a true syndrome, was not described and defined until the 1990 original NIH guidelines, and so Metformin is in those original guidelines based on some of the insulin sensitivity work that Andrea denefe Did and but in terms of the syndrome, it's really new, right? 35 years. But that's kind of ridiculous, if you think about it. And a bit of a sad commentary on women's health, again, why I'm interested in this field in general. It is the leading cause of female infertility in the United States. When women with PCOS have extra weight, they have an eight fold higher risk of type two diabetes. And then the we're still on the fence about cardiovascular disease or not. So there's some really good studies trying to figure out cardiovascular

Dr. Gabrielle Lyon: 12:03

disease that seems like a lot of women.

Dr. Melanie Cree: 12:06

It is, it is a lot of women, and it is, the prevalence is going up because it is tied to extra weight. And so as weight is going up, the prevalence is going up. And one of my colleagues, Ricardo Aziz, just published this within the last year, looking at the prevalence rates of PCOS. And it's not just that we're diagnosing it, it's that it's going up and for in teenagers, we looked at our cohort of patients, so it was about 500 patients, and we looked at our patients who had extra weight, who were diagnosed with PCO, and we found that the rate of type two diabetes was 18 fold higher in the highest risk patients, and those patients were of Mexican, Hispanic heritage, Hispanic really encompasses people with different genetic risks. So individuals from Puerto Rico are very different than individuals from Mexico. So in individuals with a Mexican Hispanic background who had pre diabetes and a little bit of liver disease, so an elevated alt 70% seven zero had type two diabetes within four years. So we certainly have some really high risk populations. And when kids get type two diabetes, it's very different than adults. It's very aggressive. And in our today's study, which is the PI of that is my division head, Phil Zeitler, we found that individuals who developed type two diabetes as a teen are actually starting to get renal failure, heart attacks, and dying by their late 20s, early 30s. So looking at that relationship between this adolescent PCOS, this increased risk of diabetes. We're talking about a very, very shortened lifespan for some of these individuals. And so that's why I'm so focused on really trying to make a difference in the adolescents so that they're not facing these outcomes later on, even just a decade later.

Dr. Gabrielle Lyon: 14:20

That is That's tremendous. And even I would assume that that would also mean lifelong infertility potential.

Dr. Melanie Cree: 14:27

It's tricky. It there's some really interesting data that's come out in the last couple years. And the way I explain PCOS is there's too many eggs in the ovary, so we've got eggs, and then you form a follicle. So, you know, that's where you've now got a center, right? And then kind of the eggshell. And normally, women have two to three follicles in their ovary. At any given time in PCOS, we have too many follicles. And so the way I. About it is that our follicles are squished and they can't get to the surface to be ovulated. So the way that you can think about it is that there are too many follicles to surface area so they can't get out. And we've heard about oops babies in women with PCOS over the age of 35 for a long time, but what they've found actually is that the infertility of PCOS in some people tends to burn out over their reproductive lifespan, and in fact, the highest rates of infertility in women with PCOS are the two ends of the spectra,

Dr. Gabrielle Lyon: 15:43

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Dr. Melanie Cree: 16:47

Lion. So what I tell my parent patients is, if having children is in your life, plan, don't plan to be an early mom. The younger you are, the more likely it is that you will have trouble with PCOS related infertility.

Dr. Gabrielle Lyon: 17:03

That's really interesting. I don't think I've ever heard that before.

Dr. Melanie Cree: 17:07

There was a nice paper. There was a paper that suggested it, that came out maybe seven years ago, and then there was one that came out a year and a half, two years ago, that really looked at rate of ovulation by age in women with PCOS, and actually found that 30 to 3536 women with PCOS have much higher rates of fertility than women who don't have PCOS, who are now dramatically dropping.

Dr. Gabrielle Lyon: 17:32

And is that, because of the natural decline in follicles making more space?

Dr. Melanie Cree: 17:36

Exactly, that's the way I think of it in my head. Is that as all of our eggs die, right? We're born with 3 million. You have about 300,000 when you start having periods. The way I think about it is that there's just too many eggs. So if you have this perfect range of fertility, that peak fertility in females without PCOS is 14 to 16. So you're right at this peak fertility, you kind of go down, fall out. And so the women start falling out around 30 right? And then really fall out around 35 and the way I think about it is with PCOS, you just start here. So you have too many eggs, you can't get them out, too many follicles, they keep dying. So it's a parallel line. It's just shifted later. So then you come into your peak fertility later, 2728 and then,

Dr. Gabrielle Lyon: 18:23

I mean, that's fascinating. And I also think, number one, you're offering a lot of hope, because we have young patients in our clinic who are 30, who have, would that be considered correct to say a lean phenotype?

Dr. Melanie Cree: 18:36

Yes. So that's where we think there's a reproductive phenotype and there's a metabolic phenotype. And this is why, hopefully, at some point we'll be able to distinguish between the two. There's been lots of proposals of, do we have four, you know, A, B, C and D, or there's an eight phenotype description, but that's where I think the the reproductive type are the ones that have those brain changes, they have more of the LH elevations, and that phenotype often has a harder problem, harder time getting pregnant. Do

Dr. Gabrielle Lyon: 19:11

we know is that just genetic and what are the numbers? Do they track? For example, if there is a reproductive phenotype, are those numbers much lower than a metabolic phenotype, just by nature of the fact that so many individuals are metabolically unhealthy.

Dr. Melanie Cree: 19:28

I think that really varies by country, and it's really hard to get a handle on because we don't know all the women that are diagnosed with PCOS. So is it that the most extreme infertility and then come to medical care, and then the most extreme metabolic come to medical care? So there's been a lot of commentary, again, by Ricardo Aziz, primarily that what we know about PCOS. Is too academically driven and centered, and too much of the sick patients, and that the the medium scope of patients who have some problems, but not horrible, is is not being assessed. And there was a paper that it was published in January, and they estimated that 70% of PCO is undiagnosed, 70%

Dr. Gabrielle Lyon: 20:19

70 How is that? What? How is that possible? Because you've

Dr. Melanie Cree: 20:23

got this middle range. So is it that women with, you know, pre diabetes, and you miss a period here and there? Is that actually within the scope of PCOS, but because your your periods aren't irregular enough that you're not coming to attention for infertility and things like that, so that it's you see the sickest of the sick, if you will, and that there's this more moderate range that don't come to attention.

Dr. Gabrielle Lyon: 20:50

How would an individual who is listening here and again, it sounds like PCOS can affect a person almost at any age, from adolescents to would it be fair to say, two menopause? Two menopause? Yes, what? And they're thinking about it, and the signs would be,

Dr. Melanie Cree: 21:09

what? So for adolescents, you have to have irregular periods, so and you have to be one year after your first period. So in the first year, anything goes, our body is just learning how to have periods and coordinate itself. So after you've had periods for a year, then it's any one time span greater than 90 days, or it is less than seven periods a year, so more than 45 days in between periods, and we do not use ultrasound in adolescence. You do not use ultrasound to diagnose PCOS until the individual is eight years after their first period. And the reason that we don't is very sad. We don't know what regular female ovaries in teenagers look like, so we don't have norms to then be able to say what too many follicles is. So that's the reason that we don't use ultrasound in adolescents. And I'm part of several labs and groups that are collecting adolescent ovary data pooling into a big database to hopefully be able to do norms. And then the other sign is signs of elevated androgens. So this can be growing a beard, male pattern baldness, hair all over the body. And then in teenagers, it's a little tricky, because it can be acne, but many teenagers have acne, so you can have irregular periods and clinical symptoms of PCOS, or you can have biochemical PCOS. So sometimes you've got people who come in with the most gorgeous skin, and they've got a super high testosterone that's three times the upper limit of normal. I was going

Dr. Gabrielle Lyon: 23:01

to ask you, what are those cutoff ranges from when an individual would come in and be considered to have elevated androgens? Would it be a point above normal? So

