Unknown

Hey everyone, welcome to the Drive Podcast. I'm your host Peter Atia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratiamd.com/subscribe. My guess this week is Dr. Hanado Tomioka, a leading expert in reproductive medicine and gynecologic surgery. Hanado's clinical work sits at the intersection of three closely related fields. Reproductive medicine, minimally invasive gynecologic surgery, and gynecologic endocrinology, a combination that makes him uniquely equipped to diagnose and treat some of the most consequential and under-recognized conditions women face today. Endometriosis affects roughly 10% of reproductive age women, about 200 million women globally, and contributes to infertility in 30 to 50% of cases. Adnemiosis, it's often overlooked counterpart, maybe even more prevalent. Yet the average woman waits 5 to 12 years for a diagnosis, often because her pain has been dismissed as normal. In my conversation with Hanado, we cover what endometriosis and adnemiosis actually are, and why they're so often missed and how diagnosis has shifted from surgical laparoscopy towards MRI and specialized ultrasound. How Hanado decides between hormonal therapy and surgery, and how those decisions change when fertility is part of the goal. Where IVF fits into the pathway for women with endometriosis, adnemiosis, or age-related fertility decline, how female age shapes egg, quality, and quantity, including the steep non-linear rise in chromosomal abnormalities after age 35, and the most common mistakes in surgical and fertility decisions, and what may be on the horizon for both endometriosis treatment and fertility preservation. So without further delay, I hope you enjoy my conversation with Dr. Hanado Tomeo. Hanado, wonderful to see you. Thank you for coming to Austin. Today we're going to talk about two things that are related, but I want to talk about them in sort of this order. The first thing I want to do is talk about the diseases of the uterus, and I think most notably we'll talk about endometriosis, but also others. And then I want to talk about infertility, and obviously talk about some of the treatments for infertility, and of course there's an overlap between those two. So let's start with the former. Orient us to what exactly this term is. I'm sure everybody's heard of endometriosis, but it's likely that not everybody understands exactly what it is. So I believe the first point is to remember the layers of the uterus, right? So we have mainly three layers, the outside layer, it's called serosa, the migral part, which is the muscular layer called myometrium, and they're in their part where the embryo implants and develop the placenta, which is called endometrium. And this layer is very important because endometriosis is a disease, a chronic disease, where an endometral-like tissue, very similar to the endometriosis, outside the uterus. Instead of being inside that layer, it goes into the fallopian tubes on the ovaries, the bowel, the bladder, sometimes the appendix, and even the diaphragm. So that's endometriosis, very important disease, around 10% of reproductive women globally have endometriosis, which means around 200 million women. And if you look into the data of infertile women, it's about 30 to 50% of women they can have endometriosis. So just to make sure I understand that 30 to 50% of women who are struggling with fertility have endometriosis. And the other way around, like if you have endometriosis, you have a chance of around 40% of being infertile. So it's causal. Yes. Okay, so let's dig into this a little bit more. So first of all, you mentioned we have three layers in the uterus. The endometrial layer is the inner layer. That's the part that sheds every month during a woman's epidemic, very dynamic, depending on the duration of the cycle. Of course, where you are in the cycle. Okay, you have a muscular layer and that's presumably functional. So during childbirth, the uterus needs to contract. So when a woman is experiencing contractions, that's what's contracting. Precisely. Okay. And then the outer layer, tell me about that again, functionally. It's just a pertinium, like the visceral pertinium. It doesn't have, it doesn't add up much, you know, we just have, but we can have endometriosis on that layer. And then sometimes it just infiltrates and transform to what we can say, we can talk about Adam, internal and Adamiosis, like external Adamiosis, I mean. Got it. And I did want to ask you about Adamiosis, because I know that they can often be confused. Before I do, I want to ask another question about endometriosis, which is, do we have a sense of the features or characteristics that predicted, for example, how genetic is it? And are there any environmental triggers for it? Great question. So we have about 50% of heritabilly. If you have a first degree relative with endo, you have about seven times higher chance of having endometriosis. So that's the meaning, mother or sister. Yeah. Okay. And we know from twin studies, also that, of course, they share some genes, but of course they are not that penetrant. We have some triggers, maybe pollution. And one thing that's very important figure is what we call the repetitive ovulatory menstruation. So what that means? Every time a woman is menstruating, part of the menstrual flow goes back through the fallopian tubes and into the pelvis. So we know that by surgery, and I'm sorry, it goes into the pelvis by going retrograde towards the ovary, but of course the fallopian tube doesn't enter the ovary, it enters back into the pelvis. Correct. So remember the fingra, like the distal part of the tubes, they are not directly connected to the ovary. They are moving around and they can pick up the lusites. This always amazed me, by the way, I don't understand why that works or how it works. And it's actually most of the time the lusite is just on the surface of the ovary. Sometimes it's inside the pelvis in the cold side, but the fingra can pick up and then permits the fertilization inside the ismos, right, inside the middle part of the tube essentially. But we know by oats that is that around 90% of women, they have this retrograde menstruation, which is amazing. So you would think why is that then just 10% had endometriosis, right? Because sometimes we just, it's not sufficient to have endometriosis, but it's probably necessary. And in most cases, there are some nuances here. But those patients with endometriosis, they might have immune dysregulation. So the macrophages can cope with that overload of menstrual flow and then the mitral tissue. They have also, like, if you have many, many, many years of retrograde menstruation that can be bad. There's an interesting story here, Peter. If you look like 200 years ago, a woman back then would have around 100 of latory cycles and their lifetime. Menarki was about at the age of 16. Now it's 12. First pregnancy around 20, now 30 or more. breastfeeding for two years per child. Now, during that period, you're not ovulating. Yes. And they used to have like five, seven children. Now you have many times. So if you compare that woman to a mother woman, it's about the fourfold increase in this retrograde off-latory menstruations. And this may be the main cause that we are seeing much more endometriosis. Not only diagnosing, but probably the prevalence is getting higher and higher. Right? So the Darwinian evolution didn't anticipate that this modern woman's reproductive pattern that we had nowadays. And that's probably the best proxy for us who use and to think about using oral contraceptives or any hormonal treatment to block to mimic that women back then. So let me make sure I understand all of that. So 200 years ago, a woman would have had 100 ovulatory cycles in her lifetime. And that would have been driven by many changes. She got her period four years later. She was pregnant more often, so the entirety of her pregnancy, she's not cycling. Once she has a baby, she's breastfeeding for very, very long, again, not cycling. And so you can sort of do the math that we didn't talk about menopause, but presumably, they might not have even lived long enough to get to full menopause. So a woman today might have 400 cycles if uninterrupted or if not intervened with. And every cycle produces the risk of retrograde flow. And then going back to what you talked about, when you get retrograde flow of blood into the fallopian tube, the macrophages that need to come and sort of take care of it can't always do the job. So presumably you're creating a nitrous for infection or something that the immune system is upset about. And if you look into the mechanism, we have this estrogen dependence. The metrolaglicions they produce by themselves estrogen. So they overexpress aromatase. There's an upper regulation in aromatase. So sometimes just blocking the ovaries is not sufficient to block the disease. We have also this progesterone resistance. So the progesterone receptor is down-regulated. So we don't have this, the action of progesterone that is very important to counteract the action of the estrogen. Now, of course, I only know this in the context of hormone replacement therapy, where to your point, when you give women estrogen unopposed, the endometrial lining gets thicker and thicker and thicker. You can get hyperplasia, which could ultimately become cancer. But tell me more about what's happening in the cycle through that. Is it basically the same thing? You give estrogen as she's ovulating. Estrogen is increasing the thickness. The progesterone surge causes the shedding. So remember the follicular, like the late follicular phase. In the metrolome, people who works with IVF know that a lot, right? Because we are aiming to look at the endometrial and the final phase of the follicular part. So endometrial is about like 8, 10 millimeters at that point. But when you have the progesterone, it opens the implantation window. So we have this so-called dis-utilization. Lepets and secretory phase comes in. And then at the outer sound, endometrial is like white, not anymore black. And this is very important for the pregnancy. But if there is no embryo inside the uterus, the corpus looking has like 12 to 14 days of life and then it just sheds because you have a decrease in estrogen and progesterone levels. So it sheds. So that is very important for endometriosis too. Because remember it's like endometrial outside the uterus. So one of the treatment pillars is giving progesterone or progestings to these patients. And the midterms is lesions, they have this progesterone resistance. What does that literally mean? You're saying that the actual endometrial cells, which are assumed are like another endothelium, because it's outside the body. Yeah, it's like troma and it glends. That resembles the endometrial lining. Okay. And they have progesterone receptors. And when you say they're resistant to progesterone, do you mean is it not like it's the same but insulin resistance where progesterone hits the receptor, but kind of. Yeah. You need much more insulin or progesterone to produce the effect. Yeah. Like why does that happen? It's complicated. I don't think we know for sure, but it's very interesting because those lesions, they also produce, they also have somatic mutations. Think about that in oncogenic genes like Keras, PIK3, PNK, Kineas, right? So they resemble, they act like cancer, especially in deep infiltrated endometriosis and adenomiosis up to 37% of those lesions, they express these oncogenes. So they grow independently. But do they have metastatic potential? No. Why is that? Because they're benign