Future of Fertility and Closing Thoughts

Hey everyone, welcome to the Drive podcast. I'm your host Peter Ati. 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 a subscription. If you want to learn more about the benefits of our premium membership, head over to PeterataMD . com forward slash subscribe. My guest this week is Dr. Hanato Tomioka, a leading expert in reproductive medicine and gynecologic surgery. Hanato'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 ten percent of reproductive aged women, about two hundred million women globally , and contributes to infertility in thirty to fifty percent of cases. Adenomyosis, its often overlooked counterpart, may be even more prevalent . Yet, the average woman waits five to twelve years for a diagnosis, often because her pain has been dismissed as normal. In my conversation with Hanato, we cover what endometriosis and adenomyosis actually are , and why they're so often missed and how diagnosis has shifted from surgical laparoscopy towards MRI and specialized ultrasound , how Hinado 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, adenomyosis, or age related fertility decline , how female age shapes egg, quality and quantity , includ the steep non linear rise in chromos omal abnormalities after age thirty five , 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. Hanato Tomiope . Hanato, 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, the it's called serosa , the middle part, which is the muscular layer called myometrum, and the inner part where the embryo implants and develop the placenta, which is called endometrium . And this layer is very important because endomet riosis is a disease, a chronic disease where an endometrial like tissue very similar to the endometries 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 ten percent of reproductive women globally have endometriosis, which means around two hundred million women . And if you look into the data of infertile women, it's about thirty to fifty percent of women they can have endometriosis. So just make sure to I understand that thirty percent to fifty percent 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 forty percent of being infert ile. 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 very dynamic, 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 pertonium. Okay, like the fusor pertinium. It doesn't have it doesn't add up much, you know, we just have but we can have enometriosis on that layer and then sometimes it just infiltrates and transform to what we can say we can talk about internal and adenomyosis, like external adenomyosis. I mean. Got it. And I did want to ask you about adenomyosis 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 predict it , for example, how genetic is it and are there any environmental triggers for it? Great question. So we have about fifty percent of heritability . If you have a first degree relative with endo , you have about seven times higher chance of having endometriosis . So that's the domain. 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 bigger what we call the repetitive ovulatory menstruation . So what that means? Every time a woman is menstruating part of the menstr ual 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 correct the pelvis. Correct. So remember the fibri, like the distal part of the tubes , they are not directly connected to the ovary . They're moving around and they can pick up the osites. 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 osite is just on the surface of the ovary . Sometimes it's inside the pelvis and the cold design , but the fembraid can pick it up and then permits the fertilization inside the Issimus, right? Inside the middle part of the tube, essentially , but we know by old studies that around ninety percent of women have this retrograde menstruation, which is amazing. So you would think, why is that then just ten percent have 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 enormitral 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 two hundred years ago , a woman back then would have one hundred observatory cycles in their lifetime . Menarchy was about at the age of sixteen, now it's twelve . First pregnancy around twenty , now thirty 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 know many times ovulated. If you compare that women to modern women , it's about a fourfold increase in this retrograde ovulatory 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 have nowadays . And that's probably the best proxy for us to 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 two hundred years ago a woman, would have had a hundred 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 and by 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 four hundred 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 macrophagias that need to come and sort of take care of it can't always do the job. So presumably you're creating anitus for infection or something that the immune system is upset about. And if you look into the mechanism here , we have this estrogen dependence , the metrogal lesions they produce by themselves estrogen. So they overexpress aromatase . There's an upregulation 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 the action of progesterone that is very important to counteract the action of the estrogen. Yeah , 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 as she's ovulating, estrogen is increasing the thickness. The progesterone surge causes the shedding. That's it. So remember the follicular like the late follicular phase . Endometrium people who works with IVF know that a lot, right? Because we are aiming to look at the endometrium at the final phase of the follicular part. So endometrium is about to like eight, ten millimeters at that point . But when you have the progesterone, it opens the implantation window. So we have this so called decidualization , lipids and secretar face comes in . And then at the ultrasound, it endometries like white , not anymore black . And this is very important for the pregnancy. But if there is no ambient inside the uterus , the corpus logum, it has like twelve to fourteen 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 treat ment pillars giving progesterone or progestines to this patients . But endometriosis lesions, they have this progesterone resistance what does that literally mean ? You're saying that the actual endomet rial cells, which I assume are like another endothelium ? Yeah, because it's outside the body. Yeah, it's like trauma and it glands like that resembles the endometrial lining. Okay. And they have progesterone receptors. Yeah . 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 you need much more insulin or progesterone to produce the effect s. 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 KRS PIK three , PINK Kinase, right ? So they resemble they act like cancer , especially in deep infiltrated endometriosis and adenomiosis up to thirty seven percent of those lesions they express this oncogenes , so they grow independently But do they have metastatic potential? No, no . Why is that? So in sense they're benign tumors. They are benign tumors . They have the machinery to grow, like to grow really fast , but probably due to the lesions and the fibrosis outside the lesions, they cannot metastasize. That's incredible. Yeah, it's like putting a one thousand horsepower F one engine into a golf cart. You just have the machinery, but you can't go further. This might be a good time to explain adenomyosis, which can clinically be confused with endometriosis but has some distinct pathology. So maybe tell us what that is. So adenomyosis, I think is the mist disease because everybody talks about or should talk about endometriosis, very prevalent. But adomyosis actually is more prevalent probably up to twenty or thirty percent of women have saying about ten percent of all women in reproductive age have endometriosis? Yes. Okay. Yes. So adomiosis is essentially the presence of this endometrial like tissue inside the myometrium. 