Dr. Melanie Cree: 23:13

this is again, a huge point of controversy, so there's a lot of difficulty in setting normative ranges for steroid hormones. And within the last 15 years, instead of using antibody linked Elisa's, they've been switching to liquid chromatography mass spec methods. And in fact, for our endocrine journals, they only accept hormones that have been run by this LC MSMS and LC, MSMS for the lower range of testosterone has not had a standard set yet. So with PCOS challenge, I'm actually working with the Center for Disease Control and the center and the lab calibration system to center all of the LC, MSMS methods to be the same as the CDC, so the CDC would be the primary method. And we've done this with one lab where I run all of my samples, and the lab, the commercial lab, where I run my samples, is identical to the CDC. And so I know those ranges, but the upper limit of normal range is anywhere from four. For free free testosterone is anywhere from four to nine. So our hospital just changed labs. Our cutoff was 6.4 the new lab is 9.2 we're all in a flurry about what to do, and we as a group have decided that we're just randomly going to use seven as a cutoff because we don't believe that it's all the way up to 9.9 so just changing a lab has completely changed. How people are diagnosing PCOS, and that is that is an absolute mess. And so what we're doing right now is gathering the data and finding cohorts where we've got saved blood samples for that we can run testosterone on, and then the women are really well categorized in terms of, do they have regular periods? Are there periods irregular? Do they have extra hair or hirsutism or acne? And so that's the stage that we're but we need funding. Well,

Dr. Gabrielle Lyon: 25:31

maybe we can get you some. Yeah. But

Dr. Melanie Cree: 25:34

so so teenagers, periods, testosterone, adult women, you can throw in the ovary ultrasounds. So for PCOS in adult women, you can have

Dr. Gabrielle Lyon: 25:46

defined by age 18 or just eight years post menarche, which is also interesting, because now we've taken a actual age range. Yes,

Dr. Melanie Cree: 25:56

exactly. So this, that's where, right? It's all a little it's all a little tricky. But so the teenagers, you have to have two adults. You have to have two but there's a choice of three. So they can have irregular periods and abnormal ovaries and no elevated testosterone, or they can be the same as the teenagers. But in both cases, you have to have not normal periods. If your periods are once a month, you do not have PCOS.

Dr. Gabrielle Lyon: 26:26

Are women misdiagnosed or potentially, let's say a woman gets a Mirena and is no longer having regular periods, or is placed on birth control and is having artificial periods in the way, depending on that type of birth control, will that treat or mask the symptom of a reproductive phenotype? Yes,

Dr. Melanie Cree: 26:50

of course, yeah. And one of the things for PCO is that you cannot be taking any sex hormones or sex steroids at the time of testing and the effects of an oral contraceptive pill can last for up to three months. The effects of a Mirena three to five months and then an explanan, it can take up to a year to get regular periods back. And so, per the international guidelines, the primary therapy for PCOS is to start oral contraceptives because of how they go through the liver. And what the oral contraceptives do is they suppress testosterone. And so a lot of patients prefer that, because it makes the beard go away and their hair starts growing back. And so if anybody's with PCOS is worried about cosmetics, then you have to do estrogen. And the thought behind it is that if you put somebody on oral contraceptives, you bring the testosterone down. Now that's taken out of that metabolic milieu. And so the metabolism should get better. What we're finding in our database study is that the birth control pills seem to be very effective in our more reproductive lean phenotype, but not as much in our group with obesity. And

Dr. Gabrielle Lyon: 28:17

that would make sense, I think, somewhat, even if the outcome for both of those things would be elevated androgens. Yes, you said something that I definitely want the audience to appreciate, and that is, depending on the lab assay, you will get different results, whether it's liquid chromatography or a different kind of method, and those results will vary based on number

Dr. Melanie Cree: 28:43

exactly so. So liquid chromatography is the only assay that is sensitive enough under 100 for testosterone. And for reference, if a male's testosterone is 250 or lower, that's considered low testosterone. Average testosterone for men is around 500 so if we're saying that the cutoff for normal for women is somewhere in this 40 range for total testosterone, then you know, tenfold less than men. And so that's why we need to have the more sensitive methods. So if it's that's

Dr. Gabrielle Lyon: 29:19

not standard of care, not yet, no. And that is what I want people to know, whether they are providers or you guys are advocating for yourself. And would it seem weird if you ask your physician, is this liquid chromatography? If our patients asked, we would say yes, and I think it's really important, because an individual might not get diagnosed, or they might get a misrepresentation of their number, yes, and it changes clinical outcomes in the way of treatment it does,

Dr. Melanie Cree: 29:48

and it really changes the diagnosis. And there's two more problems with testosterone. Testosterone has what we call a diurnal rhythm, so it's highest in the morning and then lowest. At the end of the day. So people will go in and have their blood drawn at the end of the day, and the doctor will say, Oh, well, your testosterone is high, normal, but it's not high. You don't have PCOS, no, you bring them back and you redo the lab in the morning, and then it's high. So if there's ever a question or you want to wait the best time to check testosterone is in the morning, during menstrual bleeding. I'm

Dr. Gabrielle Lyon: 30:26

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Dr. Melanie Cree: 31:48

And if you are high, then then you have high, you have PCOS. And the other problem is that free testosterone, which is your active testosterone is bound to sex hormone binding globulin. If you have excess weight and excess insulin, your SHBG is low. So again, this is what we're finding in this big database, is that the average total testosterone, which is affected by the SHBG, is much lower in our patients who have excess weight than in our patients who do not have excess weight, because if they don't have excess weight, they have higher SHBG, so they have higher total testosterone. So a lot of the time, if people are just doing a total testosterone and you do it in someone with excess weight, they're told they don't have PCOS. But if you were to run a free testosterone, their bio available, bioactive testosterone is much higher.

Dr. Gabrielle Lyon: 32:49

Why is that? So help me understand so sex hormone binding globulin. So I think of hormones like kids. They don't get to go anywhere by themselves. Yes, they are bound to a protein. Sex hormone binding globulin binds exactly what it sounds like. Sex hormone bind binding globulin. So if a woman who is over, oh, that would make sense. If a woman is overweight, she's going to have less, and her total will be higher. Her total will be lower. See, why is that? Well,

Dr. Melanie Cree: 33:16

because the so the free is bound to the total, yes, or the free is bound to the SHBG. You have less SHBG, so you've got 50 kids waiting in line, okay, but you only have 10 busses, right? And that's in somebody with extra weight. So busses, being the SHBG, you can only get 25 of those kids on. So you've got a total testosterone of 25 which is normal, but you've got 25 free, which is your bioactive and high in somebody who's lean, you will have 50 kids, 20 busses. So now your total is going to be much higher and you have less free, but your free is still high because you have PCOS I see. So what happens is, if a physician only orders a total testosterone, and somebody has extra weight with a low SHBG, they will have a falsely normal testosterone and be told they don't have PCOS. So in fact, the guidelines say that you should draw a total testosterone and a sex hormone binding globulin and calculate the free androgen index. And the reason that we don't do free testosterone is the assay isn't good enough. So there's a lot of these little subtleties that make it challenging for physicians to make a diagnosis and can be very frustrating for patients. So if a patient is having a testosterone drawn, they want to ask for a testosterone panel in the morning when they are having menstrual bleeding and. And oh, there's one more part. Oh, and it needs to be lcmsms, yeah,

Dr. Gabrielle Lyon: 35:05

liquid chromatography, yep. What about LH and FSH? You said that in PCO, they are flipped. The ratio is flipped. Is that consistent? Does it depend on the cycle time? Should that be used in diagnosis.

Dr. Melanie Cree: 35:21

So LH and FSH are not part of the guidelines

Dr. Gabrielle Lyon: 35:25

you can they be.

Dr. Melanie Cree: 35:29

I would argue maybe FSH because that can show if an FSH is high, that can show ovarian failure. So you would see that in primary ovarian failure, but if you're having primary ovarian failure, then you're having symptoms of menopause. So you could argue that if you're a good clinician and can get a good history from your patients, you can often rule out primary ovarian insufficiency there, the ratio is two to one in approximately 70% of patients. So that's the other thing is, it's not consistent enough. So maybe if I have a patient who's got borderline testosterone, and their periods are, you know, kind of right at the edge, are they irregular, not not regular, then I might get an LH, FSH, to help me figure that out,

Dr. Gabrielle Lyon: 36:21

I have a body composition question between the reproductive phenotype and the metabolic phenotype. Typically, we associate testosterone with more muscle mass, greater strength, many positive attributes to body composition. Do we see that of any benefit for the reproductive phenotype versus the metabolic phenotype.