tumors. Yeah, benign tumors. They have the machinery to go, like to grow really fast, but probably due to the adesions and the fibrosis outside the lesions, they cannot metastasize. That's incredible. Yeah, it's like putting a 1000 horsepower f/1 engine into a golf car. You just have the machinery, but you can't go further. This might be a good time to explain adenomiosis, which can clinically be confused with endometriosis, but has some distinct pathology. So maybe tell us what that is. So adenomiosis, I think, is the missed disease because everybody talks about or should talk about endometriosis, very prevalent. But adenomiosis actually is more prevalent probably up to 20 or 30% of women have adenomiosis. And you're saying about 10% of all women in reproductive age have endometriosis? Okay. Yes. So adenomiosis is essentially the presence of this endometrial-like tissue inside the myometrum. So inside the muscular wall. So back then, they used to call this internal endometriosis. Understood. But now we are calling this disease differently because they share some mechanisms, but they are different. If you're looking to the studies of single-cell transcriptomics, Linda Judis, last year published one beautiful paper about this, they don't have the same molecular pathway. So they are different diseases. And the mechanism is. What's the overlap? I'm sorry to interrupt you. So they have the same oncogenic somatic mutations. Adenomiosis also have this progesterone resistance and estrogen dominance. So they also produce or overexpress aromatase. So it's pretty much the same, but they are different diseases. And of course we have cure. And adenomiosis, if you do a hysterectomy, you take out the disease. It's just a disease in the uterus. Endometriosis, it's outside the uterus. And what is the overlap in women who have won the other and both? So obviously 20% have won, 10% have the other. How many have both? Difficult to be precise here, Peter, but we think up to 70%. Up to 70% of endometriosis patients. Because they might have some type or some degree of adenomiosis. And that's very important for the infertile couple. So the mechanism in adenomiosis is the so-called TIR. So it's tissue, injury and repair. So essentially the endometriosis is going inside the uterus, like breaking that junctional zone, which is a thin layer between the endometrium and the myometrium. And it's going inside and disrupting and breaking the lines and producing those islands of cysts and ecogenic birds that increase the volume of the uterus and makes it very soft to the touch. During surgery, you can palpate the uterus. But why? Is there a defect in the junction between the endometrium and the myometrium? Yes, and probably that somatic mutations, that aggressiveness, that they go inside. But we're not sure about why. But they can't get through the myometrium. They can get through the myometrium. And we have some like risk factors. For example, when you have a miscarriage, when you have c-section, so you break the line mechanically, when you do a curretage, you break that or even hystereoscopy for lachromyomas or polyps, you can break that acutely and the endometrium can invade the myometrium. Okay. So again, just to orient everyone, myself included, adenomyosis is a disease where endometrial tissue spreads outward from the inner part of the uterus into the muscular layer of the uterus. Mainly is that sort of an interrotopia. And we have another type of adenomyosis. It's not consensus, but some authors they call it external adenomyosis in which the endometriosis that deep infiltrated endometriosis is going inside the myometrium from the serosa to the myometrium. And now we have not only endometriosis, but adenomyosis. But there are some authors that think they are, it's not correctly to say that it's adenomyosis. So mainly adenomyosis that we're talking about. From a demographic standpoint, how does it overlap? Is it young women? Is it a disease of the fertile years? do women experience this denovo after menopause? Is it all the same sort of presentation? Traditionally, ademiosis was called a disease of the women at 40s, because she had like pregnancies, sometimes the sections, and you know, the curators and miscarriage. But now we are seeing younger patients with ademiosis, even without pregnancies. And again, this must be very confusing because it would be easy to confuse this for endometriosis, I assume. We haven't even talked about the presentation, so we can do that in a minute. But well, let's actually do that. Let's talk about presentation. So maybe we can start with the traditional presentation and then the nuance. So what is the. If you were taking a bored exam and it was trying to show you a woman with endometriosis, how would she present? So typically those women, they have pain, like pelvic pain. Sometimes they just organize their lives around their pain. And tell me what that means. Is pelvic pain akin to a UTI? Is it akin to what would be the closest thing that someone would understand who doesn't have it? I like the framework of the 60s of endometriosis. The first day would be dysmenorrhea, which is pain during menstrual period. So they have this lower abdomen. And this is not cramping, this is an actual pain. Pain. That sometimes just pain medications don't resolve it. Completely. Sometimes those patients, they go to the ER to receive intravenous medications. Intravenous medications. And they have. The second is deep dyspharunia, which means pain during intercourse, especially in the profound posturus wall of the vagina. Third day would be dyschisia or pain during bowel movements, especially during the uterus. And the uterus is how close to the rectum. It's close, it's adjacent to the alien. Yeah, yeah. And sometimes we can have lesions right there in the septum. Fourth day would be dyseria, like pain during urination, especially cyclic pain, usually during the menstrual period. We can also have bleeding, but that's not very common. Fifty would be difficulty in getting pregnant, so difficulty in conceiving infertility. And the last one would be. I'll put the D just for a hook, for a memory hook, but it's dysfunctional chronic pelvic pain. So those women can present with pain for more than six months without any relation with the cycle. So you have a lot of dysmeread of pain, you know. Okay. And then help us understand how that differs. If as a clinician, you were trying to make the distinction between endometriosis and admiosis based on symptoms. Is that possible? Yeah. Admiosis mainly. Sometimes the patients are asymptomatic, by the way, around 10% of women with endometriosis might be asymptomatic. So their only symptom would be for infertility potentially. Potentially, or they just normalize the pain, which is a problem. They think that it's normal, or they're told that it's normal. But admiosis mainly presents with bleeding, uterine bleeding. Like, sometimes those patients they get anemic, and they bleed a lot during their periods. Let's take one quick detour to understand another condition that produces bleeding, which is fibroids. Maybe explain what fibroids are and how it's different from admiosis. So fibroids, they are very common up to 70 or 80% of women will have one fibroid. Mostly asymptomatic. There are benign nodules inside the uterus, can be just right at the endometrium, so-called submokosu. Inside of my metrum, intramuscular, or on the cirrhosis. Like, sub cirrhosis. And they can get very, very large nodules. Sometimes it disrupts the anatomy of the uterus, especially the endometrial cavity, and provokes miscarriage. And they can bleed too, especially the submokosu. We classify them by the International Federation of Organic Colleges and Obstetricians by 0 up to 7, depending on the classification up to 8. And the 0, 1, and 2, they are submokosu. So they are the problematic for fertility and for bleeding. And that's counterintuitive to me. Why would the submukosu ones cause more issue than the ones that are closer to the lining? Actually, the submokosu, they are the closest to the lining. So 0 will be just inside the cavity. OK. One is mainly inside the cavity, but a part is in the myometrium. And then two is mostly in the myometrium, and a part is inside the uterus. And the number three would be just touching the endometrium. OK. Got it. And then as you go all the way out to the cirrhosa, it gets lower and lower-- or higher and higher number, but lower and lower severity. Yeah. OK. Probably not severity, but clinical implications, right? OK. OK. So the woman with-- you said 10% of women with endometriosis could be asymptomatic, or their only presentation could be infertility. So that would suggest that when we start talking about infertility, one thing that should be in the differential diagnosis is untreated endometriosis. But otherwise, most women are going to experience some pain with something, pain within a course, pain with her cycle, urination, everything. Then on adenomyosis, what percentage of those are asymptomatic? I don't have the number in my head, but I would say that probably one-third, because it depends on the phenotype and the intensity of the disease. So if you just have one leosis, myometrocyst, which is a presentation of adenomyosis, probably these patients, they don't have any symptoms at all. But if you have a very diffused adenomyosis, or even an adenomyoma, which is a nodule of adenomyosis, they bleed out. It's very painful, especially the period is very painful. And again, it might sound like a dumb question. What is causing the actual pain? Great question. Great question. Actually, we have three types of pain in anemotorosis, period. That's, I think that's the most complicated part for Earth's gynecologists to understand, because we're not trained for that. But there is the so-called no-susceptive pain, pain from the lesion directly. So it just hurts. And here, surgery and treatment, hormonal treatment, can help. Second layer is the so-called no-siplastic pain, where the nerves are infiltrated by the lesions. And you can have burning sensations, sometimes on their legs, on the back. And here, medications can help, sometimes gubapentin and SNRIs, right? Surgery can remove some of those lesions. We do this technique called nerve sparing. Very difficult, sometimes it's possible to do, but we can try. And the third layer, and most difficult to treat, is the no-siplastic pain, when we have central sensation. So you can have a beautiful surgery, your pelvis is clean, but you can still have pain. It's like, imagine this analogy. Imagine, like, an ametrosis lesion, it's a burglar. So surgery can remove the burglar. Hormones can lock the door. But once you have this alarm system ringing and ringing years after years, the wiring changed. And now, even a wind can trigger still arm. And even removing, without the burglar, without the doors are locked, but you need to-- you need a different specialist here. We need a physiotherapist, a pelvic floor, physiotherapist, and also a pain specialist to treat those patients. And that's why the delay in diagnosis and treatment of ametrosis is one of the main causes of this central sensation. It's very important for us to treat, even empirically, nowadays. The ACOG just published this March, 2025, '26, a new guidance on ametrosis diagnosis. And it allows us to not only diagnose clinically, but treat it. Because if you have just based on clinical symptoms, if you have a patient that has pelvic pain, dysmenorrhea, dysparronia, and so on, you can give her a medication to avoid this disease burden year after year later. What's the