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 look into the studies of single cell transcriptomics, Linda Judas last year published one beautiful paper about this , they don't have the same molecular pathway. So they are different diseases. And the mechanisms 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 a over express aromatase . So it's pretty much the same, but there are different diseases and of course you have cure and osis if, you do a hysterectomy, you take out the disease. It's just a disease in the uterus . Endomet riosis , it's outside the uterus. And what is the overlap in women who have the other and both. So obviously twenty percent have one, ten percent have the other. How many have both? Difficult to be precise here, Peter, but we think up to seventy percent . Up to seventy percent seventy percent of endometri osis patients they might have some type or some degree of adenomyosis and that's very important for the infertile couple . So the mechanism in adenomyosis is the so called TI R. So it's tissue injury and repair . So essentially the endometries going inside the uterus , like breaking that junctional zone, which is a thin layer between the endometrium and the myometrum and it's going inside and disrupting and like breaking the lines and producing those islands of cysts and echogenic buds that increase the volume of the uterus and makes it very soft to the touch. During surgery it can palpate the 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 do when you have a miscarriage, when you have c section , so you break the line mechanically . When you do curtage , you break that or even hysteroscopy for legomyomas or polyps, you can break that acutely and endomet rium 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 it's that sort of inter actopia , but we have another type of adenomyosis . There's not like it's not consensus, but some authors they call it external endomiosis in which the endometriosis, the deep infiltrated endometriosis is going inside the myometrium from the ser osa to the myometrium and now we have not only endometriosis but endomiosis . There are some authors that think there is it's not correctly to say that it's adenomyosis. So mainly adomiosis 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 de novo after menopause or is it all the same sort of presentation? So traditionally, adenomyosis was called a disease of the women at forties because she had pregnancies, sometimes sexions and cortage and miscarriage . But now we are seeing younger patients with adenomyosis , 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 nuanced. So what is the if you were taking a board 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 a UTI ? Is it akin like what would be the closest thing that someone would understand who doesn't have it? I like the framework of the sixties of Eometndrios is. The first D would be dysmenora, which is pain during menstrual period . So they have this lower abdomen. This is not cramping, this is act anual pain. Pain. Okay. That sometimes the just pain medications don't resolve it completely. Sometimes those patients they go to the ER to receive intra venous intra intravenous medications. Intravenous medications . And they have the secondary is deep dysperoonia , which means pain during intercourse, especially in the profound posterior wall of the vagin a . Thirty would be dysk ia or pain during bowel movements , especially during the uterus is how close to the rectum. It's close. It's adjacent. Yeah. Adjacent. And sometimes we can have lesions right there in the septum. Fourth D would be deseria, like pain during urination, especially cyclic pain, usually during the menstrual period , we can have also like 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 will put the D like 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 with out any relation with the cycle . So you have a lot of this myriad 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 adenomyosis based on symptoms. So is that possible? Yeah, yeah. Adomyosis mainly sometimes the patients are asymptomatic . the way By, around ten percent 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 adenomyosis. So fibroids they are very common up to seventy or eighty percent of women will have one fibroid . Mostly asymptomatic. They are benign nodules inside the uterus can be just right at the end of medium , so called submucosa , inside the mimetrium, intramuscular or on the ser osa, like subcirosis . And they can get very, very large, right, nodules. Sometimes it disrupts the it can disrupt the anatomy of the uterus, especially the endometrial cavity and provokes miscarriage and they can bleed too, especially the sumoglosis . We classify them by the International Federation of Gynecologies and Obsetracians by zero up to seven depe,nding on the classification up to eight. And the zero, one and two, there are submucosis. So they are the problematic for fertility and for bleeding. And that's counterintuitive to me. Why would the submucosal ones cause more issue than the ones that are closer to the lining? Actually the submucosal they are the closest to the lining. , zero will be like just in the endometer inside the cavity. Okay . One is mainly inside the cavity, but a part is in the myometrium. Then two is like mostly in the myometrian and a part is inside the uterus. And the number three would be like just touching the endomet rium. Okay, got it. And then as you go all the way out to the cerosa, it gets lower and lower or higher and higher number but lower and lower severity. Yeah, okay. Probably not severity, but yeah, clinical implications, right? Okay . Okay, so the woman with you said ten percent 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 with intercourse, 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 pair because depends on the phenotype and the intensity of the disease . So we have if you just have one layocyst, myometrioscyst, which is a presentation of adenomiosis, probably these patients they don't have any symptoms at all . But if you have like a very diffused adomiosis or even an adenomyoma, which is a nodule of adomiosis , they They bleed it out. It's very painful especially the period is very painful. And again, might sound like a dumb question. What is causing the actual pain . Great question, great question. Actually we have three types of pain in endometriosis peter. That's I think that's the most complicated part for us gynecologists to understand because we're not trained we're not trained for that . But there's the so called nosiseptive 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 nosiplastic pain where the nerves are infiltrated by the lesions and they can have burning sensations sometimes on their legs and the back . And here medications can help, sometimes gabba pentine and SNRIs, right? Surgery can remove some of those lesions . We do this technique called nerve pairing . Very difficult sometimes impossible to do, but we can try . And the third layer and most difficult to treat is the nosiplastic pain when we have central sensitization . 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 endometriosis lesion is 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 , you know, triggers the alarm . And even removing without the burglar, without, you know, the doors are locked, but you need to you need a different specialist heres. 