Dr. Melanie Cree: 36:48

You know, I don't know for the for the reproductive phenotype. I I know a lot more about the the metabolic phenotype. That's where the majority of my research is. And we do DEXA scans to get muscle mass. So I'm very familiar with the muscle mass in the individuals with excess weight, and what I find really interesting is that they don't have more muscle than individuals of the same body mass index, same weight, who don't have PCO. And this is, this is actually one of the hypotheses behind us using amino acids to decrease liver fat in PCO, because you would think they have extra testosterone, they should have extra muscle mass, and they don't. And so our thought is that when you give amino acids, you actually drive muscle protein synthesis, pull out the non essential amino acids, and so then you don't have enough amino acids to go and make fat properly. But it's always something that I've noted and wondered, is, why don't they have more muscle mass? And one of my partners works and specializes in boys with Klinefelter syndrome. And so one of the things and Klinefelter syndrome, their testes start dying, so they have lower testosterone, or they don't even go through puberty. And one of the things that Dr Shanley Davis and I have been talking about a lot, is, is this somehow an estrogen to testosterone ratio? And so is it that if you're in this certain ratio area, that you have increased metabolic risk and you don't see the androgenic effects on muscle that you would So boys with Kline filter much higher rates of metabolic disease, visceral fat, central obesity, and that's what we see in girls with with PCOS. So we've looked at that as well. One of the other comparisons that we've done is one of my other partners is just trying to understand, when you have a transgender individual, what happens to their muscle mass. And at the beginning of starting testosterone in somebody who is trans male, their estrogen to testosterone ratio is in this kind of same ballpark as individuals with PCOS or Klein filter, and so we did the same metabolic tests in them, and then when they were at full testosterone. And the interesting thing is, you don't see that metabolic phenotype in the individuals taking exogenous testosterone

Dr. Gabrielle Lyon: 39:35

on their end ratio. That's really fascinating. I not sure what to make of that, but Right? Because you obviously wouldn't give an individual what I'm hearing you say is the testosterone being elevated doesn't have in an individual with a metabolic phenotype of PCOS, does not have the same input, even if their testosterone is high. On muscle mass, and one would expect correct exactly quality of that tissue is different. Which I am so excited to talk about, the quality of skeletal muscle tissue, especially with this metabolic phenotype, what role? And you said something else also I can't ignore, which we have to go back to. Maybe we'll start with the skeletal muscle, and then circle back to the amino acids, because, again, you trained at Galveston. You worked with Bob Wolf, again, one of the OGS in amino acid metabolism. Don also Don Lemon also worked with him. And you are utilizing amino acids to improve liver outcomes, yes, and that is unbelievable. So let's start with the difference in muscle mass, or the role that you think muscle mass plays in PCO.

Dr. Melanie Cree: 40:51

So some of my initial work in in PCO was looking at mitochondrial function, and this idea of the relationship of mitochondrial function and insulin signaling really came around with with David Kelly and Jerry Shulman in right around 2000 and so the thought was that if you don't have adequate mitochondrial function, that you get a buildup of diacylglycerols, DAGs or ceramides. Scott Sumner, out of University of Utah, is really interested in the effect of ceramides, and that these compounds actually directly interfere with downstream insulin signaling, so they cause phosphorylation in the wrong place, and essentially insulin resistance in skeletal muscle? Exactly, yes. So there was this thought that is, is insulin resistance in skeletal muscle really related to mitochondrial function? And so this was really coming in, that was what I worked on for my PhD dissertation. So I've focused on that particular aspect for a while. And so what I liked was I learned that in geriatrics and burn trauma in my training. And then we went and looked at individuals with type one diabetes, type two diabetes, with Kristen Nadeau. And then I looked in PCO. And so that's when I started my career in Colorado, and so it's really cool. You put someone in the MRI machine, and we max test them to see what their maximal force is. And we're doing pushing down on a pedal. So we're really testing the soleus and the gastroc, and then we have a special MRI coil that goes around behind. And what we can do is they exercise in the muscle, and we can see the ATP turn into ADP at two second intervals. And then when they stop exercising, the ADP turns back into ATP. And then we have special formulas and fitting routines that we do, and we can directly measure rates of oxidative phosphorylation in somebody who is just laying in the magnet. And so what we did is we did these muscle measures oxidative phosphorylation, and then we did what's called a hyperinsulinemic you glycemic clamp. So you give a large amount of insulin. If you're sensitive to it, you need a lot of sugar to maintain your blood sugar. If you're not sensitive to it, you don't need much blood sugar. And so we looked at that relationship and found that, indeed, girls with PCOS had lower rates of oxidative phosphorylation than did girls of the same weight without PCOS. And for that trial, I did individuals with excess weight and individuals without so that's fascinating. There were totally mitochondrial changes with PCOS. How old were these individuals? Where they were young, yes, average age of 15, so it's 12 to Yeah, it's 12 to 21 has been all of my trials. I mean,

Dr. Gabrielle Lyon: 44:08

we have to highlight that age. Yeah, 12 to 21 you are seeing skeletal muscle insulin resistance, yes. And were all of these individuals overweight, or were they just sedentary? Two thirds were

Dr. Melanie Cree: 44:22

two thirds were overweight, and then 1/3 were not. So it was in both BMI categories across the board, and they both had abnormalities as well in their insulin sensitivity when compared to similar weight individuals and when we gave them a sugary drink, the individuals who had extra weight, many of them were in the pre diabetes range. None of the girls who didn't have extra weight had glucoses After taking the drink that were high per our definitions of diabetes and per our clinical definitions. Yes, but when you look at their glucose and their insulin curves relative to girls with normal periods the same weight, they're still much higher. And so even individuals who do not have excess weight have insulin resistance. And you have to say that again,

Dr. Gabrielle Lyon: 45:14

because this is the only often, the only time people will hear what you are talking about is some work out of Yale, right? So you had mentioned Shulman or penderson in Copenhagen, yeah. But what you are saying, I have never heard somebody talk about a euglycemic clamp exercising skeletal muscle with a metabolic phenotype of PCOS. So you just have to say it again, you guys are so I feel so lucky to be having this conversation, because what you are pointing back to is skeletal muscle as, frankly, one of the only organ systems we can do anything about, directly, voluntary, exactly.

Dr. Melanie Cree: 46:01

And in that study, the other two pieces of that study that were very concerning is the cardiovascular changes. So in that study, we also did ultrasounds of the carotid arteries, and we found that in the girls with PCOS and extra weight, their carotid arteries were stiffer, which is one of the first steps towards high blood pressure, and their plaque was thicker age 15. We can see that we also did vo two peak testing on these individuals, and their peak testing was coming in. I think the average was 19 to 20. And for reference, congestive heart failure is 15. So our 15 year old girls have plaque. They've got stiffening so they're well on their way to high blood pressure. Their exercise performance is terrible. They can't upregulate their cardiovascular volume when they try to exercise. Their mitochondria are abnormal, so 60% of them have fatty liver disease. I mean, this is part of the reason that I'm doing this. But the thing is, is that they all have insulin resistance, and so this is where, again, coming back to the guidelines, lifestyle changes are recommended for every patient with PCOS regardless of body size, because even those who don't have extra weight have insulin resistance, and we've shown that really nicely in kids, and as I had mentioned, Andrea Dene showed that really well in adults. And so that's where it comes back to lifestyle and exercise, obviously, is one of the best ways to increase insulin sensitivity. The findings of that first study really changed how I do exercise counseling for my patients. So the American Academy for pediatrics is an hour of exercise five days a week. And if you try to go do that in somebody who has a vo two peak of 19, they will pass out their heart. Can't do that. So I've stopped, actually, in our patients that are very sedentary, I've actually stopped using the word exercise and started using the word activity. And everybody has step counters now where they look on their phone, and most of them are getting 1000 to 3000 steps a day,

Dr. Gabrielle Lyon: 48:27

1000 to 3000 steps a day. That is sedentary muscle. That is, hands down, insulin resistance, sedentary muscle. Are you seeing fat infiltration in that tissue at this age, at 15? Oh,

Dr. Melanie Cree: 48:40

yeah, yeah. When you go to do those MRIs looking at the mitochondrial function, we do the imaging, and what you can see is that if you have a nice, healthy muscle, you don't see a lot of marbling in the fat

Dr. Gabrielle Lyon: 49:00

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Dr. Melanie Cree: 50:26

with diabetes looks like the Wagyu beef, like it is just completely if you've ever seen it not cooked, it's like 40% white from all of that fat. So that would

Dr. Gabrielle Lyon: 50:40

mean, sorry, interrupt. That would mean less mitochondrial function. I'm assuming that means less strength, less oxidative capacity. Is that the outcome of a marbled changed in composition muscle?