typical age of presentation today for endometriosis? I don't think we have a typical presentation anymore. We're seeing an ametrosis in teenagers. Look at this data. It's up to 50 and 75% of teenagers with pelvic pain. They have ametrosis. three quarters, they have in the materials. And what percentage of teenagers have pelvic pain? Not sure. Presumably it's like 5% or so. Yeah, I think a little bit more. So we are seeing teenagers presenting with endometriosis. And just normally. Again, going back to the etiology of this, anytime you see an increase in the prevalence of something you have to assume there's some environmental trigger, and it would be hard to explain just the number of periods because if she's a teenager, she's still well below 100. So what else do you think. Do you think there are some health factors? Do you think it's. So for example, we see more PCOS today, presumably linked to more insulin resistance and lifestyle factors that drive that. Is there anything else that you think could be increasing the prevalence of this young. You don't have definitive data here, but probably even microplastics, we have some studies about that pollution. Or you mentioned pollution, yeah. Yeah, diet, probably the. You know, this sad diet, it's all poor sleep because remember, poor sleep. Immune system. Immune. Immune system regulation, the macrophages, they just jump from one to the other type and this may increase the risk of endometriosis. So we are not sure about this question, but. It's probably many things, which is what makes it so complicated. Yes. So, the implication, of course, of what you just said, with the burglar analogy is you need to treat as soon as possible because the longer you wait, the more you rewire in a negative fashion. So let's talk about treatment options for. Well, let's actually talk more about the diagnosis. Let's go down the formal. So, a woman presents to you or to a gynecologist and with a story and actually how uniform is the understanding of this amongst primary care doctors and gynecologists? Or is everybody attuned to making the diagnosis based on a presentation or do women slip through the cracks? Oh, yeah, unfortunately not. Because if you look like the diagnosis, the labeter is 5 to 12 years depending on the country. I believe in the US is around 6 years. And in Brazil? Brazil around 7 years. So from the first symptom up to the diagnosis, can you imagine like 5 up to 10 years? No, I can't understand that. So that means that for a period of 5 years, a woman is saying to somebody, "I'm having symptom X, Y, and Z," and they're not able to make the diagnosis? Mainly because of I think three factors here. The first one is this cultural normalization of pain, right? Female pain, especially. So they are told that, "Oh, that's normal. Just have a medication, have an anti-inflammatory and go." But some teenagers, they just can go to school. They miss school. Sometimes they miss work. They cannot properly work. So the estimate cost is around 80 to 120 billion per year. And two-thirds of that is productivity loss, not only medications and hospitalizations and surgeries. So that means that we have this big culture, unfortunately, of normalization, right? And mislead. The second one is that we don't have a biomarker, like a simple biomarker, like a blood biomarker, right? We need a very good imaging system. That's actually very simple, not that complex, like a transvaginal ultrasound, but with a specialist or even an MRI. And yeah, I think that's, and the third one would be that traditionally the diagnosis has been made with diagnostic laparoscopy, right? That is a big step to take. Yeah, we shouldn't do that anymore. Okay. So let's talk a little bit about that. So for folks unfamiliar with the term diagnostic laparoscopy, laparoscopy, of course, is when you put actual cameras and air, in deflate the abdomen, put cameras inside. And this is a surgical procedure, requires general anesthesia. And I guess the rationale for doing that was we are looking for endometrial tissue inside the abdomen. So that's as good a place to look as any. And it's easier to look with your eyes, which is what you're able to do with a camera in an insufflated abdomen than it is to look with a CT scan. But now you mentioned MRI and then obviously ultrasound. So when did the shift of diagnostic acumen or success start to move towards non-invasive or non-surgical treatment? That's a good point. Around 25 years ago. Okay. So if you, for us in Brazil, the specialized ultrasoundography is a very good exam. We have, we have Dr. Luciana Shamier, who's now in Boston, the best general. Monoar learned that they are like one of the best radiologists in the world for endometriosis. And they developed this protocol in which you have bowel prep. Like, not just like a colonoscopy or a sickoid. And like much more like simple. Okay. You have this enema in like one hour before the exam and now residue diet. But that simple protocol with gel inside vagina. So you can look into small lesions and the bowel bladder. And you can even see the layers of the bowel. So it's a beautiful exam. But that started around 25 years ago. And that's not widespread yet. I know that I was just talking to Luciana today and she told me that in, I think in Mayo Clinic Arizona, there's one doctor doing that. Scott Young, but not for everybody. I think in the US, mainly is MRI. M MRI and ultrasound sonography, they have very high sensitivity. And 95, 98% and very high specific to, but for superficial lesions, just let me go step back. We have three types of three phenotypes, right? The superficial lesions, the deep infiltrative endometriosis and endometriomas, the cysts of endometriosis. So for those superficial lesions, ultrasound, sometimes it leads to. You say superficial, you mean superficial away from the endometrium closer to the peritoneum. Actually, I am peritoneum, but the. Not deep within the peritoneum. Just sitting right on top. On top of the peritoneum, but less than five millimeters. Okay. And so just to orient everybody, because the anatomy here is actually a little confusing. This means imagine you could go inside a woman's abdomen. And what do you see? Well, you see nothing because it's all collapsed. So let's assume you can put air into the air and blow it up and separate everything. You have bowels surrounded by peritoneum, you have the kidneys behind the blood vessels, et cetera. It's basically just a potential space. And what would be. And by the way, included on top of that peritoneum, you would see the uterus, you would see the ovaries. The phypoptines. The phypoptines between them. The ligaments. Is the most common place you're going to see these endometrial deposits situated on top of uterus fallopian tubes and ovaries? Right behind it. Yeah. Right. Behind the uterus, the ligaments, like the so-called uterus sacral ligaments. Because just of the anatomy and gravity, you know, most lesions, they just stay there. But sometimes they can travel. Yeah, you said it could get up to the diaphragm. So that's a big, that's a big transit. Yeah. 80% on the right side because of the anatomy of the sigmoin. So it blocks the left side mainly. But yeah, the bladder around 10 to 12% of endometriosis patients, they might have urinary tract lesions. But mostly it's. And then between what about between the rectum and the uterus? That's rare. Because the space is too tight. Yeah. It's to go inside from the uterus sacral ligaments, from the, like, behind the uterus and go to the septum. Yeah. So that's rare, but that's very hard to treat. Because sometimes it goes deep into the muscle, the muscle floor, you know, of the pelvis and invades the nerves. And those patients present with lots of fibrosis. Okay. So, if you're doing an ultrasound, how is this? This different from any normal trans-vaginal ultrasound is the difference that you're doing the enema and the bowel prep so you can get a better look posterior? Very important question, Pierre. If you do a normal ultrasound and you don't have endometriosis and the report doesn't mean that you don't have an endometriosis. That's one of the most important things I think in this episode. So if you complain about pain, you have dysminorrhea, dysperinia and so on and you do a normal ultrasound, that's one of the problems of the diet. That's a very, very low sensitivity. A very low sensitivity. Yeah. We see that a lot. But we haven't, we have three layers. of ultrasound. This is the normal one, they're a regular. The augmented ultrasound with this lighting sign so you can use the probe to push the posterior wall of the vagina and see if there's any addition there. So and sometimes we even without bowie prep it's better than the normal ultrasound but the best will be the detailed protocol with an expert with this bowie prep to look into the pelvis like. And who does this? A radiologist or the gynecologist? A radiologist. Sometimes is a gynecologist specialized in radiology. And again just because I've never done any of these procedures so it's not clear to me what the difference is. So a regular transvaginal ultrasound, I assume is a relatively small device like the size of a pen. No, a little larger. How big in diameter. We'll be something close to this. So basically an inch and diameter. Two centimeters in diameter. Okay. And you mentioned that the second thing you want to be able to do is push the probe into the posterior or the furthest part of the uterus. Now are you doing that because you're trying to get the probe to look further or you're trying to elicit it. Yeah, to move the uterus. Okay. So you can see this is lighting sign, lighting sign, right? Okay. And MRI cannot do that right? Right. It's static. It's static. Yeah. And the probe can see 180 degrees plus in front. Yeah. Okay. So then when you're and again, I'm still a bit unclear as to why the bowie prep is needed. So you can check for endometriosis in the ball especially, especially in the rectum. I see. And if you have stool in the rectum, you can't get. Yeah, you need it. On the other side. Yeah. Okay. Or liquid. Yeah, we need liquid. Okay. Air is not good for ultrasound. Yeah. Yeah. Okay. So is this a different device? Is the ultrasound a different type of device? Good question. No. Actually, the difference is just the experience and the protocol. But it takes time. And what is the official name of the protocol? It's called a detailed protocol for endometriosis with bowie prep. It depends on the. Okay. So if someone's listening to this now and they want to do this, it sounds like you've already mentioned mass general mayo in Arizona. Is it possible that there's someone who lives in a city where there's nobody that does this in the US? Definitely. I was talking to my friend and she told me that in the US, this is the woman at MGH. Yeah. Yeah. Yeah. One of the best. Yeah. And in the US, it's mainly MRI. But they do the augmented ultrasound. Okay. So you can do that the second layer. But just a few clinics in the US probably Mayo Clinic, Cleveland Clinic, they are doing the protocol for endometriosis. And why is that? Because it takes lots of time. Like one hour exam. Yeah. So you need to allocate the person and also you need, of course, the machine is not available all the time. So we, because we in this country, obviously have so many MRI machines, it's easier to do that. It sounds to me like the MRI is very good, high sensitivity, high specificity. The drawback is you don't get the dynamic phase. But you don't, yeah, but it's not that good for bowel endometriosis. And is it a safe assumption that a woman who's