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 endometriosis is one of the main causes of this central sensitization. And it's very important for us to treat even empirically nowadays, the ACOG just published this march twenty five twenty six , new guidance on endometriosis diagnosis . And it allows us to not only diagnose clinically, but treat it . Because if you have just based on clinical symptoms, right? If you have a patient that has pelvic pain, dysmannarea, dysparoonia, and so on , you can give her a medication to avoid this disease burden after years later. What's the typical age of presentation today for endometriosis? I don't think we have a typical presentation anymore. We are seeing endometriosis in teenagers. Look at this data. Up to fifty and seventy five percent of teenagers with pelvic pain , they have endometriosis. Three quarters they have endometriosis. Like what percentage of teenagers have pelvic p ain? I'm not sure. Not sure. Presumably it's like five percent or I think a little bit more. A little bit more . Yeah . So you are seeing teenagers presenting with endometriosis . And if just normal again, going back to the ideology 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 one hundred . So what else do you think? Do you think there are some health factors? Do you think it's like 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 We don't have definitive data here, but probably even microplastics . We have some studies about that . Pollution. Oh, you mentioned pollution, yep. Yeah, diet, probably you know, this sad diet that you talk talk . Poor sleep because remember poor sleep the immune system. Yeah, immune system regulation. The macrophages they just jump from one to the other type and this may increase the risk of endometriosis. So we're 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 anal ogy 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 path. So a woman presents to you to a gynecologist with a story and actually how uniform is the understanding of this among st 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 no, because if you look like the diagnosis, the layper five to twelve years depending on the country . I believe in the US is around six years. And in Brazil ? Brazil around seven years . So from the first symptom up to the diagnosis , can you imagine like five up to ten years No, I can't understand that. So that means that for a period of five 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't go to school . They miss school, sometimes they miss work , they cannot like properly work . So we have the estimate cost is around eighty to one hundred twenty 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 misleading. 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 im aging 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 leaparoscopy, right? Which 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, insufflate the abdomen, put cameras inside. And this is a surgical proced ure. It requires general anesthesia . And I guess the rationale for doing that was we are looking for endomet rial tissue inside the abdomen. So that's as good a place to as 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 twenty five years ago. Okay . So if you for us in Brazil, the specialized ultrasonography is a very good exam . We have we have Dr. Lucia Nanasham ier, who's now in Boston, the Mass General . Manuel , 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 not just whitecopy. Yeah, like much more like simple. Okay . You have this enema in one hour before the exam and no residue diet . But that simple protocol with gel inside the vagina . So you can look into small les ions and the bowel and bladder , and you can even see the layers of the bowel. So it's a beautiful exam . But that started around twenty five years ago . And that's not widespread yet. I know that I was just talking to Lucillana this day 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 U. S. mainly is MRI MRI and ultrasonography they have very high sensitivity , about ninety five to ninety eight percent and very high spe cificity too. But for superficial lesions, just let me go step back. We have three types of three phenotypes, right? The superficial lesions, the deep infiltrated endometriosis and endometriomas , the cysts of endometriosis . So for those superficial lesions, ultrasound sometimes it means you say superficial, you mean superficial away from the endometrium closer to the peritoneum? Actually pertineum, but deep within the perineum. Just sitting right on top. On top of the pertineu. Yeah, 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. But let's assume you can put air into there and blow it up and separate everything . You have bowel 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 perineum, you would see the uterus, you would see the ovaries, fallopian tubes, fallopian tubes between them. The ligaments and is the most common place you're going to see these endomet rial deposits situated on top of uterus fallopian tubes ovaries? Right behind it . Yeah, right. Behind the uterus the ligaments, like the so called uterosacal ligaments because just of the anatomy and gravity, you know, yeah most lesions they, just stay , 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. eighty percent on the right side because of the anatomy of the sigmoid. So it blocks the left side mainly . But yeah, the bladder ten to twelve percent of endometriosis patients, they might have urinary tract lesions , but mostly it's what about between the rectum and the uterus? That's rare because the space is too tight. So it needs to go inside from the uterus hiccoral ligaments from the like behind the uterus and go to the septin. So that's rare, but that's very hard to treat because sometimes it goes deep into the muscle floor 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 different from any normal transvaginal 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, Peter. If you do a normal ultrasound and you don't have an ometriosis 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 , if you have dysmanoria, dysparney, and so on, and you do a normal ultrasound , that's one of the problems. That's very, very low sensitivity. Very normal ultrasound. Yeah, we see that a lot. But we have we have three layers of ultrasound . This is the normal one under a regular the augmented ultrasound with the sliding sign . So you can use the probe to push the posterior wall of the vagina and see if there is any adhesion there . So and sometimes even without bowel prep, it's better than the normal ultrasound . But the best would be the detailed protocol with an expert with this bowel prep to look into the pelvis like and who does this? A radiologist or the gynecologist? A radiologist.s Sometimes 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? Would be something close to this arm. Okay, so basically like an inch in diameter. Two centimeters in diameter. . 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 pro be to look further or you trying to elicit to move the uterus. Okay . So you can see this sliding sign, right? MRI cannot do that right? It's static. It's static. Yep. And the probe can see one hundred and eighty degrees plus in front. Yeah . Okay . So then when you're and again, I'm still a bit unclear as to why the bowel 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 on the other side. Yeah. Okay. Or liquid. Yeah, we need liquid. Okay . Air is not good for ultrasound. Yeah. Yep. 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 right . What is the official name of the protocol? It's called a detailed protocol for endometriosis with BauerPrap. 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 the woman at MGH. Yeah, yeah, yeah. Yeah , one of the best. Yeah . And in the US it's mainly MRI , but they do the augmented ultrason ography. Okay. So we can do that the second layer , but just a few clinics in the US, probably Mayo Clinic, a Cleveland Clinic , they are doing the protocol for endometriosis. And why is that? Because it takes lots of time, like one hour exam. So you need to allocate the person and also you need, of course, the machine is not available all the time, right? 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 spe cificity. The drawback is you don't get the dynamic phase. But you don't, yeah, but it's not that good for bowel endomet riosis. 