Dr. Melanie Cree: 50:55

Yep, yeah. So you can visually see that on imaging, and now we've got really nice algorithms that you can take an image, and then the algorithm will go through and figure out how much in this area, how much is fat and how much is muscle, so that you can get a better sense of rather than like size per size and attributing it all to muscle. You can see muscle to distinguish between the muscle and the fat, which

Dr. Gabrielle Lyon: 51:22

is unusual, because typical imaging, for example, you know, a DEXA doesn't really differentiate. It'll say it doesn't differentiate. Also share about this, because this is now we're getting really granular into skeletal muscle as this organ of longevity and as a focal point. Yes. So please share. So

Dr. Melanie Cree: 51:40

DEXA basically breaks things into fat, muscle and bone based on an overall density. So it basically puts an x ray out from the top and then collects it on the bottom and the arm moves across your body and is very general with the MRI. Muscle is dark. Fat is white. So even if you have, for example, take your quad muscle. You take a quad muscle in an athlete, and if you look at it on MRI, it's solid gray, just totally homogenous gray. It's all muscle. You do the same thing for somebody who has extra weight, or somebody with with type two diabetes, and you look like that uncooked Wagyu beef. You've got all of this white fat in there. So when you look volume for volume, the individual with the fat in that muscle belly is going to be less strong because they have less fibers in there. And so yes, that's exactly what you see. And then those muscle fibers are completely surrounded by these fat cells, which release their own chemicals and maybe, and maybe influencing the insulin sensitivity at that level,

Dr. Gabrielle Lyon: 53:00

I have two questions, two follow up questions for that. Number one, do you believe that skeletal muscle adipose or I'm at intramuscular adipose tissue starts first and then and again? I understand that I'm making kind of a differentiation, and it might not be accurate, from what I have read and understand, it seems as if there's a distortion in skeletal muscle first,

Dr. Melanie Cree: 53:31

you know, it's it's tricky. I think there's probably multiple pathways, right? So my initial work is in burn trauma and insulin resistance. With burn trauma, or any kind of trauma, occurs nearly immediately. So is that part of that is your acute hormones, so epinephrine and other you know, some of those acute stress phase hormones cause insulin resistance. TNF, alpha causes insulin resistance. Interleukin one, interleukin six, right? So our inflammatory cytokines and all you know, some of the hormones cause insulin resistance immediately. So is there a way to completely shut off insulin with different or insulin sensitivity in the muscle rapidly, yes. And in that case, you know, is it starting in the skeletal muscle? No, but that's where the it's coming from, all these excess hormones, but that's where you see it.

Dr. Gabrielle Lyon: 54:37

What about the average overweight, young individual who's sedentary,

Dr. Melanie Cree: 54:41

so that's where you if you don't exercise, you have less mitochondria and less active mitochondria within the cell. So when you're sedentary, you've got this less healthy muscle. You eat a bunch of sugary, fatty food, your body tries to burn all of that it can. Plant, you get the reactive oxygen species, you get the diacylglycerol and you get the ceramides. And that can also be turned on very quickly. We can give people intralipid infusions, and you can make the muscle insulin resistant within six hours. So that's a completely different mechanism that you can get insulin resistance. And so is it, you know, a combination of foods that are making us more inflammatory because they have chemicals and things in them. Then we're sitting around, and you've got all of these different hits coming into the skeletal muscle. And so then you see that insulin resistance in the skeletal muscle, then you're not taking up the glucose. Well, where does extra sugar go? If it can't go into the muscle? Well, then it goes into fat tissue, and then goes through de novo lipogenesis. And now you've got more now your fat tissue, fat in your liver,

Dr. Gabrielle Lyon: 55:55

yeah. How fast if an individual begins to exercise, and let's say they are doing resistance training and they're or doing activity to deeply deplete some glycogen, right? So we are now moving this swamp of ceramides and diacylglycerol out of the tissue. How long do you think it will take to begin to and I've always wondered this, to begin to utilize some of that intramuscular adipose tissue? And I asked this for two reasons. There's the athletes paradox, and that is triglycerides within skeletal muscle utilized for energy. Yep, that's not what we're talking about, right?

Dr. Melanie Cree: 56:40

No, so, so what we are talking about, the fat is next to the muscle cell. So this is i Mat. So it is fat cells next to muscle cells, not within muscle not within muscle tissue. Within muscle tissue is imcl, intramyocellular lipid. So that's the difference. So it's adipose tissue, I mat because it's adipose tissue, imcl, because it's within the cell. And so originally, the thought was that the size of the lipid pool, now I'm talking imcl, the size of the lipid pool within the cell was a reflection of poor metabolic health. So then people realized, oh, wait a second, not only do people with excess weight have these really big pools of imcl, but athletes do as well. And so that's where the athletes paradox came from. Why do athletes have these big globs of fat inside their their muscle cells. And in fact, what we've come to realize is it's the rate of turnover and the location of turnover. So athletes have this glob of fat that's right next to the mitochondria in individuals with obesity or type two diabetes, they are not touching. They are on other sides of the cell, so totally useless. Cannot be utilized for fuel. They're right. They're here. Whereas athletes, it's like, Okay, let's get our energy substrate as close to our mitochondria as possible, so that we can be the most efficient. We're not having to move substrate across the cell. The other thing that they found is that it has to do that with the rate of pool turnover. So in athletes, you will like replace out that pool. If you go run a marathon, you're going to totally empty out that intramyocellular pool. You're going to eat afterwards, and you're going to replace it. And so athletes may even have a larger pool, but it's right next to the mitochondria, and it's turning over very quickly. Because it's next to the mitochondria, it's

Dr. Gabrielle Lyon: 58:45

not affecting the composition in a way where it would be taking up mitochondrial space or limiting the contractile tissue. It's really there to support that activity

Dr. Melanie Cree: 58:55

Exactly, exactly. It's almost like, if you think, I mean, we're very It's essentially the same concept of glycogen, but it's fat and so right? You have these really big glycogen stores, and then you have much better endurance, right? But athletes have that. Individuals with obesity don't have those excess and they have

Dr. Gabrielle Lyon: 59:13

more Imad intramuscular adipose tissue, which is extra tissue around the myocytes

Dr. Melanie Cree: 59:22

exactly so two different fat pools. So, yes, the size of the imcl is not what matters. That's where.

Dr. Gabrielle Lyon: 59:31

How do we address the IMAT? Is it addressable exercise?

Dr. Melanie Cree: 59:35

Exercise the IMAT use have more IMAT in individuals with insulin resistance, you have more IMAT in individuals with excess weight. And this, I can tell you, just from doing the biopsies, when I do the ultrasound, you have, you

Dr. Gabrielle Lyon: 59:52

have to stop, and you have to tell people this, because I gotta tell you, when I was at WashU doing muscle biopsies, we were not as sophisticated. I was. Sorry, Sam, you are amazing. The lab is amazing. But we were getting up at 430 in the morning do a muscle via doing muscle biopsies on the vastus lateralis. You know, we didn't know we're hitting I mean, we're taking muscle, but in terms of identifying fat tissue, please tell us what you are doing. Yeah.