having pain with stool is more likely to have bowel endometriosis? Definitely. So then if you have a woman who is suspected of having endometriosis, but has none of the rectal symptoms, are you more confident that the MRI is going to make the diagnosis? Yeah. Probably sufficient. Okay. But if you are planning a surgery, the ultrasound is or me is essential. You would never operate without the surgery. Yeah. We have the privilege in Sao Paulo to have access to probably five or six very good radiologists that do this type of. You're five or six people in one city that can do that. Sao Paulo is one of the best city to do probably the best city. Italy is also a good country for that. But it depends on people, right? So Manor Lendo, Luciana Shamiye, Analizani, Call, and there are a few radiologists that are very experienced, not only in diagnosing, but also the follow-up of those patients. So for instance Luciana, she used to not only do the ultrasound, but then she would go inside the OR with the surgeon to look to correlate what she did. That's brilliant. That's the brilliant. But that's very, very unfortunately. So you made a very interesting point, which is you can make the diagnosis with MRI with one blind spot, which is Rectol. Now let's talk about treatment. So I will just start to interrupt. Just a bit clear. MRIs is better for extra pelvic lesions, such as diaphragm, and for the lateral part of the pelvis, where the ultrasound loses its echinocity. Yes. So for instance, to see the ureter and to look for the deep pelvis, the nerve infiltration, it's better than the ultrasound. So do you do both? Sometimes, mostly both. What's the sequence of MRI, by the way? Is it special? Does it require a dental? No. No. So non-contrast. No, T1, T2. They just usually put some gel inside a vagina. T1, T2, that's it. Okay. So relatively easy MRI. Yeah. Probably a 20-minute scan. Yeah, but there are some pitfalls, like movements, bowel movements. Yep. The patient cannot stand too much. Sometimes you just get some artifacts. Yep. Okay. So now let's assume you have the diagnosis. What are the treatment options? How do you think about non-surgical and surgical treatment options? So it depends a lot on the object, right? If the patient is trying to conceive, yes. We have another section. If she's trying just to get a better life without pain and not wanting to conceive now, we have much more options. Okay. So let's start with that. Let's start with 20-year-old woman not trying to conceive, but having pain and just wants symptom resolution, but wants to preserve the option of conception in five years. So we have a list of questions. First one is, do you want to get pregnant in the future? How many children do you want? It's hard to answer that if you are 20. How is your ovarian reserve, AMH, anthropocal count, very important? Disease phenotype, what I mean here, do you have endometrioma, the cyst, because this is a very special phenotype, which can lead to lower ovarian reserve and also the surgery can impair the anthropocal count and even the AMH. And how's the pain? If she's presenting with pain, we mainly start with a pill, like a birth control pill, because those patients, they usually are not trying to conceive, so they want contraception, right? And if the patient doesn't have endometrioma, we can use an IUD, like a marina or a chylina. In addition to an oral contraceptive? No, we tend to use just one. So marina is not good for cysts because it doesn't suppress the ovulation, right? So, but the patient has like no endometrioma, you can use either a marina. Benefit is like five years of treatment. And a marina is progesterone coded, why would you use a marina over any IUD? Because you need the progesterone action. You're trying to suppress endometrial hyperplasia. That's it. And to avoid the menstruation. Okay. So in other words, a regular IUD doesn't necessarily suppress, whereas a marina will. It's just an inflammatory event for a contraception. It's a prevention exception. Yeah. Okay. And do you all things equal in this example I gave you? So 20-year-old woman who wants to preserve her right to fertility, but at the moment is just trying to deal with pain. She has pelvic symptoms. How are you deciding between the marina and the oral contraceptive? That's a good question. If she doesn't have myofacial pain, which is like at contractions, and the muscle part of the pelvis, and the marina is a good option. So no endometrioma, no myofacial pain. Marina is a good option. But sometimes they just don't want to insert a marina, right? So you can start with a pill, a progesterone only pill like an orethane drone or diana gest or a desogist realm, or you can use a combined contraceptive pill like the traditional ones. Estrogen progesterone. Yeah. Ethineos estradiol or just estradioplus progesterone. And you don't use a low dose. You don't use a low low eston or you do. Yes. We prefer using the lowest effective dose. Yeah, because remember, astrosyn can activate, can activate the lesions. So it's better to use the low dose. But they have points to like, they are pretty much similar. So if we do that three months or six months later, the patient is not better. We can change the matter. or we can plant surgery. But mainly we try to use medications. And why is that? Because if you do surgery right from the beginning, it's very probable that this patient is gonna recur in the materials like in five years or even ten years. And she'll need more surgeries afterwards. And the surgery here is a laparoscopic procedure. It's a blunt force tool. You're going in and you're literally laparoscopically and you're cutting out. Exciting. And are they that visible to the eye? Yeah. Most of the lesions, they are visible. But there are some tiny lesions that we cannot see. And that's why probably the recurrence rate, it's not actually recurrence. Think about how different this is from cancer. Right? Like endometriosis presents like metastatic peritoneal cancer. And no one in there's no treatment that would ever involve surgery for that. You treat this systemically. Once the cancer is at that level, it's only systemic treatment. And the reason, of course, in part is because you can never get it all. Even if you only took what you can see, you know you're missing things that are below the threshold of your vision. And so is that not the case here? Or is it the case that you're missing things? And that when you say the problem with surgery is she's going to recur in five years, is it that she recurred in five years or is she's just going to present with what you didn't see? Yeah, that's the point. Yeah. Sometimes even with a good surgery, excising all the lesions, if you don't use a medication after surgery, recurrence rate is around 10% per year, especially in an ametriomas. So it might be that surgery doesn't cause recurrence. It's just that surgery is a- It's not a sign of recalcitrant disease. It's disease that doesn't respond to medication. And that's why those patients need repeated surgery. And that's where the progesterone resistance come in, you know? And do you have an assay to measure this or is it just a clinical diagnosis? We don't have it. Yeah, we don't have it. And remember, they produce, they're remitate, they produce their own estrogen, like their own fuel to keep growing. Even so we don't have like a chemo for an ametriosis. Yeah. We just have this a violator blockage, you know? We just suppress ovulation. And by doing that, we, of course, we decrease the risk of recurrence. There's a study published that show that if you insert a marine after a surgery, recurrence rate is 88% lower to a placebo. So it's better to use something after surgery. So coming back to that patient with the patient 20 years old, probably she's gonna respond to medication. If not, we can change the medication or we can plan surgery. But always we should think about this as a chronic disease. And there's this concept that was published in Nature reveals 70 years ago by a surgeon from a French group that calls the endometriosis life. What that means that we should not only treat like the main symptom, but we should think about the life of this patient that has this disease that is chronic, like type two diabetes, type one diabetes, and so on. But we are mainly doing just one appointment, one surgery or one medication and go. We're not thinking about the life, like what's gonna be like in five, 10 years, right? So we should change the mindset on that. - Okay. Let's now consider a woman who's in her late 30s. She's had two kids. AMH is declining, so she's technically still fertile, but is not trying to conceive again and is mostly just trying to deal with her symptoms. And she has significant lesions in her pelvis. How do you approach her? - So first line in medical therapy, because remember if she doesn't want to conceive, she needs contraception. So we could use a combined pill or a protesting. In Brazil, we have this dianogess, which is a very good protesting for endometriosis. In the US, we have the natisa. Natisa is like estrogen, estradioplus dianogess, but you need to use only the active with dianogess. There are 22 pills inside a box. And if she responds well, that's it. We are controlling the disease, right? - And if not, you go to surgery. - Or we can use the marina. - Okay. So now let's go same question. 36 year old, everything I said is the same, except now she wants to conceive, but her AMH is, as I said, declining and therefore the clock is running out. - So probably the objective is have a baby, right? - Yes, she wants a baby. - Just controlling pain. - That's right. - But sometimes they present with both. - Yep. - Pain plus infertility. So this patient, we have a series of questions that remember infertility is a couple of disease. Probably the only disease that I know in medicine that involves two people. It's defined by the incapacity to achieve pregnancy after one year of trying to do that. So you need to investigate the male factor, sperm analysis, and you need to investigate other factors that not only endometriosis can impair infertility, right? So you need to ask to request a carrier type and some other exams like his terrestrial pincogram. So let's say you do the fertility workup and you do not see any evidence in the male for with motility count or anything like that. And I'm making this up because I don't know if this is how it would present. They don't seem to have difficulty with a chemical pregnancy, but it never, she's always miscarrying at four weeks, six weeks, eight weeks. She's never getting passed. Is that consistent more with maternal age? - Yes. - Okay. So how does the infertility of endometriosis present structurally? Is it, they don't even, they can't implant? - Very good question. Actually, now we mainly think of the mechanism about a mechanical mechanism. We think that it's mainly mechanical, not biological. - Okay. - So the tubes are compromised. So they can't pick up the old sites or they can permit the fertilization inside the tube and transport the embryo back into the uterus. - Right. - And surgery can fix that sometimes. If the tubes are not too damaged, but we have some additions not too much, but you know, you can do that by laparoscopy or robotic surgery. But it depends a lot on the couple. If Mayo factor is okay, if age is okay and the couple just want like one child, probably this 36 year old woman, she has time to do that. And if she doesn't get pregnant after one year of surgery, - You just make sure I understand. And the surgery you're proposing is a laparoscopic procedure where