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 for me is essential. You would never operate without the surg thisery without . Yeah, we have the privilege in San Paulo to have access to probably five or six very good radiologists that do this type of five or six people in one city that can do that. Sain Ptaulo is one of the best cities to do probably the best city. Italy is also a good country for that , but it depends on people, right? So Monor Lendo, Luciana Chamier, and Luisinico, 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 is. And that's brilliance. Brilliant. Yes. That's the brilliance. But that's very rare, unfortunately. So you made a very interesting point , which is you can make the diagnosis with MRI with one blind spot, which is rectal . Now let's talk about treatment . So I will just start to interrupt just to be clear, MRIs is better for extra pelvic lesions such as diaphragm. Yep , and the lateral part of the pelvis where the ultrasound loses its ecogenicity. Yes. So for instance, to see the uritar and to look for the deep pelvis , the nerve infiltration, it's better than the ultras . So do you do both? Sometimes, mostly both. Yeah. And what's the sequence of MRI by the way? Is it special? Does it require gadelinium? No. No, so non contrast, no T one, T two . They just usually put some gel inside of vagina. T one to two, that's it. Okay. So relatively easy MRI. Yeah , probably a twenty minute scan. Yeah, but there are some pitfalls, like movements , you know, bowel movements. The patient cannot stand too much, you know , 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 we have another section. If she's trying just to get a better without pain and not wanting to conceive now , we have much more options. Okay, so let's start with that. Let's start with twenty 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 twenty . How is your ovarian reserve A maj entrophic 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 entrophological count and even the MR MH . And how's the pain ? Like if she had 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 Niodi like a marina or kylinum In addition to an oral contrast we tend to use just one. Okay. So merina is not good for cysts because it doesn't suppress the ovulation, right? So if the patient has like no endometrioma, you can use either a merina benefit is like five years of treatment. And a marena is progesterone coded. Why would you use a Merena over any IUD? Because you need the progesterone action . You're trying to suppress endometrial hyplasia. That's it. And to like to avoid menstruation . Okay. Menstruation. Yes. So in other words, a regular IUD doesn't necessarily suppress whereas a marina. Just an inflammatory event just for consideration for misconception. Yeah . Okay . And do you all things equal in this example I gave you. So twenty 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 Merena and the oral contraceptive? That's a good question. If she doesn't have myofascial pain, which is like contractions in the muscle part of the pelvis . And merine is a good option. So no endometriola, no myofascial pain. Merene is a good option . But sometimes they just don't want to insert a merina, right? So you can start with a pill , a progressin only pill like Norethendrone or Dianajes or Desog o, or you can use combined contraceptive pill, like the traditional ones . Estrogen progesterine. Yeah, ethaniol estradiol or just estradiol plus progesterine. And you don't use a low dose. You don't use a low low astin or you do. Yes. We prefer using the lowest effective dose. Yeah, because remember astrogen can activate , it can activate the lesions. So it's better to use the low dose . But the data 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 method or we can plan 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 going to recur endometriosis 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 cutting out exciting. And are they that visible to the eye? Yeah . Most of legions 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 recurring. Think about how different this is from cancer , right? Like endometriosis presents like metastatic perine al cancer . And no one 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. 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 it's she's just going to present with what you didn't see? Yeah Yeah., that's that's the point. Yeah. Sometimes even with a good surgery exercising all the lesions, if you don't use a medication after surgery , recurrence rate is around ten percent per year , especially in endometriomas. So it might be that surgery doesn't cause recurrence. It's just that surgery is not completely 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 me asure this or is it just it's a clinical diagnosis? We don't have it. Yeah, we don't have it. And remember, they produce aromatase, they produce their own estrogen, like their own fuel to keep growing Even so we don't have like a chemo for endometriosis . We just have this ovulator 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 marina after a surgery, recurrence rate is eight percent lower to place bo. So it's better to use something after surgery. So coming back to that patient with the patient twenty years old , probably she's going to 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 seven years ago by Charles Chapron, a French group that caused the endometriosis life . What that means is 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 I diabetes and so on . But we're mainly doing just one appointment, one surger y, or one medication and go. We're not thinking about the life , like what's going to be like in five, ten years , right? So we should change the mindset on that . Okay Okay , let's now consider a woman who's in her late thirties , 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 medical therap y because remember if she doesn't want to conceive, she needs contraception . So we could use a combined pill or progestine. In Brazil we have this dienogest which, is a very good protestine for endometriosis. In the US we have the natiza . Natis is like estrogen estrodioplus dienogest , but you need to use only the active with diamondoges . There are twenty two 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 a marina. Okay . So now let's go same question. thirty six 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. Controlling pain. That's right. But sometimes they present with both. Yeah, pain, plus infertile . So this patient we have a series of questions that remember, infertile is a couple's 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 like sperm analysis and you need to investigate other factors that not only endometriosis can impair infertility . So you need to ask requests a karyotype and some other examples like a historosopingogram. So let's say you do the fertility workup and you do not see any evidence in the mail 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 past. Is that a does that is that consistent more with maternal age? Yes. Okay . So does how does the 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 . So the tubes are compromised so they can't pick up the occipites or they can permit the fertilization inside the tube and transport the embryo back into the urus. And surgery can fix that sometimes if the tubes are not too damaged, but we have some adhesion's not too much, but you know, you can do that by laparoscopy or robotic surgery . But it depends a lot on the couple . If male factor is okay , if age is okay and the couple just want like one child , probably this thirty six year old woman, she has time to do that . And if she doesn't get pregnant after one year of surgery and just to make sure I understand how the surgery you're proposing is a laparoscope procedure where you attempt to remove any at all adhesions and just doing that , the hope is that the fallopian tubes become less dis paraged. And restore the 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 endometriosis and non endometriosis pelvis. For instance , we have C reactive protein, IL six, CNF alpha, but clinically , it's mainly anatomical problem, right? 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 the utopkandometrum is also dysfunction al molecularly . But clinically, not that much. Why is that? Because we have beautiful data and papers published like twenty years ago that compared women without endometriosis don't oral sites, so good quality embryos and they transferred the embryos, the implantation rate, miscarriage rate, and light birth rate were pretty much similar . So which means that clinically , endomet riosis probably doesn't impair implantation . And that's very important for IVF too , because if you have a frozen embryu,ous you do IVF and you freeze all the embrus . If the patient has endometriosis , does she benefit from surgery before doing the frozen embry transfer? Probably not. But if she has adenomyosis , she will probably benefit from doing the hormonal suppression because you cannot operate on adenomyosis mainly just the ad enomyomas. They are not that common , but we cannot treat the uterus unless you do a history . Yes. So in other words, the only women who can be relieved surgically from adenomyosis or women who no longer want to conceive because you're going to do a hysterectomy . Do you do the oupherectomy as well? And the subject depends on her age and and reserve, but we always do the sub injector. You always take the tubes out when you take the over the uterus now. Yeah. Great. Yeah. Is that standard of care? Oh yeah, there's no gynecologist that could ever leave tubes. Yeah. You know that they should. Yeah, they should . Yeah. 