Dr. Melanie Cree: 1:00:18

So when you do a classic biopsy, you're using both your hands. You're just going in blind. You know where the vastus is. You have a rough idea. You obviously you don't push too hard, you, you, we call it hand feel. So you can absolutely feel when you cross the fascia that's outside of the muscle. So I'm giving you like nightmares here, thinking

Dr. Gabrielle Lyon: 1:00:41

like, Oh my gosh. And I'm thinking, Melanie, how many did you do where you're finally like, oh my gosh, I'm only, I only have to use one hand, and I don't have to do it blind. Because I swear to you, every day I went in, I'm like, oh my god, yeah,

Dr. Melanie Cree: 1:00:54

it's so it's a lot different. So we wanted to get this IMAT, but it's throughout the muscle. And so how do you exactly

Dr. Gabrielle Lyon: 1:01:03

and to to share with people, the biopsy amount is so small,

Dr. Melanie Cree: 1:01:09

it's fifth it is, if we get the size of a pencil eraser, we're happy, yes, yeah. And if you don't, you are sweating bullets because you are yes there, and you're like, oh my gosh, yes. Now I have to go back. So we wanted to see, could you find IMAT if you used an ultrasound? And now you can get an ultrasound, you can get an ultrasound probe and hook it into your phone and download the app, and you've got high quality ultrasound. So the availability of easy, cheap, portable, it's $4,000 so

Dr. Gabrielle Lyon: 1:01:42

hook a sister up. Yeah, unbelievable. So

Dr. Melanie Cree: 1:01:45

now we've got this, you know, really readily available ultrasound, and then so we I, I'm right handed, so I've got the ultrasound in my phone. So I've got the ultrasound here we have it attached to an iPad, which is just laying on the bed. But then what I'm using in my in my right hand is the one handed biopsy needle that we use for liver biopsies, prostate biopsies, things like that. And so because I've got the ultrasound, and I'm ultrasound guided, I can get the tip of the needle right above the eye mat that I can find with the ultrasound, and then it's just press your thumb and it'll go right through that fat. And so now that we can find and target that fat, we can now study that. I have

Dr. Gabrielle Lyon: 1:02:32

a crazy thought, Yeah. And do you think so there's body fat percentage? Yes. There's skeletal muscle mass, yes. Do you think that there is a percent IMAT that is healthy versus not, and if it is accessible in the imaging landscape, which obviously you're not doing an ultrasound of the whole body of or at least the quadriceps of the legs to try to identify IMAT? Do you think that there is a role for assessing how much IMAT there is an individual? So

Dr. Melanie Cree: 1:03:10

we are doing the motor PAC trial, which is the largest government funded exercise study ever, and we've got individuals who are highly trained athletes. We've got younger people, older people. Some are doing different weight training regimens, and we are doing that MRI that I was talking about before, where you really get that high resolution through and so you can measure body, full body, or just the leg, the quad, the quad. So we're doing the vastus. So we're doing that imaging on the vastus, where we've also done a muscle biopsy that we're measuring mitochondrial function on. We're doing the the MRI mitochondrial function on the on this muscle, and then we're actually measuring that amount of I'm at so we extraordinary. We're doing the last, the last patient visits are in April, so, and then we've got to, you know, process all the results. So give

Dr. Gabrielle Lyon: 1:04:13

me two years. No, I went to go visit Blake Rasmussen, yeah. And I was like, Dude, what's happening with this? Oh, well, where are we going to publish this? Was that when he was at San Antonio, yes, yes. Is there? Do you think that there? And I know that this is kind of we don't have the data yet, but is there a correlation between body fat percentage? For example, let's say there is an individual is 30% body fat percentage. Is there some correlation where we might imagine that their IMAT would be 20% or is there a number? Do you think that it is very individual, or is there some correlation between body fat percentage and IMAT? So I think or you. Is it IMAT versus body fat percentage? I think

Dr. Melanie Cree: 1:05:03

it's I think it's location. So I think body fat percentage is really deceptive, because we know that central adiposity is metabolically much worse than peripheral adiposity, right? So the the kind of old school thought was, if you are a pear shape, so you've, you know, for women, you've got all your fat on your thighs and your bottom, but you have a skinny waist that you're much more metabolically healthy than somebody who's in apple shape. So they could both be 30% fat, but the person who's in apple shape that has all of this visceral fat, which we know is bad, is going to be less metabolically healthy. So body fat, in and of itself, as a number, I think, is really hard to relate to metabolic health. Other than that, it's, you know, grossly high or low. You have

Dr. Gabrielle Lyon: 1:05:57

to say that. Again, this is probably one of the most fascinating conversations I've ever had. I mean, we are talking and challenging paradigms of belief and framing up how people are thinking about things. Yes,

Dr. Melanie Cree: 1:06:12

so body fat. Body fat doesn't percent. Body fat doesn't tell you anything. It's where the fat is that's the problem. So if you have the fat in your gut, in your viscera, what about in skeletal muscle? And so if you've got this, I'm at from the work that we've done so far with with Brian Bergman's work. If you

Dr. Gabrielle Lyon: 1:06:32

Brian, we're still trying to get you on the podcast. Friend Yes. Dr greener, she promised me that she's going to put in a good word.

Dr. Melanie Cree: 1:06:42

So, you know, we've done individuals who exercise who don't exercise. We've done before bariatric surgery, and again, this is matching with those MRI findings. I think this i Mat is a real problem. So I think in your athlete, you don't have IMAT, you've got a ton of rapidly turning over close to the mitochondria imcl. And then in people with excess adiposity, you've got IMAT. And then if, for whatever reason, you have more IMAT than somebody else, it looks like you maybe even have worse insulin resistance. So going back to your question, what does IMAT mean? Could we ever use IMAT and why to give us that? Well, the processing we tried to measure IMAT 20 years ago in Galveston, and it took forever. The the the software is now getting to the point that we could do that. If we were in Japan, where everybody gets an MRI for cheap. I bet you in Japan, once we have an idea of norms, then you'd be able to go get an MRI slice of your thigh and see, and

Dr. Gabrielle Lyon: 1:07:58

it could say, this is your percent body fat. We don't care about this. Yeah, this is your percent I'm at, and we care about that, yep, yeah. That would change the game. It would completely

Dr. Melanie Cree: 1:08:07

change it. And I think that that's where you know. So what we're doing now is we've been doing visceral fat for a while, right? And the best way to do that is we do an MRI through the abdomen. We always do it right at the level of the umbilicus your belly button. I got one of those. Yep, because it's, it's always the same place. Yeah, really fascinating. Yeah, it's the place. It's not, yeah, it's not the amount. I have another

Dr. Gabrielle Lyon: 1:08:34

question. The muscle protein synthesis response there is obviously healthy filet tissue. Individuals have high imcl they have great mitochondrial function, good mTOR response. Is an individual, and I don't know if anyone knows this, but I've seen some evidence that obese individuals may possibly have a blunted muscle protein synthesis effect? Perhaps it could be overcome with amino acids I don't fully know. And I think this is at University of Illinois. I think it was bird. Eric bird, potentially. Do you think that there is a change in an anabolic response with elevated levels of IMAT, are people less responsive to resistance training?

Dr. Melanie Cree: 1:09:29

That's what I mean. That's what Dr Bergman is doing right now. In the data that we're looking at, he had extra we had pre post exercise. Right now we're doing pre post diet. In terms of the overall anabolic response to muscle protein synthesis in somebody with obesity, I think that's going to come back to insulin resistance. So some of some of the previous work that I did with Kevin Tipton was we had a grant from Gatorade and a grant from. Dairy. And so we had individuals do the leg extension. We're studying the quad. They did the leg extension, and then they had a drink of Gatorade, which is carbs, only low fat milk, carbs and protein and whole fat milk, carbs, protein and fat. And we measured the rate of protein synthesis with stable isotope tracers. And we also measured the gut responses so glucose and insulin. And what we found actually was that the over the four hour post drink time period, the whole milk led to the highest rate of muscle protein synthesis.