you attempt to remove any at all adhesions. And just doing that, the hope is that the fallopian tubes become less dysfunctional. - You can restore their anatomy and the functionality of the pelvis. - And is that because it is such a mechanical issue where the adhesions can literally kink the fallopian tubes or create obstructions? - Yeah, primarily yes. But of course, we have plenty of data showing that we have molecular differences between and the mitriosis and non-inimiterosis pelvis. For instance, we have a C reactive protein, IL-6, TNF alpha, but clinically, it's mainly an anatomical problem. - This is, it's so hard to believe that it's that crude, if you will, that it's plumbing basically. - Yeah, but there are some authors that may argue that implantation, so that the u-top can the metrum is also dysfunctional, more likelyly, but clinically not that much. Why is that? Because we have beautiful data and papers published like 20 years ago that compared women without endometriosis don't know all sides, so good quality embryos and they transfer the embryos, the implantation rate, miscarriage rate, and life birth rate were pretty much similar. So, which means that clinically endometriosis probably doesn't impair implantation. And that's very important for IVF too, because if you have a frozen embryo, you do IVF and you freeze all the embryos. If the patient has endometriosis, does she benefit from surgery before doing the frozen endometrosis? Probably not, but if she has endomiosis, she will probably benefit from doing the hormonal suppression, because you cannot operate on endomiosis mainly, just the endomyomas, they are not that common, but we cannot treat the uterus. unless you do a history of love. - With a left-winger. - Yes. So in other words, the only women who can be relieved surgically from admiroosis are women who no longer want to conceive. Because you're gonna do a history of me. Do you do the ufferectomy as well? And the subpoena-- - Depends on her age and over and reserve, but we always do the subpoenajectomy. - You always take the tubes out when you take the uterus now. - Yeah. - Right, yeah. Is that standard of care? - Oh yeah. - There's no gynecologist that we ever leave tubes. - Yeah, we-- - We know that that's the thing. - They sure, yeah, they sure. - Okay. So I didn't understand something you said a minute ago. You said that when you took a donor egg, a healthy, young, perfect donor egg, chromosomeally normal, morphologically perfect embryo, and you transferred it, it had the same rate of failure as the woman with endometriosis is own egg, correct? - No. - If you are looking just for recipients of donor eggs, one group has endometriosis, the other one is knowing the metriosis, confirmed by laparoscopy, it's very important because mainly those studies, they are very heterogeneous, and they just don't know if the patient has endometriosis. So my opinion is that the missing factor is edelmeiosis, it this can confound implantation rate and miscarriage rate. So what I'm saying is that if you transfer a good embryo in a uterus of a patient with or without endometriosis, we have pretty much same results. - Oh, okay. - You understand that? - Yep. - So, but if a patient with endometriosis is doing IVF, she will probably have less, less, less, less mature sites and less embryos to transfer, which means that she needs much more cycle to do than the patient without endometriosis. But that doesn't mean that the quality is impaired. It's very subtle. We have also molecular data showing that all sites with, in patients with endometriosis, they are not normal, but clinically, if you're looking to the data, just ask, IVF patients with endometriosis or without endometriosis, is there any difference in quality? Probably not. - Okay. - Even any play rates, they are similar. - Because you're matching for age. - That's it. - Yep. - Age is the proxy for endometriosis. - For endometriosis. - I guess yeah. - Okay. - So in the case of this woman who's in her late 30s, are you going to treat her surgically and give her a year? Are you going to harvest eggs to give her a year? Like, what is your algorithm? - So probably we're gonna offer both options, but IVF is the way to go here. Because up to 34, the difference between a blastocyst with 31 or 34 years old, like in a patient that is 31 or 34, is not that different. It's about 35% of any play. About that. If you are 30, is it that high? - Yeah. - A 31 year old woman has a 35% chance of any play. - 30 to 35, almost one third of blastocyst they are, any play. - I mean, I just don't think of 31 as old. - Yeah. - I know. - I think I almost think of that as prime reproductive age. - Yeah, prime time would be like 25 up to 30. Because it's very easy to-- - So it falls off very quickly in 30. - Especially after 35. - And 35, any play is? - Is around 40% around 40. And 38, around 60%. 40, around 70%. 40 to around 80, 85%. So it rumps up. And so that's very important. So if you draw-- - I wanna make sure you and I are talking about this very casually, but I wanna make sure the listener understands what we mean. Any employee is when the egg is split and you don't get an equal number of chromosomes. So you get either two or zero instead of the one chromosome you want. And that's almost uniformly fatal. Those almost always result in miscarriages. There are a few notable exceptions like trisomy, Down syndrome, which is what trisomy 21. - Yeah. - So the definition is like, any employee is an abnormality in the number of chromosomes. So we have 46xx, a female or xy, a male. But so the normal way would be like 33 chromosomes from the egg, x and 33 from the spur, x or y, right? So if you do the math, will be 46. - But-- - 23 and 23. - Yeah, 23, sorry, 23 and 23, yeah. So 36 again. But if you have like problems in the egg because essentially any employee they come from-- - The old side. - Yeah, that's right, like 93 and 95% they come from their outside with due to errors and meiosis. So they don't split the chromosomes and now you can get monosomy, one less or trisomy. As you said, they are the most quote, unquote, dangers because those babies can live, they can have the disease. Monosomy is not, we don't have a compatibility with life, just the monosomy of x, which is a term. - Tertus, yeah. - So mainly we're having an implementation failure problem so infertling and that's invisible to the exams, right? So a 30 year old woman with normal exams can get pregnant. Why is that? Because she's 38. Most embryos, they are not normal at that time. And we can have also miscarriage risk here. - Okay, so you're gonna pursue both paths in parallel with her, but given her age, you're going to harvest some eggs and have them handy. - Yeah, just coming back to the case. So we could do potentially two ways to route here. First one would be to go directly to IVF, then freeze the, or the old sides or embryos, mainly embryos here. Then we can transfer the embryo later on. Between freezing the embryos and transferring, you can perform surgery when if the patient has large endometriomas, like larger than five to six centimeters because they can, - They can get that big. - Yeah, that's the same as massive. - I have a patient now, she has 12 centimeters in one side and eight centimeters in the other side. Is the size proportional to the symptoms? - No. - No, 'cause you tell me that I would assume this woman can't leave her house, like that seemed debilitating, but no. - Yeah, that's the problem of the classification system that we have. We tend to use the ASRM, that's the American Society for Reproductive Medicine Classification, but it doesn't capture it at all because it doesn't match the severity of the disease. It's a classified one to four, like mild, minimal, moderate and severe disease, but it's just like a map, like a surgical description. It doesn't match with pain, neither for too long. So that's a problem. So an ASRM four would be like very severe disease, but she can be asymptomatic while a stage one patient could be like at their homes, just having pain. So that's a problem we have. But we have, like talking about classification and scoring, we have this enometriosis fertility index, which is a score based in some, you give like zero to four, depending on the quality of the tubes and the fembra and the ovaries after surgery. So you can predict the rates, the pregnancy rates after surgery. So if the score is high, like nine or 10, they have almost 65% of chances of getting pregnant naturally after surgery. So that's useful, which means that if the tubes are not okay, they are dilated or you did have to proceed, you need to do a sub-injectomy, probably the chances are not that high after surgery, so you can walk them through IVF directly. So just coming back to that patient, so if you freeze the embryos, then you can operate on the endometriosis. If there is indication, mainly indications are large endometriomas, pain, the quality of life is not good, you can operate on them. And small bowel lesions that can obstruct, and sometimes you retire all involvement, which can lead to kidney function loss. Actually, I had a patient with, she had a nifractomy, left nifractomy. Due to endometriosis in the ureter, like silent disease. Most-- - Did you develop tyderinophorosis? - I don't know, the process and the urologist performed an effect on me. Oh, yeah. So those are the red flex, those are the red flex to perform surgery even without symptoms. - Yeah. - Like appendix is important too, because sometimes it just mimics neuroindocrine tumors. It's essentially the same phenotype. - Wow. - And small bowel and ureter, you need to operate on them. - Okay. Let's talk about a 32 year old woman comes to you, she has had difficulty conceiving. Two failed IVF transfers. You're seeing her for the first time. You do a workup, you find she has adnomyosis. What can you do to help this woman? - That's very common, a very good example, Peter. So if she still have embryos frozen. - Yes, let's assume she still has, so she has three embryos still frozen. Two of them, she got a lot, she had a decent reserve, but two have failed and now, but they don't want to waste anymore without knowing what's going on. So that's what they came to. - So she has embryos that have frozen and you can perform if she didn't do that yet. A GNRH analog or agonist use before the transfer, what that means, that you can treat adnomyosis with medication, suppressing the ovulation and suppressing the estradiol levels. So you can produce like a menopause symptoms. That's the side effect. But we have data showing that this can increase implantation rate, but decrease miscarriage rate and increase liporerate. So you are treating the uterus, right? So estrogen can triggers admiosis lesions, can-- - Just like endometriosis. - Just like endometriosis. And if you use a general agent agonist, we have now in the U.S. - What are the preferred ones? - We prefer, like we have much more data with analogs, the agonists. Luproin, it's called the Gossaroline. They are injectable, right? So continuously, monthly, right? So two to four months with this, and then we transfer the embryo using just tiny levels - This is the smallest amount of estrogen. - Yes. And high amounts of progesterone. - Okay. - So that's the strategy. Nowadays we have the antagonist, the oral antagonist in the U.S., they are very expensive. They are called elagolics, relegalics, but they are oral medications. We just have just one paper published last year that compared the use of antagonists versus agonists. And they are pretty much the same. Here we have less