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, chromosomally normal , morphologically perfect embryo and you transferred it, it had the same rate of failure as the woman as the woman with endometriosis' own egg, correct? No . If you if you are looking just for recipients of donor eggs , one group has endometriosis . The other one is no endometriosis confirmed by laparoscopy. It's very important because mainly studies are very heterogeneous. And they mix and they just don't know if the patient has adenomyosis too . So my opinion is that the missing factor is adenomyosis . 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 . You understand that? Yep. So but if a patient with endometriosis is doing IVF , she will probably have less ocytes, less mature occytes and less embryos to transfer , which means that she needs more , 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 look into the data, just ask , I've had patients with endometriosis or without endometriosis, is there any difference in quality ? Probably not. . Even any play rates they, are similar . Because you're matching for age. That's it. Yeah. Age is the proxy for chronic nervologis, yeah. Okay . So in the case of this woman who's in her late thirties , 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 going to offer both options, but IVF is the way to go here because up to thirty four , the difference in between a blastocyst with thirty one or thirty four years old in a patient that is thirty one or thirty four is not that different . It's about thirty five percent of anuploty. About that . If you are thirty is that high? Yeah . A thirty one year old woman has a thirty five percent chance of anuploty? thirty to thirty five . Almost one third of glasses they are any bloody. I mean, I just don't think of thirty one as old . Yeah , I know . I think I almost think of that as prime reproductive age. Yeah, prime time will be like twenty five up to thirty because it's very fall. So it falls off very quickly thirty. Especially after thirty five. And thirty five annually around forty percent , around forty and thirty eight around sixty percent , forty, around seventy percent , forty two around eighty, eighty five percent . So it rumps up . And so that's very important. So if you draw I want to make sure you and I are talking about this very casually, but I want to make sure the listener understands what we mean. Anyuploidi 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 tricomi down syndrome, which is what Tricomi twenty one. Yeah. Yeah. So the definition is like anyploy is an abnormality in the number of chromosomes . So we have forty six x , a female or xy, a male . But so the normal way would be like thirty three chromosomes from the egg, x and thirty three from the sperm. X or Y, right ? So if you do the math will be forty six , but three and twenty three. Yeah, twenty three sorry, twenty and twenty three . So forty six again . But if you have like problems in the egg , because essentially anyployee they come from . Yep, maternal like ninety three and ninety five percent they come from the Ow side due to errors in meosis . So they don't split the chromosomes and now you can get monosom , one less or tricomy. As you said, they're the most quote unquote dangerous because those babies can live, they can have the disease. Monosomy is not we don't have compatibility with life, just the monosomy of x, which is term inal. So mainly we're having an implantation failure problem, so infertile and that's invisible to the EXMs, right? So a thirty year old woman with normal exams can get pregnant. Why is that? Because she's thirty eight . Most ambros they are not normal at the time . And we can have also miscarriage risk here . Okay , so you're going to 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 like two ways to route here. First one would be to go directly to IVF, then freeze the or occipites 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 get that big. Yeah, that seems massive. Yeah. I have a patient now she has twelve centimeters in one side and eight centimeters in the other side . Is the size proportional to the symptoms? No , no. So it's not because you tell me that, I would assume this woman can't leave her house . Like that would seem debilitating, but no, that's necessarily 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 all because it doesn't match the severity of the disease. It's classified from 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 fertility . So that's a problem. So an ASRM four would be like very severe disease, but she can be asymptomatic while stage one patient could be like at their homes just having pain and so on. So that's a problem we have. But we have like talking about classification and scoring. We have this enemyosis fertility index , which is a score based in some you know , we give like zero to depending on the quality of the tubes and the female and the ovaries after surgery . So you can predict rates, the pregnancy rates after surgery . So if the score is high, like nine or ten , they have almost sixty five percent 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 subpingectomy , 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. Main indications are large endometromas , pain . If the quality of life is not good, you can operate on them , and small bowel lesions that can obstruct and sometimes urital involvement , which can lead to kidney function loss . Actually, I had a patient with she had anphractomy, left nephractomy due to endometriosis in the uritar , like silent disease . Most of you developed hydroonephrosis? Hydronephrosis, and the urologists performed anphectomy . Oh , yeah. So those are the red flags those are the red flags to perform surgery even without symptoms . Like appendix is important too because sometimes it just mimics neurindocrine tumors . Yep . It's essentially the same phenotype. Wow. And small bowel and ur m , you need to operate on them. Okay . Let's talk about a thirty two 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 adenomyosis . What can you do to help this woman? That's very common. A very good example, Peter. So if she still has ambrios frozen? Yes, let's assume she still has so she has three embryos still frozen. Two of them, you know, she got a lot. She had a decent reserve, but two have failed and now they don't want to waste anymore without knowing what's going on. So that's why they came. So she has ambrils that got frozen and you can perform if she didn't do that yet , GNRA analog or agonist use before the transfer. What that means that you can treat adenomyosis with medication , suppressing the ovulation and suppressing the astrodio levels so it can produce like a menopause symptoms if that's the side effect . But we have data showing that this can increase implantation rate , but decrease miscarriage rate and increase light birth rate. So where does that work? You are treating the uterus , right ? So estrogen can triggers atomiosis lesions, can just like endometriosis. Just like endometriosis . And if you use gener ation antagonists, we have now in the what are the preferred ones ? We prefer , like we have much more data with analogs the agonists . Lupron , it's called the Goser oline . They are injectable , subcutaneously, monthly, right? So two to four months with this, and then we transfer the embryo using just tiny levels of smallest amount of estrogen. Yes , and high amounts of progesterone . Okay . So that's the strategy. Nowadays , nowadays we have the antagonist, the oral antagonists in the U. S. they are very expens ive. They are called allegolicks and religolics , but they are oral medications. We had just one paper published last year that compared the use of antagonist versus agonists and they're pretty much the same . Here we have less side effects. They're very expensive I think around one thousand dollars per month . So in Brazil we don't have these medications , we mainly use the agonist . And by doing that, we can achieve similar rates of pregnancy and miscarriage as patients if she didn't have endometriosis. Adamomyosis, sorry. Okay , so you're going to go four months. By the way, it's not clear to me why an agonist and an antagonist both work . Oh , both produce a lower level of estrogen. So mainly is the initial mechanism, the molecular mechanism in which the agonist can do a call we call this flare up effect . So it occupies the receptors and it triggers a flare up of FSH and LH and then can lead to ovulation . But after two to four weeks of medication , then you down regulate the receptor and then you have this suppression horm,on al 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 like 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 in volume . But sometimes the lesions they are there. 