Dr. Gabrielle Lyon: 1:10:44

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Dr. Melanie Cree: 1:12:09

that that was because of when you have fat in a meal, you don't get the insulin spike, and then back down you get insulin, and essentially your insulin area, the curve is almost the same, but it's a very different profile. And so when you have insulin activating, you go into the insulin receptor, and just as you said, you then go the mTOR pathway. So the presence of insulin drives protein synthesis. So with that lower, longer insulin profile, you're now getting a longer mTOR signal to drive protein synthesis. So that's interesting. If you have somebody who has insulin resistance, you're not going to get that mTOR signal from insulin to drive your muscle protein synthesis. So after a meal, they may have hyperinsulinemia, but it may not be enough to cause to overcome the intracellular insulin resistance. So I think that's where that, that's where in terms of what you eat, comes into play, and overall, why do people with obesity, have that. So that's certainly one aspect. And then there's the other aspect of, does this IMAT change what's happening in the skeletal muscle that's right next to it? And that's what we're what Dr Bergman studying. Do you have

Dr. Gabrielle Lyon: 1:13:36

a hunch? I You're a scientist, so I know you might not give me a hunch, but

Dr. Melanie Cree: 1:13:39

I mean, I think that, you know, we know that a lot of the problems with with fat, and we see this in PCO as well. A lot of the problems with fat when it's in the wrong place, is it releases those, those cytokines, well, those cause insulin resistance, right? We talked about that in burn trauma, right? It happens immediately. Is this IMAT unhealthy like visceral fat, and releasing some of these cytokines that directly cause insulin resistance. One of the other things that that Dr Bergen's found is it's releasing chemokines, which then bring in your immune cells, and then your immune cells, and in particular, macrophages are a problem. So now you've got this, this kind of macrophage beacon, pulling all these macrophages into your skeletal muscle when you don't need to be doing that,

Dr. Gabrielle Lyon: 1:14:30

yeah, that's that's not a good strategy, is it? Yeah. Do you think that the influence of exercise, whether it's resistance training or cardiovascular activity, contracting skeletal muscle based on intensity and duration release myokines, so the same compounds like TNF, alpha, interleukin six, interleukin 10, are released from exercising skeletal muscle. Do you think in part that creates a correction,

Dr. Melanie Cree: 1:14:58

potentially but. Potentially. I mean, what everybody wants, right, is those myokines exercise in a bottle. Yeah,

Dr. Gabrielle Lyon: 1:15:03

Sign me up. Yep, I'll take that IV. But they've

Dr. Melanie Cree: 1:15:07

got to have, they, I mean, they have to have multiple effects, right? So especially if you're weight lifting, you end up building muscle mass and or, you know, if it's if you're running, you end up getting these nice, healthy, long, lean muscles. So all of this muscle remodeling that happens over a duration of time is certainly related to some chemicals, and I would assume is along the lines of myokines. And then, as you exercise, you change insulin sensitivity, so then you can actually use the amino acids that are coming in, and then your protein synthesis will get better as well.

Dr. Gabrielle Lyon: 1:15:45

And we know that just increasing exercise from where you are. And then going back to my patients, I don't say the word exercise right. We talk about activity, and I just want them moving right. And once we're moving, then we can talk about trying to do whether it's resist exercise, yep. Do you think that, or I know that you primarily focus it focus on the metabolic phenotype. Do you also have patients that are reproductive phenotype? Do they see improvements when they're doing resistance training or cardiovascular activity?

Dr. Melanie Cree: 1:16:16

Anything that improves insulin sensitivity is going to be better for peace, for PCO, and even in the absence of of even in the absence of weight loss, exercise is going to make a difference. And diet changes in the absence of weight loss are going to make a difference. Tell me about those diet changes. So we finished a trial using oral semaglutide in girls with PCOS, and they're in the process of writing it up, and it was randomized two to one, semaglutide versus a versus diet. And it was a 16 week study. They met with our dietitian, the diet arm met with our dietitian every week. And in particular, we worked on portion sizes, fruits and vegetables, but then specifically cutting sugar and fructose out of the diet. And at the end of the trial, the girls taking the semaglutide had lost on average, 10 pounds. The girls that were doing the diet, on average had lost three pounds. But the improvements in testosterone between the two groups was nearly identical. Whoa, I was not expecting you to say that, and the changes in cholesterol was nearly identical. So I was really surprised, because I thought that, you know, semaglutide was going to knock diet out of the park totally, and it absolutely did not. Was it because it was oral versus injectable, or dosing, or, I mean the time, duration of time, but also response to semaglutide. So within the semaglutide group, if you broke those out into those who lost more than 5% of body weight versus those who did not, you saw more of a difference.

Dr. Gabrielle Lyon: 1:18:01

Is, well, how are the GLP ones like ozempic a game changer, if at all, for PCOS.

Dr. Melanie Cree: 1:18:10

So there are eight adult papers and two pediatric papers that have this data in it. So it was in the 2018 guidelines. So a

Dr. Gabrielle Lyon: 1:18:18

total of 10 papers, 10 papers out of, yeah, hundreds of 1000s, maybe, and so we're doing really well when it comes Oh,

Dr. Melanie Cree: 1:18:27

PCOS research is so paltry. And so what those papers showed is that weight loss improves reproductive function in individuals with PCOS and so kind of the dogma that we say is 60 to 70% of women can improve their menstrual cycles and get their cycles more regular with 5% of weight loss. So we're always going for that five that seems pretty standard across Yep, that 5% and so that's kind of what we were, what we were looking at. And this is again, coming back to lifestyle. Lifestyle. Lifestyle is Central, and PCOS across the board. It doesn't matter your weight. It doesn't matter the kind either it sounds like. And so what I find so exciting about these dietary findings is that even in the absence of weight loss, by eating a healthier diet, you can improve your PCO. And I think that people need to hear that, that if you've really changed your diet and you're not losing weight, you're not failing just by changing your diet, you are making yourself healthy. How do you define a healthy diet? So basically, no liquid calories. If you think calories

Dr. Gabrielle Lyon: 1:19:49

out, no, no. Every you know, regular Coke is out. My producer loves regular Coke. What else? Oh,

Dr. Melanie Cree: 1:19:56

all the coffee drinks, the energy drinks, that's out. Yep. So if you think about it, coming back to this insulin pattern, if you have liquid calories, they go in really fast. They go into your bloodstream really fast. Your glucose goes up super fast. And then in response, you release this big insulin spike. So say your ovary is only affected by insulin. If your insulin is greater than 80, so you drink the sugar, you shoot up to 120 now we're totally making our ovary make testosterone, and then we come back down, and you'll have that pattern every time. And in fact, we hear a lot of people complain about two to three hours after eating, I'm light headed, I'm sweaty, I'm shaky. I just need to eat something. It's this reactive hypoglycemia pattern. And so what I tell my patients is, if you have those symptoms, whatever you ate two and a half hours ago, your body doesn't like your body's telling you, I can't handle this. So you just see those huge insulin swings with any kind of liquid carbs. And so that's the first thing that we talk about getting rid of, and then any of the white foods. So because, again, they get digested very fast. And so they again have this super fast sugar spike in with more insulin being released. So white pasta, white bread, white rice, white potatoes, all of those simple carbohydrates go into your body very quickly, right? Versus complex carbohydrates have more fiber. They take longer, so you get your sugar coming in slower and longer, and so your insulin doesn't go above that threshold to then stimulate the ovary. And so that's essentially what we saw in our study, that this is essentially a low glycemic diet, a calorie restricted, low glycemic diet in individuals with PCOS, in the absence of weight loss, significantly include improved their reproductive and metabolic factors. What about dietary

Dr. Gabrielle Lyon: 1:22:03

protein? There's a lot of great data, and you, you know, you might say that there's a slight insulin response in the ingestion of dietary protein. We get that question a lot, and I would say it's a phase one insulin response. It's nothing compared to a coke or some kind of exactly caloric load, and especially working with Bob Wolf, where do you like to see protein? Is that something you guys think about in terms of protecting lean mass and changing body composition. So

Dr. Melanie Cree: 1:22:35

if you decrease one thing, you have to increase the other thing, right? So you could, you could say, oh, we're going to cut all the carbohydrates, or you could say we're going to eat a lot more protein. So those will, by default, go off when we do our for the my current semaglutide trial, we're doing the injectable and we're doing a full 10 months working with the same Carly as the most amazing dietitian. She does all my research studies with me. So in the first four months of the medication, when you're you go up a dose every month. So the first four months, we're just doing dose escalation. And during that time, Carly is really talking about this, sugary foods, the simple foods, kind of fatty foods. But then once we hit four months, then we start talking about protein and making sure that individuals are getting enough protein as their portion sizes are so much smaller. But there's a paper I should show you. It actually just came out this week, and I believe it was tirzepatide, and it's from the company. It's from the drug companies data, and they did dexus pre post, and they found that the amount of muscle mass lost is proportional to what you would expect for the amount of weight