side effects. They're very expensive. I think around $1,000 per month. So in Brazil, we don't have these medications, we mainly use the agonists. And by doing that, we can achieve similar rates of pregnancy and miscarriage as patients, if she didn't have any matrices, add a myosis, sorry. - Okay, so you're gonna go four months, by the way, it's not clear to me why an agonist and an antagonist both work. - Oh, yeah. - Did they both produce a lower level of estrogen? - So mainly the initial mechanism, the molecular mechanism in which the agonists can do a call, we call this flare up effect. So it occupies the receptors and it triggers a flare up of a facetional age and then can lead to ovulation. But after two to four weeks of medication, then you don't regulate the receptor and then you have this suppression, hormonal suppression. So you produce the menopause essentially, chemically. But the antagonist, the action is right in the first medication. So you don't have this flare up effect. But essentially the objective is the same. - So you said about four months of that and if you were to take an ultrasound of that woman every month, what would you be seeing in her myometrium? How would it be changing? - Good question, not much. But yeah, sometimes we just see the uterus shrinking, a little bit, like reducing the volume. But sometimes the lesions they are there. - And it's not easy to-- - And why did this woman have a hard time conceiving? You said this is a common presentation. But what is it that in this woman with, and let's assume that this is IVF. So we know that these are good eggs, right? These are chromosomally normal eggs. What prevented the implantation in her? - Actually, it's a problem in pregnancy maintenance. - I see. So she implanted, but something happened in the first week or two weeks or where is she typically failing? - It sticks to eight weeks. - Oh wow. Sometimes even further. - Okay. - And why? - Because there are contractions in that junctional zone. - Yep. - And the uterus is just trying to kind of expel the amers. - And okay, so then you give her four months of treatment, but you said you don't really shrink the adenomyosis. - More phologically, not that much. - But chemically, you change. - Chemically, yes. - And then you can give her the embryo back, low dose of estrogen, lots of progesterone, the embryo implants. And is there a critical window in which she just needs to make it through to then not have the adenomyosis or any form of contraction be a problem? Does this increase her risk of premature labor if it starts to contract too soon? Like how does it play out through their nine months of pregnancy? If you do the treatment, you have higher chances of implantation and lower chances of miscarriage. But we don't have data on pregnancy complications. But we know that anemotriosis and adenomyosis, they can increase the risk of preterm birth, like pre-acclimatum, pre-eclimatum, and small for gestational age, c-section rates. So if you're speaking to this woman before you'd go through all of this, you would say to her, look, if you were a 32-year-old with none of these issues, you had no adenomyosis, you had nothing, and we were just doing IVF because there was some reason you were struggling to conceive, your rates of success would be X. Now because of this condition, how much less are your chances of success? - That's a long 30% less with adenomyosis. - Wow. - But it depends on the phenotype. If you have the involvement of the junctional zone, you have a three times higher risk of miscarriage. - Because it's more likely to contract. - Yes. It's right on top of this surface where the embryo is going to be planned. - And remind me again, did you tell me already why you think adenomyosis is occurring? We think there's a disruption, basically in the boundary layer. - Plasticity, yeah. The desitualization, the progesterone resistance, the contractions in the junctional zone, and the ureth, sometimes they just, you can see, yeah, the hypertrophy, you can see the contractions sometimes in the illiterate cell. - Are there drugs in the pipeline that are trying to address the progesterone resistance? - No. - No, I guess I know. - It seems like that would be an interesting area of study. Because if the, for example, we know that insulin resistance is largely mediated by a failure inside the cell when the insulin molecule hits the receptor and it triggers the kinase in the cell. And we have a sense of what that is. And there's even a drug that can target that directly. So it's conceivable that with enough understanding of what happens when the progesterone molecule hits the progesterone receptor inside the cell, what creates the resistance seems that that would be one opportunity. - Yeah, probably. But we are now just giving them-- - You're just giving them more and more progesterone. - Give them more progesterone. If that woman who was 32 had been diagnosed immediately, could she have been treated with high-dose progesterones and other hormonal therapies to have not arrived where she is? - Like doing pregnancy? - No, pre-pregnancy. In other words, could she have been maintained on some sort of birth control routine for three years prior to trying to conceive and would that have increased her odds? - That's the point, Peter. We think that if we diagnose another lesson or even a young woman earlier, we can avoid 40% of the lesions or the diseased burden. So we have probably a-- but we don't have much data on that. - So why don't we have much data given the prevalence of this condition? - Because if you look at the economic side, NIH infests 15 times more dollars on diabetes than endometriosis. But endometriosis patients might cost around $16,000 per year while a diabetic patient would cost $12,000 per year. So we don't have much funding for that. - Why do you think that is? - That's a complicated question. And I think that's because we're just recognizing that Endometriosis now is an important factor. We're seeing movies and documentaries about that. So I think that's just, it's coming up, you know, that's it. I think that's just a question of time, probably. Like menopause, right? Yeah. That we're seeing this revolution. Are there any other good case examples you can think of that, well, actually, let me give you one more. So let's take another one where a woman is 30 years old. She would like to conceive, but she's not trying to at the moment, but her symptoms are horrific. So she has the worst symptoms you've ever seen, truly debilitating. When you look at the ultrasound and the MRI, you don't see a very high burden of disease. You see a very diffuse disease, but nothing big. You will always try chemical therapy first. You'll always try hormone therapy first. And that patient know because she's, she's going to try to conceive. So we have data showing that if you do that, you control the symptoms, but you don't have a cumulative effect after stopping the medication. So you are treating the disease while you are using the medications and the medications they are mainly contraceptives by nature, right? So after you stop the medication, you just lost some time. So that patient probably will benefit from surgery because you can treat the pain and then she can try to conceive naturally. What is the biggest mistake that happens with respect to surgical intervention? I'll say that if you have a patient that has central sensation and you think that this surgery is going to resolve that, that's a biggest mistake because surgery doesn't attack that layer of pain, the nocyplastic pain. So we need sometimes physiotherapy, eight weeks before surgery to prepare the pelvis and then you operate on them and after surgery, two to four weeks, you can restart the physical therapy. So that would be the optimal approach. The second mistake is to take out all the cysts that you know, that you see, like the no-metryomas because that can impair fertility by reducing, not fertility per se, but IVF outcomes because you reduced AMH. Because each of those cysts explain why that's the case. Because they are not actually very defined cysts, they are like pseudo cysts. So when you strip them all, you end up by taking some follicles and all sides, they are healthy adjacent to the cyst. So we have data showing that- Wait, you're saying that endometrial cysts are dragging follicles with them? No, they are like very attached to the cortical part of the ovary where the primordial follicles are. So when you take out the cyst, you do a cystectomy, you can reduce AMH by 40%, sometimes 50%. So you don't want to take the cysts out if you're trying to preserve fertility? Yeah, but that's a double-dice sort. Why? Because the presence of the cyst decrease the- They image because it's praying. Yeah, it can decrease the AMH. So shouldn't you harvest the eggs first? That's it. Okay, that's it. And the mechanism is beautiful, explained by this phantom reaction, the same one that we know, and it produces hydroxyl molecules that are very toxic to the DNA. So they end up having this so-called follicular burnout. So patients with endometrioma, they might have before surgery a lower-vari reserve. And if you operate on them, you are just decreasing this- Now, this lower-vari reserve, so I think that's one big mistake. I think maybe the third mistake would be to leave a damaged tube, a hydroxylpings just to preserve the tubes, but we know that this can reduce the IVF chances by half. So if you have a dilated tube- Why? Because the mechanism is like washing the neighbors, they are connected to the urinary virus. So you're saying even if you implant- Yeah. In the uterus, just having the damaged philopian tube can decrease the success of that- Yes, by half. By half. So there is that widely known? Yeah. Yeah, we have a cochlearine review on that. Okay. So we have this mechanical effect and also the- It's embryo toxic. Yeah. cytokines. So you need to- You need to take out that. You need to do a soap injectomy. In your practice, how much time are you spending on endometriosis, inclusive of discussions around fertility? Like how often are you operating for this? Operating? Yes. Like you mean surgery, right? Yes. Probably 20% of cases. 