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? Six to eight weeks. Oh wow . Yeah, 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 angerous. And okay, so then you give her four months of treatment, but you said you don't really shrink the adenomyosis. Morphologically, not that much, but chemically you can chemically yes, yeah. 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 prem ature 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 endometriosis and adamiosis, they can increase the risk of pretern birth, like preclimp pre aclimpsia and small for gest ational age , c section rates . So if you're speaking to this woman you'd go through all of this , you would say to her look,, if you were a thirty two 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 thirty percent less with AMYosis? Wow. But 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 like the surface where the embryo is going to imply. 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. Yeah, the dis alization, the progesterone resist ance, the contractions in the junctional zone , and the ur as sometimes it just you can see even yeah, yeah the hypertrophic. You can see the contractions sometimes in an ultrasound. Are there drugs in the pipeline that are trying to address the progesterone resistance ? No, I'm not going to say no. It seems like that would be an interesting area of study. Yeah . 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 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 a progesterone receptor inside the cell, what creates the resistance ? Seems that that would be one opportunity . Yeah . Yeah, probably . But we are now just you're just giving gesture. Jesus. If that woman who was thirty two 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 during 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 adolescent or even a young woman earlier, we can avoid forty percent of the lesions or the disease burden . So yeah, probably yes, 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 like invests fifteen times more dollars on diabetes than endometriosis . But an endometriosis patients might cost around sixteen thousand dollars per year while a diabetic patient would cost twelve thousand dollars 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 that well, actually let me give you one more. So let's take another one where a woman is thirty 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. That patient no because she's gonna 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 medic ations and the medications they are mainly contraceptives by nature, right ? So after you stop the medication, you just lost some time, you know . 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 surg ical intervention What's the patient selection mistake? I would say that if you have a patient that has central sensitization and you think that this surgery is going to resolve that. That's the biggest mistake because surgery doesn't attack that layer of pain, the nosiplastic 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 cs that you know that you see, like the endometriomas because that can impair fertility by reducing not fertility per se, but IVF outcomes because you reduced AMH . And because each of those cysts explain why that's the case? Because they are not actually very defined cysts. Okay , like pseudo cyst . So when you strip them out you end up by taking some follicles and all sides that 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 AMAG by forty percent, sometimes fifty percent . So you don't want to take the cysts out if you're trying to preserve fertility . Yeah , but that's a double dice . Why? Because the presence of the cyst decrease the AMH can decrease drainage . It can decrease the AMH. So shouldn't you harvest the eggs first? That's it. Okay, yep, that's it. And the mechanisms is beautiful, explained by this phantom reaction, the same one that we know . And it produces hydroxyl, you know, molecules that are very toxic to the DNA . So they end uped having this so called follicular burnout . So patients with endometrioma they might have before surgery a low ovarian reserve . And if you operate on them, you are just decreasing this now that this lower variable reserve. So it's I think that's one big mistake . I think maybe the third mistake would be like to leave a damaged tube , a hydros pins just to preserve the tubes . But we know that this can reduce the IVF chances by half . So if you have a dilated tube, because the mechanism is like washing the nebrus , like they are connected to the uterus. So this you're saying, even if you implant in the uterus, just having the damaged fallopian tube can decrease the success of by half by half. So there's that widely known. Yeah, yeah, we have Cochrane review on that.. Okay So we have this mechanical effect and also the it's embryot ic cytokines. Secret down in we need to take out that you need to do a soap injatomy . 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? Yes. Probably twenty percent of cases. twenty percent of your cases are removing endometriosis. Yeah. But you know, I have a fertility clinic. So I have the, you know, this bias . People tend to come to me to do IV Okay, so let's pivot and talk a little bit about that . You have arguably the premier fertility clinic in Sao Paulo 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 anniuploidy and 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 forty two 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 annually rates by year after year . And it's very interesting to know that it's not linear 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? Yep. But the sweet spot will be around twenty five . And even at you saying at twenty , you have a worse chance than you do at twenty five because the egg is more likely to be missing a chromosome. Yeah, I would say that the risk of annual plotting is probably higher at twenty than twenty five . 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 twenty five year olds having babies More than twenty year olds or eighteen year olds and obviously thirty year olds. That's really saying I want this a twenty five year old woman is the perfect fitness to carry , deliver and raise a child? That's exactly why I think, but we don't we are not sure yet about that . But that's interesting because do we think that that's drifted ? Like do you think two hundred years ago if we could go back in time, do you think it would have been lower or do you think? 