Dr. Gabrielle Lyon: 1:24:00

lost totally. And we've been saying that and looking at that forever, because we treat patients in our clinic, right? And we with the increase in dietary protein and resistance training and activity like you say, we see the amount of loss that one would expect, nothing extraordinary. We do not believe that there's something special about a GLP, one or any of those agents that somehow accelerate muscle mass, muscle mass. So I

Dr. Melanie Cree: 1:24:29

think the issue is right. So it's really important to understand the inclusion, exclusion criteria and what else is happening in the study in addition to the drug so for the weight loss drug trials, individuals are given dietary counseling, and they're instructed on how to exercise. And so the thing to remember about the drug trials and their efficacy is the drug is on top of solid lifestyle, and many of the people that are taking these medications. Patients are not doing solid lifestyle changes. So is it that if you're taking these medications and you're completely sedentary, do you lose a little bit more muscle mass, maybe, but that's because of the sedentariness. It's not the drug, not the drug per se. It's because of the it's because of caloric intake induced weight loss in the absence of adequate exercise. All the all the drug does is the drug makes it easier for you to decrease your calories, right? Because in the people who are taking the drug in the clinical trials, no change, their muscle mass is decreasing proportionately. So it really comes back to, you know, drugs are a tool to decrease your appetite, but at the end of the day, the best way to be healthy is to change your food and make sure you have good activity. And if you don't, then you're going to get a mismatch. So if you are only decreasing your calories, and you're not in not exercising, you're in trouble, and you're not going to build muscle. But that's not the drug. That's just because you're eating less,

Dr. Gabrielle Lyon: 1:26:08

that that would make a lot of sense. Do you think with the again, I recognize that there's not a ton of data out on these GLP ones and these dual agonists and the generations are going to keep coming out. Oh, yeah, yeah. Will Metformin that was typically used as an insulin sensitizer? Do you think that will still be first line, or do you think eventually we're going to move to GLP one?

Dr. Melanie Cree: 1:26:34

We're, I mean, we're already talking about that in our pediatric diabetes population. We were talking about that about a year ago, actually, that at what point are GLP ones going to become first line for diabetes, rather than Metformin, because they're so much more effective in terms of glucose management, but I think much more effective and body weight well, and I think also because of all of the additional related end organ problems, right? So for the trials now that are four or five years out, right, it reverses congestive heart failure. It looks like it's it's a primary preventative for cardiovascular disease, the same as a statin. It's really great for the kidneys, and it seems to reverse chronic kidney disease. The data on semaglutide for liver fat and fibrosis was just was just released at a liver meeting in December. It hasn't been published yet. And then there's preliminary data on tirzepatide and retreat on liver fat or liver fibrosis. And when you look at the data, there's a new the first ever drug to reverse fibrosis in the liver was approved last April, and it's interesting as well, thyroid receptor. I'm forgetting the name the company's madrigal, but I'm forgetting the name of the drug. Sorry. I think it starts with a T with a lot of vowels and an x and a reasonable but, you know, so everybody's excited. Oh, there's this new, you know, liver specific drug and blah, blah, blah, blah, blah. Well, if you go look at the efficacy of the GLP ones for liver disease relative to this new drug that everybody's so excited about, the efficacy of the glps on fatty liver disease is so much better than this medication that's already FDA approved for liver disease. So if you look at what does a GLP one do, comprehensively, for a patient with diabetes or a patient with metabolic syndrome, not only does it make you lose weight and bring your glucose down at the time, but in terms of long term disease, you're preventing cardiovascular, renal, liver disease. There was, I can't remember if it was tricepatide or retrued cured obstructive sleep apnea, because you lose enough weight that you open the airway up. So that's why I think, because these GLP, because the weight loss with the glps, is so profound, it has all of these effects, they should be first line, right? Do

Dr. Gabrielle Lyon: 1:29:17

you think that that's a blind spot in the Treatment of PCO, right now,

Dr. Melanie Cree: 1:29:23

the trial that I finished with the GLP one is the first to be completed in the world. There's another one that's, by the way, why I wanted you on the show.

Dr. Gabrielle Lyon: 1:29:31

So I talked to some, a few of our colleagues, and I said, Who is the best? Who is the best on PCOS, PCO and GLP one, and they said, well, guess what, there's one trial that's been completed, and this is the person, yeah, yeah, that's a big deal. Did you get any pushback for thinking about it, for doing it? Was there any restriction or, well, heat that you got?

Dr. Melanie Cree: 1:29:59

I called it a. Double jump. So the reason that my first trial is done with the oral medication is the injectable wasn't on the market, right? This is what happens with COVID grants and everything else

Dr. Gabrielle Lyon: 1:30:10

using we're not even using oral. It's are we? There's

Dr. Melanie Cree: 1:30:14

the original oral that came out is still on the market, and they're testing much higher oral doses for weight loss. So the oral is available for patients with type two diabetes. I have one patient who's on it because she just too terrified of the injections. But so when I, when I initially wrote this grant, it was written with liraglutide, which is an injection once a day, and then the oral semaglutide came out, and so we switched to the oral semaglutide, but we were doing this for PCO in teenagers. So all of this has had FDA investigational new drug applications because that oral was approved for adults. Well, now I'm doing kids type two diabetes. Now I'm doing PCO, so that's where I it was. It's a double jump. So there's just a lot of a lot of hoops. To be honest, it took Bob and I almost nine months to get through my IRB and the FDA for the amino acid trial. I have never had as much regulatory problem as the amino acid.

Dr. Gabrielle Lyon: 1:31:22

Are you serious? I'm shocked by that.

Dr. Melanie Cree: 1:31:26

Oh, so were we they? I was told to put all female this. This is what blew my mind. I was told to put that. I needed to put all females. What is

Dr. Gabrielle Lyon: 1:31:38

the metabolic effects of an essential amino acid supplement in adolescents with PCOS and obesity. Was it this? It's my

Dr. Melanie Cree: 1:31:44

current trial. It's my current trial. It's the same as that at the same card. Well, it's boys and girls now. So that one was PCO. Now, I'm doing any kid with fatty liver disease, but they told me that in order to give people amino acids which our whole body is made of and we eat every day. I needed to put girls with fatty liver disease on birth control pills. What does estrogen do in the liver? It increases hepatic fat. It increases triglycerides. So please, FDA, so let's give I can't give them a food, but you're gonna tell me to give girls with fatty liver disease estrogen, when estrogen can worsen fatty liver disease in somebody with metabolic syndrome. I mean, Bob and I have never been so blown away. But why? Do you have any idea why? Oh, well, because taking essential amino acids could be bad for

Dr. Gabrielle Lyon: 1:32:41

we're still there. We're honestly still there last year, we're still there seriously. So

Dr. Melanie Cree: 1:32:49

no, that's shocking, yes. So isn't that amazing? It was much easier for me to get a GOP one approved for experimental use than amino

Dr. Gabrielle Lyon: 1:32:59

acid. So to me, that is just an indication as to how there is such a gap in what is perceived, and then, yes, what happens clinically, and whether someone is thinking about something mechanistic. Where would that even come from? You know, is that it's still that traditional. Well, you know, brown chain amino acids are elevated in obesity, which, which we replicated in teenagers, also branched chain amino acids, insulin, glucose, triglycerides, these are all substrates of excess right branch chain amino acids do not cause diabetes, and I am shocked. I'm 100%

:: 33:37

in that boat with you, and so are

Dr. Gabrielle Lyon: 1:33:39

your colleagues, other world leading experts, yeah, protein metabolism, yeah, yeah, it again. Why is the world so confused? Probably in part, because we have world class experts like yourself, who are collaborating, who are trying to make inroads into science, and then we have old school beliefs or individuals that are not experts in that field Making Global decisions about what can and cannot happen,

Dr. Melanie Cree: 1:34:07

right? Right? The education isn't in the information isn't in the right hands. It's horrible in PCO, Sasha ote, the head of PCOS challenge, and then one of my colleagues, Anuja do Chris. She's at UPenn and is a leader in international PCO. They were both in a BBC article in December, and it was something like 85% of information on the internet regarding PCOS is false.