20% of your cases are removing endometriosis. Yeah, but you know, I have a fertility clinic, so I have the, you know, dysbias. People tend to come to me to do IVF. So- Okay. So let's pivot and talk a little bit about that. You have arguably the premier fertility clinic in- In Saupalo in Brazil. And this is a huge clinical interest of yours. What do you think is the most misunderstood thing about fertility that we haven't already discussed? Now you've already made a very important point, which is it's a disease of two people, not one. But as it pertains to the female side of the equation, you've also shared- numbers that are even worse than I imagined with respect to aneuploidian age, what else do you think is just not fully realized by a person or a couple out there that are trying to conceive? I want just to emphasize that age is the most important factor. And even doctors don't just, they just don't realize it. Because sometimes you just see the patient with the doctor trying, like they operate on them and they try to conceive naturally at 42 years old. So that's a big mistake because you're just feeding this desire of natural pregnancy that it's not that common at that age and the risks are very high. So age is probably, nobody knows that a lot. So what I do in my clinic during the appointment, I show a table. We can put in the show notes of the aneuploid rates by year after year. And it's very interesting to know that it's not linear. It's not linear. No, it's exponential. And it's not only explanation, but it's like this. We have a sweet spot. It's a j-curve. It's a j-curve. Very young patients, they can have monosomy. Oh, I didn't know that. Yeah. And we see that in other primates. We don't know why, but that's not that risky for the couple, right? Because monosomy, they don't live, right? But the sweet spot will be around 25. And even at that age. So you're saying at 20, you have a worse chance than you do at 25 because the egg is more likely to be missing a chromosome. Yeah, I would say that the risk of aneuploid is probably higher at 20 than 25. But of course. That's incredible. Yeah, it's incredible. And do you think, I mean, this is a silly theoretical question. Do you think that's because evolution is trying to optimize for 25-year-olds having babies? Yeah, that's why. More than 20-year-olds or 18-year-olds and obviously 30-year-olds. That's really saying, I want. This is a 25-year-old woman is the perfect fitness to carry, deliver, and raise a child. That's exactly what I think. But we're not sure yet about that. But that's interesting because. Do we think that that's drifted? Like do you think 200 years ago if we had you back in time, do you think it would have been lower or do you think it would have been? I don't think so. Because the mechanisms, they should be the same, right? That's unbelievable. Yeah. So that means that if you are 25 and going to IVF, not all the embers there are going to beeuploid. About 20% or 25% will be aeuploid. Even at 25%. 20 to 25% of your eggs are already in your blood. So you never are walking around fully employed? So what I say to my patients bigger is that reproduction in humans, it's very inefficient. So if you think about it, you need one egg. You lose 1,000 eggs every month. You lose 1,000 eggs? Yeah, you lose 1,000 apoptosis. But you just have cohort of like 10, 15 and of them just 1 ovulate and you have millions and thousands of sperm just for one. to go inside and produce the embryo. And you need one year to say that it's not working, right? Because infertility is not just, oh, try this month. If you're not pregnant, you have infertility, you know, you need to try much more. That's because our reproduction system, it's not that efficient. If you look into the day of like mouse or rabbits, any play rate is very low. You're very efficient at producing good embryos. And that means that when we do IVF, we are just grouping, we're just like making more embryos, but we are not increasing their quality. So if a woman is 40, you sometimes need to do much more cycles. But all things equal, if you take the 40-year-old versus the 25-year-old, once you have you-ployed eggs, are the qualities the same or other non-visible changes. So for example, we know with sperm, they're not the same. Even though chromosomally they appear the same between 25 and 50, we know that genetically they're different. And so older fathers are more likely to produce children with more neuropsychiatric, polygenic conditions. But what do we know on the eggs? That's a good point. We have data on that. There's a beautiful table showing that the clinical pregnancy with a e-ployed embryo at 30, 35, 40, and so on. It's pretty similar. But we know from the lab, if you ask an embryologist, she would say that the embryo is not that quote-unquote "bugafo," sometimes more phallologically they are different. The morphal kinetics, they are not similar. But clinically it's not that big difference. Interesting. Yeah. Would you advise a woman who's listening to this, who's 25 years old, who is in graduate school, business school, law school, medical school, pick your favorite, who still has five, six, seven years ahead of her in really, really working hard and does not want to have a child in that period of time. Maybe she hasn't even met her partner yet. But she deep down thinks she wants to have a child. But it's possible she's not going to be thinking about it for another 10 years till she's 35. So she's 25. And you're her regular GYN. Just you're doing your regular exam. She tells you all of this. Would you advise her to freeze eggs right now at 25? Not for all the patients, but I would say that it's reasonable to do an AMH, like check your reserve. But let's say she's normal. She's not a head of time. She's not behind time. She's just a normal 25 year old. But thinking about the J curve, which is the difference between being 25, 30 and 35 is significant. And she's not just from an optionality perspective. She's, she can't tell you, I'm not oh, I'm definitely going to do it by 30. In which case, maybe you could say, okay, it doesn't change much. Yeah, if she's not, if she's sure that she wants, she wants child, children in the future, I will talk to her. But the chances, you know, look at this statistic, Peter, what do you think is the the rate of patients that come back to use their own all sites, like globally? All the women who freeze eggs. Yes. You're saying how many of them never come back and touch them? Yes, of 100 women that froze their eggs. Like how many come back are coming back to do something with them? Yeah. 75. Actually, around 10%. What? Yes. 90% of women who freeze eggs never touch them. Yeah. Or because they have to get pregnant maybe. They got pregnant. Okay. Sometimes they just don't want to use that. But the sweet spot would be around 30 something, 32, 35 because the cost effectiveness of doing that is better than at 25. So biologically, of course, does it make sense to freeze earlier? Yeah. But the chances of the time you spend on it, the cost, you spend. Let's help me understand the costs. And I know it's different in Brazil from in the US. But it's in Brazil. This is all paid by out of pocket. This is so I think in the same in the US, I don't even understand. Yeah. US, I think there are some differences. Some insurance might come. Yeah. But let's talk about the cash price of doing it in Brazil. So if this 25 year old came in, said I want to go ahead and do this, what is the cost of harvesting of doing one harvest cycle? In Brazil, she would spend about $5,000 US dollars. US dollars because our currency is like 5, 1, 2, 1. Yeah. Yeah. Yeah. Okay. So she spends $5,000 US dollars to do one harvest cycle. And then how much does she spend per year to keep them in storage? Yeah. It's like $150. So not prepared to do that. Okay. So the big cost is she's going to incur that. And again, I'm just being devil's advocate. My view is if you could afford $5,000, why not do it at $25 instead of 30 just because you've capped your downside. Your downside is your out $5,000. Your upside is how many would you expect? How many you employed eggs do you expect to get out of a 25 year old per cycle? We were talking about blastocysts or angriose and they five today seven about 80% around 80 80 75 80% of the angriose there you apply. But since this is not embryos, you're not going to be fertilizing these. Yes. You're just getting an egg. Yes. So we have a, so you don't touch them. You don't. Yeah. Just freeze the M2 outside the mature all sides. You won't know until you fertilize about 75% of the all sides. They are matured. So we freeze just the mature eggs and we have some calculators to like to estimate the pregnancy rate and not only that, but the life birth rate depending on the age and number of eggs. So at the age, probably if you have like 15 eggs, your chances are higher than 80% I'll have one at least one baby, which still seems not that high. But yeah, but remember a photo of all the way to baby meaning yeah, yeah. So how many embryos and then each implantation has a rate of fall off. Okay. So so biologically, of course, that makes sense, but economically it doesn't. I think that yeah, that's just economics. Okay. The risk is pretty low. Like the risk of over-intortion and bleeding and you know, infections. It's about 1% and the main driver of that cost is the medication. The procedure is it split about equally? Yeah. One third medication. One third, yeah. One third like clinic and one third like lap. Yeah. What is the median age of women who are coming to you to have eggs frozen, but they're not planning to fertilize? Mine is 37 38. Yes, very high. Why so high? Why are they coming so late for eggs? Because I think that's just a new treatment, kind of new treatment. And because I have bias, as we're in some sort of like, you're treating the hardest cases. Yeah, probably. So when a 37 year old woman comes to you, I assume she's been trying for a while to get pregnant because she's 37, she's probably had many aneuploidic miscarriages. So she comes to you and says, look, we can't leave this to chance anymore. You're going to do a cycle. You will typically get how many ozites in her. So my infertile patient is even older, like 40. Like a social freezing is around 37. So it depends a lot on our ovary reserve. So if the reserve is like normal for 40 year old woman, what's a typical AMH for a 40 year old? It would be around one, okay. Nm per amel. And that corresponds to roughly how many eggs left depends a lot on the cohort on that cycle, which can be different between the follicular phase and the luteo phase. And that's very important from a practical standpoint because sometimes we check the ovaries, we do the anthropological count that's not fine. We wait and recheck another phase because it varies a lot. But we would expect around eight eggs, something like this. And eight eggs at 40 is not sufficient mostly to produce a new ployed angril. Oh my god. Because eight eggs, you're going to fertilize them and more than half of them are going to be aneuploid. So you might get two. Seven, 80% of them. Okay, so you might get one to two you ployed to implant. Yeah, we see that it's like a funnel. It's very important for the layperson to understand that you have the follicles. Each follicle might have one all-side. Every all-side has a chance of being matured, 75%. Every matured egg can be fertilized, and on day one present this pronucleine, we say that it's fine. - That's the M2 phase. - Yeah, after the M2 phase. And then from day one to day five or day six, which is a blastocyst, around 30 up to 60% of those day one can develop into a blastocyst. It depends a lot on the sperm quality too, and the lab, of course. And on top of that, you have the any play you rate. - Yeah, so hence the inefficiency, you're just multiplying negative numbers after, you're multiplying so many small numbers together that the outcome is very difficult. - So when the patient is freezing her own eggs, it's very important for her to know that, you know, the final step. - The final step. - Very important, because sometimes it's very sad to see a patient that is coming back, like she froze her eggs at 34, and she's coming back at 40, and she had just eight eggs, and now you thought them, and then you produced just one blastocyst, and it doesn't plan, so that's it, and now she's 40. - Yeah, which again goes back to my question of why isn't every 25-year-old woman who is unclear on her timeline? I guess, you know, it's funny, like I wonder if in countries where population growth is not high enough. So if you look at a country where the reproductive rate is below 2.1, and that turns out to be a lot of countries, and immigration alone won't solve your demographic problem. You actually need denovo reproduction. This strikes me as a reasonable cost for the government to bear. - Yeah, Japan is facing this right now. So Israel, you can do how many cycles you want, you need to produce your family. So