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 twenty five going to IVF , not all the ambros there are going to be Uploi . About twenty percent or twenty five percent will be anuploy , even at twenty five twenty , twenty to twenty five percent of your eggs are already . So you never are walking around fully euployed. So what I say to my patients speaker is that reproduction in humans , it's very inefficient . So if you think about it, you need one egg, you have just you lose a thousand eggs every month . You obviously make one. You lose a thousand. Yeah, you lose a thousand apoptosis , but you just have a cohort of like ten, fifteen , and of them just one 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 like, it's not just oh try this month. you If're not pregnant, you have infertility . You need to try much more . That's because our reproduction system it's not that efficient . If you look into the data of like mouse or rabbits . Any pulate urine is very low . They'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 ambros, but we are not increasing their quality . So if a woman is forty , you sometimes need to do much more cycles . But all things equal. If you take the forty year old versus the twenty five year old , once you have have euploid eggs, are the qualities the same or are there other non visible changes? So for example, we know with sperm they're not the same. Even though chromosomally they appear the same between twenty five and fifty , 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 exact same? That's a good point. We have data on that. There's a beautiful table showing that the clinical pregnancy with euployed embryo at thirty, thirty five, forty, and so on. It's pretty similar . But we know from the lab that if you ask an embryologist , she would say that the embryo is not that quote unquote beautiful. You know, sometimes morphologically they are different . The morpholog ics, they are not similar , but clinically it's not that big difference. Interesting. Yeah, yep. Would you advise a woman who's listening to this, who's twenty five 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 ten years until she's thirty five. So she's twenty five . She and you're her regular GYN, just you're doing your regular sort of exam. She tells you all of this. Would you advise her to freeze eggs right now at twenty five? Not for all the patients , but I would say that it's reasonable to do an A . Like check your reserve, right? But let's say she's normal. She's not defit, she's not she's not ahead of time, she's not behind time. She's just a normal twenty five year old , but about the thin Jking curve , right, which is the difference between being twenty five, thirty and thirty five is significant. And she's not just from an optionality perspective, she's she can't tell you , Han, Iat'mo definitely going to do it by thirty. 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 ren in the future , I would talk to her, but the chances , you know, look at this statistic, Peter , what do you think is the rate of patients that come back to use their own oil sites? Like glob ally. All the women who freeze eggs. Yes. You're saying how many of them never come back and touch them? Yes, of one hundred women that froze their eggs. Like how many come back are coming back to do something with them. Yeah . seventy five . Actually, around ten percent . What? Yes. ninety percent of women who freeze eggs never touch them. Yeah , or because they got pregnant they got pregnant . Sometimes they just don't want to use that . But the sweet spot would be around thirty something, thirty two, thirty five , because the cost effectiveness of doing that is better than at twenty five . So biologically , of course, does it make sense to freeze ear lier But the chances of the time you spend on it, the cost you spend help me understand the costs. And I know it's different in Brazil from in the U. S., but I assume in Brazil, this is all paid by out of pocket. So I think in the same in the US, I don't even understand . Yeah, U. S., I think there are some differences some insurance might come. Yeah. But let's just compliment Let's talk about the cash price of doing it in Brazil. So if this twenty five year old came and 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 five thousand dollars. US dollars. US dollars because our currency is like five yeah . Okay, so she spends five thousand US dollars to do one harvest cycle . And then how much does she spend per year to keep them in storage It's like one hundred and fifty dollars compared to the 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 five thousand dollars , why not do it at twenty five instead of thirty ? Just because you've capped your downside. Your downside is your out five thousand dollars. Your upside is how many would you expect? How many euployed eggs do you expect to get out of twenty a five year old per cycle? We were talking about blastocysts or embryos in day five to day seven, about eighty percent . Around eighty eight seventy five, eighty percent of the embryos there euplied. But since this is not embryos, you're not going to be fertilizing these. Yeah. You're just getting an egg. Yes. So we have a little So gram. You don't. Yeah. Just freeze the freeze. The M two O side, the material oxide. You won't know until you fertilize . About seventy five percent , seventy five percent of the all sides they are matured . So we freeze just the mature eggs and we have some calculators like to estimate the pregnancy rate and not only that but the lifebirth rate depending on the age and number of eggs . So at that age probably if you have like fifteen eggs your chances are high er than eighty percent of having one at least one baby . Which still seems not that high, but yeah. But remember a photo but that's all the way to baby. Meaning. Yeah, yeah. So how many embryos? And then each implantation has a rate of fall off, et cetera. Yeah . Okay . So biologically, of course, that makes sense . But economically it does. Yeah, that's just economics . Okay . The risk is pretty low. Like the risk of over intrusion and bleeding and infections, it's about one percent . And the main driver of that cost is the medication, the procedure , is it split about equally? Yeah. One third medication, one third procedure. One third like clinic and one third like lab . 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 thirty seven, thirty eight is 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 control you're treating the hardest cases. Yeah, probably . So when a thirty seven year old woman comes to you, I assume she's been trying for a while to get pregnant because she's thirty seven , she's probably had many anuploidic 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 ocyes in her hand. So my infertile patient is even older, like forty. Like a social freezing is around thirty seven . So it depends a lot on in reserve. So if the reserve is like normal forty year old woman. What's a typical AMH for a forty year old? It would be around one nanogram per mil. And that corresponds to roughly how many eggs left. Depends on a lot on the cohort that cycle, which can be different between the follicular phase and the loot phase . And that's very important from a practical standpoint because sometimes we check the ovaries. We do the anthropholic account. That's not fine . We wait and recheck another phase because it varies a lot . But we would expect around eight x, something like this Okay . And eight eggs at forty is not sufficient mostly to produce a new plight embryo. Oh my god. Because eight eggs, you're going to fertilize them and at more than half of them are going to be anuployed. Yeah. So you might get two seven eighty percent of them. Yeah. Okay, so you might get one to two euployed to implant. Yeah, we say that it's like a funnel. It's very important for the lay person to understand that . You have the follicles. Each follicle might have one ocy . Every occy has a chance of being mature, se venty five percent , every mature egg can be fertilized and on day one present this pronuclei. We say that it's fine. After the M two phase? Yeah, after the M two phase and then from day one to day five or day six, which is a blastocyst , around thirty up to sixty percent of the 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 anniplayer rate. 