Dr. Gabrielle Lyon: 1:34:35

85% 85% what do you think the biggest misconception

Dr. Melanie Cree: 1:34:42

is? I I would say the biggest misconception is that lifestyle doesn't work and people giving up

Dr. Gabrielle Lyon: 1:34:55

85% of the information is wrong. Mm, hmm.

Dr. Melanie Cree: 1:35:00

There is no specific diet that's good for PCO. And I can tell you it popped. I have all sorts of PCOS. I want to see your Instagram. It's got to be like PCOS Diet, the supplement to cure PCOS. Yes, exactly your special world. Oh, my goodness, all of that, all of that. So, yes, no, a new PCO diet just popped up on my Instagram feed. And it doesn't matter. It doesn't just get rid of the sugar and don't eat to excess. Can it makes a difference? Can it be reversed? It is the same as type two diabetes. It can be lifestyle managed. So for what, again, for that 60 to 70%

Dr. Gabrielle Lyon: 1:35:47

but I was reading that there's a 90 a 99% quote, cure rate resolution on the medication of type two diabetes, well, but

Dr. Melanie Cree: 1:35:57

you're still taking the medication. Totally cured because you're taking the medication that it's managed. So the different, the difference is, and this is me being a little bit semantic, but if you're cured of cancer, you do not have any cancer in your body, left, right? It doesn't matter what you do. There is nothing that you can do that's going to influence whether that cancer comes back or not, right? So that's cured in diabetes or PCO, you get below a certain weight threshold, and your periods come back. So that's where I call it lifestyle manage. And I certainly see that in patients where, you know, we use a medication, and their periods come back, and then they gain the weight, and their periods go back away. And so this relationship with weight and insulin resistance is so inherently tied, especially in this metabolic PCOS. So as long as they stay healthy and below whatever weight threshold their brain likes to have regular periods, then they don't have any symptoms of PCOS. They're still susceptible for PCOS. If they gain that weight, then their PCOS symptoms will come right back. So that's why I call it managed, not cured, because that makes sense. If you change something key in your insulin resistance, or something like that, your symptoms are going to come back.

Dr. Gabrielle Lyon: 1:37:18

Yeah, and that makes sense. It's, you know, we see a lot of diseases related to insulin resistance. Some people get PCO. Other people get cardiovascular disease. Other people get Alzheimer's disease, exactly a somewhat of a root cause. There's multiple mechanisms, as you pointed out, and then the end result is, it's almost as if Which organ you are susceptible, which organ system an individual is susceptible to getting divergent from what would be normal, exactly.

Dr. Melanie Cree: 1:37:47

And I think what, what makes me really sad about the glps and all the struggle with the insurance coverages and the cost and things like that, and is when I first, when patients were first completing my first semi trial, there was nothing. I was like, Okay, we'll just keep going. And you know, periods would get better. They gain the weight back. Their periods are gone again. And so the problem with, the real problem with the glps is the weight regain. So we have to be on it for, well, it's a certain percentage of a certain percentage of weight loss. So for the semaglutide, they broke it down by how much, what percent body weight you had lost, and then you stopped the drug, and then they looked at your body weight. They followed those individuals for another year, so if you lost at least 15% of your body weight a year after stopping, you were still below your starting weight. But if you lost 10% of your weight, stop taking the drug, within a year, you're right back up to where you started. So it's not sustainable. So again, these medications are not curing obesity. They're managing obesity and only when you're you continue to when you continue to take it. And so, like some patients, I had my my biggest loser, if you will, is 96 pounds. Um, but you know now we've got her on point five every 10 weeks, or every, sorry, every 10 days. So you've reduced, you're

Dr. Gabrielle Lyon: 1:39:21

now essentially changing the kind of dosage from the standard, whatever it is, 2.5 or five,

Dr. Melanie Cree: 1:39:30

yep, like, once they're at a target, once they're at a goal weight, then we switch, but if I take her off, so she had an interruption in insurance, and she had two months off and just and, and she's talking about, this isn't she's like, I know how much to eat. It's she's like, my hunger just comes back. And we did a pilot functional MRI trial, and what we found, my colleague, Ali Shapiro, found, was that there is better connectivity. After taking a GLP one between the hypothalamus and the limbic system, so emotional parts of your brain and decision making parts of your brain, so that that's extraordinary, and that awesome, and that that's extraordinary. That's why they're looking at GLP ones for addiction, because it is actually changing these connections in the brain. And,

Dr. Gabrielle Lyon: 1:40:19

you know, it would be amazing if it would stay maybe there's a possibility, and that's the grant goodness, yeah,

Dr. Melanie Cree: 1:40:26

that's, that's what Dr Shapiro wants to look at. So she wants to look at brain changes in teenagers versus brain changes in adults. So if you have a growing plastic brain, right? Neuroplasticity is the rate of turnover. If you have an adolescent brain with a lot more neuroplasticity, and you improve all of these connections by taking a GLP one when their brain is done growing, does that maintain? Is there? Is there a long term remodeled brain effect of GLP ones, if you take them in, adolescents versus adults, don't have nearly as neuroplastic a brain, and so

Dr. Gabrielle Lyon: 1:41:12

I know it's totally unfortunate. I know like what? I promise I'm trying to learn Spanish, but, yeah, terrible. You know, I do want to mention something that I think is really important, and there's a lot of confusion around. There is insurance coverage of depending on the medication, whether it's some semaglutide or tirzepatide, which is also moderno. And then there are compounding pharmacies, and not all compounding pharmacies are the same, and the ones that they are coming after are those that are not in the same compliance. I don't know if you're familiar with what that looks like, but there is a different it's a 503 a compounding pharmacy versus a 503, B, yes, you are aware that that's amazing. I

Dr. Melanie Cree: 1:42:04

am aware of that because we're running into a lot of problems with stable isotope tracers. A lot of us, I can't do stable isotope tracers at my hospital anymore. Well,

Dr. Gabrielle Lyon: 1:42:13

it will certainly be fascinating as to what happens, because it, you know, people should be able to get the medications that they want. And yeah, there should be body autonomy, and there should be medications that are affordable, and it should not be $1,000 for an EpiPen even I understand that it's not right now. But also, the cost of paying out of pocket for some of these medications are astronomical. And I'll say one more thing is compounding pharmacies allow for precision dosing, where you can have a particular dose made that is much more viable for the patient. For example, if someone is using an injectable pen of, you know, a standardized dose, let's say the individual is a much smaller human, or cannot tolerate that dose. Compounding pharmacies when they are really the best at what they do and have the highest standards. I think it's, it's really important that they stay around. I

Dr. Melanie Cree: 1:43:09

mean, it does offer the, I mean, it does offer the flexibility. It also costs. I mean, I don't even know what it costs to bring a drug to market, right? Like 100 million or something like that. So, no no big deal. Nbd, you know. So in some ways, you know, the drug companies do need to make their money back, right? I mean, as much as people complain and hate on them, we also wouldn't have our medications if we didn't have them, right? And they take big risks. I mean, if you look at how many, how many drugs go through phase one or phase two, that don't even get into phase three tons. So much, right? So, but yeah, I this the side effects with these drugs are are no joke, that's right.

Dr. Gabrielle Lyon: 1:43:51

Especially with semaglutide, we see less that with terzapatide or moderno, seems to be much more. It seems to be tolerated much better. And then I have a feeling that as these generations increase, that the side effects will continue to be low. Dr, Melanie Cree, I have found this conversation to be one of the most exciting and enlightening. Thank you, because the work that you are doing, I believe, has not only the ability to change a landscape for women, but also how we frame and think about muscle and insulin resistance and what the outcomes and possibilities are there. So thank you so much for coming on.

Dr. Melanie Cree: 1:44:31

Absolutely it was fun.

Dr. Gabrielle Lyon: 1:44:33

If you learned something new today about PCOS, share this episode with someone who needs to hear it. So many women and pre teens and teenage girls are struggling with PCOS and don't even know that these options exist. And if you want more cutting edge science on hormones, metabolism and longevity, make sure to subscribe so you don't miss our next episode. Finally, if you want to dive deeper, check thedescription for links to Dr Cree latest research and resources on managing PCOS the right way. Thanks for watching and we'll see you next time.