I think from a longevity perspective, you're right, you can avoid this disease called infertility, but you can prevent that by freezing all sides earlier, but I think that's a problem of excess right now. - Yeah. - We have the technology. - Yeah. Okay, now let's talk about something very extreme at the other end of this spectrum. So you now talk about that woman who's 40, she's come back only to realize that nothing worked, but she still wants to have a baby. So right now, her only option is to use an egg donor, correct? - Mm-hmm. - Okay. In which case, she will use the egg of a young woman. She'll use the egg of a 25 year old woman, likely with her partner's sperm, and that's fine. That's a great treatment, right? That works. - Mm-hmm. - That works very, very well. But I have now heard about an emerging technology where that woman who is 40 can use her genetic material with the remainder of the egg from a donor so that she has all of the benefits of the young egg except she gets her genetic material in there, so that the donor is only providing the scaffolding and she could even use a surrogate. Help me understand that technology. - Yeah, that technology is called mitochondrial replacement therapy. So that doesn't solve the problem because the problem is in the nucleus, right? So the problem is chromosomal. I think two papers published last year in New England, New York, North Madison, by a UK group, Newcastle. But 22 patients with mitochondrial disease, remember we have like 20,000 up to 25,000 genes and 37 genes in the mitochondria, the so-called mitochondrial DNA. And for those very specific cases, they basically took out the pronucleae from the parents, embryo, fertilized after fertilization. So they have, and they want the pronucleae, they take out. And they insert in a inucleated, all-site, new, all-site that has this new mitochondrial that are normal, they are supposed to be healthy. So this solves just the problem of the cycoplasm, the mitochondria. - I see. So it is not solving the age problem. - No, got it. And this, as far as I know, is not available for infertility. But there are some clinics, I think, in North Cyprus or Greece. And they are like selling this as an egg rejuvenation that's misleading in my opinion. But you are just trying to replicate, it's like a battery swap for the egg, but you're not changing the engine, right? The engine is the main problem. - So is there currently anything on the horizon for the 40-year-old woman who wants to conceive and would like it to be her genetic material, even though she no longer has eggs, or if she has any eggs, they're not dividing correctly. - There, I think, yeah, not for that situation, but there's a clinic in the UK that is trying to freeze ovaries, like cortex, like long years before menopause, like to prevent or to postpone menopause. - Yep. - Very interesting idea, but we don't have publications on that. Actually, we have a huge line, like a huge weight list of patients trying to do that. Makes sense, but we don't have data. - Sorry, just make sure I understand that. So the analogy would be somebody would type one diabetes that gets implanted pancreatic or beta cells that secrete insulin. - Oh, tall of us, yes. - Yes, autologous. Is this her own ovarian tissue that was set aside earlier in life? - Like, at 30s. - At 30s. - So they do a partial uphrectomy. - Yeah, and you can then transplant like 45, when you are 45, and then you can postpone. There is actually a, like a math behind that. It can postpone menopause like 10, 15 years, sometimes even more. - Where do they re-implant? - In the same, like, yeah, pertenew. - Okay. - Or you could put in the subcutaneous suit. - Huh. - And so you're not only postponing menopause from a hormone perspective, you're postponing fertility. - Yeah. - Actually, that's mainly for menopause. - Okay. - To produce her own. - That's just to produce estrogen and progesterone. - Yeah. - Yeah. But for all sites, we have data over in cortex freezing. - Mm-hmm. - But the better outcomes, they come from the egg freezing. - And why would this atologus ovarian implantation or transfer be superior to just standard menopausal hormone therapy? - That's the question. I just gave a lecture last year about that. So I think because of the culture thing about menopause, right, about hormone replacement therapy after 2002, July 2002, the WHO, right? I think there's just this big misconception about menopause hormone therapy. It's much easier to just give estrogen and progesterone and sometimes testosterone than freezing the ovary and then transplanting and probably getting pre-menstrual syndrome in our symptoms during that. But we don't have data. But to your question, probably in the future, we're going to have stem cells producing new olsides. We're not there yet. - I read an article very recently suggesting that that could be five years away. What's your view on that? Are you optimistic? - Not that much. I think more like 10 years. - Why? Why so difficult? - What has to be done? Explain what it is, first of all. - I think I'm not the right person to answer that. But it's very hard to produce a neck. It's easier to produce its perm. And we don't know the consequences of that. So we need data after doing fertilization and transferring to see if those babies are healthy, they're still healthy. - We're doing this in animals right now. - Yeah. - Which animals? - I think cattle, probably. - Are they doing this in primates yet? - I'm not sure, but probably yes. - Okay. What has to be done is you have to demonstrate that you can take a pluripotent stem cell and somehow turn it into an egg. That hasn't been done yet. If you can do that, you have to ensure that that becomes crumbazomally and genetically normal in the long event. - That has been, there's a publication about that. - That you can make the egg out of a stem cell. - Yeah, but we are not sure about the consequences and the clinical benefits of the safety of the animal. Has it been done in mice? Yeah. And in mice because their lifespan is short enough, does it produce a normal phenotype? Yeah. Okay. So that's promising, but not guaranteeing. Yeah. Yeah. But that's going to be like a game changer for us. Yeah. I think when we do that, we are going to not do any more of its vacation, like frozen, we are not freezing eggs anymore, right? So just imagine that. So you're saying in 10 years, any couple of any age could potentially reproduce? Probably. I don't know if that's safe, that's going to be safe. Like, if you ask me, you are 30. Me and my wife, we are healthy. We don't have any fertility problems. Would you do IVF or try naturally? Always start naturally. And why is that? Well, that's a bit different. I mean, I think I would say for cost and just there's no reason to rush. But look, if you struggled for a year, we wouldn't hesitate to do IVF. Right. But for me, I think we are, like IVF is the first baby was born in 78. So it's actually a new technology. We can't reproduce everything that we would need to reproduce inside the tubes naturally. There are some epigenetic facts which we can control and we don't know what are the consequences. So if the couple has this natural chance, I will try naturally. That's why it takes a whole new level. The problem is, yes, you can count on stem cells. But we're going to be better to use my own old size that just froze like 35. I don't know, probably yes. Is there anything about IVF that we don't know that worries you? Like what are the unknown unknowns about IVF? Pigenetics. Yeah. Like, please. What shows up phenotypically? Probably some malformations, some neurological consequences, heart disease. Do we see this in the epidemiology? I mean, so again, people born of IVF are still very young. They're not even 50 yet. These brown is like 40 something. She's 48. Yeah. But we see definitely some signs. We're not sure about whether it's a selection bias. Yeah, that's the hard part is how do you get out? Because by definition, you're talking older parents, you're talking about more affluent access. Infertility. Infertility. There's so many confounders. And we're never going to do a randomized control trial for IVF. But there's data showing that same couple that needed IVF and then now they are getting pregnant naturally because sometimes it happens, right? That it's mainly a bias, a selection bias problem, not the technology itself. Yeah. Yeah, but it's a new, a new technology, right? So what are you most excited about in your field today? Actually, I was very excited about this new guidance from ACOG. Very simple. Because probably we're going to avoid complications of endometriosis and admiosis, especially in those vulnerable adolescents and not only treat the disease, but as like statin in longevity, you can modify the disease progression. Early. And avoid infertility. And I'm very excited about this. So we should spread this word, right? And there's one molecule called HMI 115. It's an anti-monocolonal antibody that targets the receptor of prolactin. Probably this leads to, it's in phase three trial now. This leads to less pain and less disease progression and metrosis because those lesions can express prolactin receptors. Very interesting. Maybe that's going to be the first biologic treatment for endometriosis that it's not using hormones. So like to your point that, no, some, why don't we have like medications that target the disease directly? Yeah, yeah. Probably we're getting that like soon. And yeah, I think the diagnosis is better. Yeah. Yeah, I think with this widespread, you know, ultrasonography and MRI and just the awareness of the disease, we're going to, yeah, not only diagnose and treat more effectively. Okay. So basically the final and closing thought here should be if you're listening to this and you're struggling with any symptoms that may be even remotely suggestive of endometriosis or admiosis or your partner is experiencing them. The biggest single win is getting that diagnostic window from six years in the US or seven years in Brazil down to six months. That's it. So you just have to be a bull in a china shop and demand a diagnosis and say, I'm not going to take no for an answer. I want an MRI. And if necessary, I want an ultrasound done with this correct protocol. That's it. That's it. And we're not going to take no for an answer. We're going to get these diagnoses. So we can start the treatment because the earlier you start the treatment, the better the prognosis. And you know, Peter, just to close that the cases that stay with me are not the most complex surgeries, not the difficult IVF cycles. They are those women that cry, not from pain, but during the appointment from really leave. They finally have a diagnosis. When I tell them, you know, you are suffering, I know that's real. It has a name. We have a plan for that. And you fairly listen to this and you have pain in, you know, you are suffering. Please don't take like this is normal. This is just your regular period. Please have a second opinion. And we have, we have technology for that. We have treatment for that. And we should do that. Right? Perfect way to end it. Hennado, thank you very much. I'm really appreciate you getting this message out. Great to be here. Thank you, man. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com/shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiamd. You can also leave us, review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have. And they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com or forward slash about where I keep an up to date and active list of all disclosures.