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 the funnel is very important because sometimes it's very sad to see a patient that is coming back like she froze her eggs at thirty four and she's coming back at forty and she had just eight eggs . And now you thaw them and then you produce just one glass of cyst and doesn't even plan . So that's it and now she's forty. Yeah . Which again goes, back to my question of why isn't every twenty five 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. If you look at a country where the reproductive rate is below two point one, and that turns out to be a lot of countries , and immigration alone won't solve your demographic problem. You actually need de novo reproduction . This strikes me as a reasonable cost for the government to be. Yeah. Japan is facing this right now. Yeah . So Israel in Israel, you can do 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 occides earlier . But I think that's a problem of excess right now We have the technology. Yeah . Okay, now let's talk about something very extreme at the other end of the spectrum. So you now talk about that woman who's forty. She's come back only to realize that nothing nothing worked. So but she still wants to have a baby. So right now her only option is to use an egg donor, correct? . In which case she will use the egg of a young woman. She'll use the egg of a twenty five year old woman likely with her partner's sperm. And that's fine. That's a great treatment, right? That works very, very well. But I have now heard about an emerging technology where that woman who is forty can use her genetic material with 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. So help me understand that technology. Yeah, that technology is called mitochondrium, a replacement therapy . So that doesn't solve the problem because the problem is in the nucleus, right? Yep. So the problem is chromosomal . And we had two I think two papers published last year in New England's Journal of Medicine by a UK group Newcastle . And but twenty two patients with mitochondrial disease because remember we have like twenty thousand up to twenty five thousand genes and thirty seven genes in the mitochondria, the so called mitochondrial DNA . And for those very specific cases they basically took out the prone nuclei from the parent embryo fertilized after fertilization. So they have in they won the pr onuclei they take out and they insert in a in nucleated occy new occy that has this new mitochondria that are normal. They are supposed to be healthy. So this solves just the problem of the cycloplast, the mitochondria I see. So it is not solving the age problem. No , got it. And this as far as I know it's not available for infertility , but there are some clinics I think in North Cyprus or Greece and they're selling this as a egg rejuvenation , that's misleading in my opinion , but you are just trying to replicate like it's like a battery swap for the egg, but you're not changing the engine horizon. Yep. The engine is the main problem . So is there currently anything on the horizon for the forty 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 . I think not for that situation, but there's a clinic in the UK that is trying to freeze the 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, I have a huge line, like a huge waitlist 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 with type one diabetes that gets implanted pancreatic or beta cells that secrete insulin. Autologous, yeah. Yes, autologus. Is this her own ovarian tissue that was set aside earlier in life? Like at thirty's at thirty's been doing partial opherectomy? Yeah. And you can then transplant like forty five when you are forty five and then you can postpone. There is actually like a math behind that. You can postpone menopause like ten, fifteen years, sometimes even more. Where do they reimplant the same period? Yeah, pertinium. Okay . Or you could put in the subcutaneous tube . 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 progresses . Yeah . But for all sites, we have data on ovary and cortex freezing , but the better outcomes they come from egg freezing. And why would this autolog ous 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 cultural thing about menopause right, about hormone replacement therapy after two thousand two, july two thousand two, WHI, right I think there's just this big misconception about menopause hormone therapy. It's much more it's much easier to just give estrogen progesterone and sometimes estaucerone than free zing the ovary and then transplanting and probably like premenstrual syndrome symptoms doing that. Yeah. But we don't have data. But to your question , we probably in the future, we're going to have like stem cells ucing new occytes . We are 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 ten 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 an egg . It's easier to produce a sperm 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 still healthy. And we're doing this in animals right now. Yeah. Which animals? How ? I think cattle . Probably. Yeah. And so are they doing this in primates yet? I'm not sure, but probably yes, yeah. Okay . So 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. And that hasn't been done yet . But if you can do that , you have to ensure that that becomes chromosom ally and genetically normal in the long event . That has been there's a publication about that. Yeah. 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 that. 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, 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 vitrification, like frozen 're not freezing eggs anymore, right? So just imagine that. So you're saying in ten 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 thirty . 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, I mean, 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 seven born in seventy eight. Yeah . 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 effects which we can control and we don't know what are the consequences . So the couple if the couple this natural chance , I would try naturally . And the stem cell takes a whole new level the problem is yes oh you can count on stem cells okay but wouldn't it be better to use my own little sides than I just froze like had thirty five. Yeah . 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? The genetics . Yeah . Like how do you think that shows up phenotypically ? Probably some malformations , some neuro neurological consequences , heart disease . Do we see this in the epidemiology? I mean, yeah, these so it's again, people born of IVF are still very young . They're yeah, you know, they're they're not Louise Brown. Louise Brown is like forty something forty . She's forty eight . Yeah . Yeah, but we see definitely some signs . We we're not sure about whether it's bias, 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, you know, affluent infertile says there's no 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 if that same couple that needed IVF and then now they are getting pregnant naturally because sometimes it happens, right ? The it's mainly a bias, a selection bias problem, not the technology itself . Yeah, but it's 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 adomiosis , especially in those vulnerable adolescents and not only treat the disease but as like statin in longevity, you can modify the disease progression early earlier and avoid infertility . And I'm very excited about this . So we should spread this word . And there's one molecule called H MI one hundred and one five. It's It's antibody monocolonal antibody that targets the receptor of prolactin . Probably this leads to it's in phase three trial now and 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 biological treatment for endometriosis that's not using hormones . So like to your point that why don't we have like medications that target target the disease directly? Yeah, yeah. Probably we're getting that like soon . And yeah, and I think the diagnosis is better . Yeah., Yeah yeah, I think with this widespread ultrason ography and MRI and just the awareness of the disease, we're going to 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 adenomyosis 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 relief. 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 if you listen to this and you have pain in your suffering , please don't 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 at Pinato. 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 PeterataMD . com forward slash show notes. 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