397 - Endometriosis and adenomyosis: diagnosis, fertility, reproductive aging, & emerging treatments

Key Takeaway

Most women don't realize that period pain isn't normal—up to 10% of reproductive-age women have endometriosis, a disease where endometrial-like tissue grows outside the uterus. If you experience severe pain during your period, intercourse, urination, or bowel movements, see a specialist immediately. The average diagnosis delay is 5-12 years, and waiting allows the nervous system to rewire, creating chronic pain that persists even after treatment. Early intervention with hormonal therapy or surgery can prevent this central sensitization.

Episode Overview

Dr. Peter Attia interviews Dr. [Guest Name] about endometriosis and adenomyosis—two often-confused uterine diseases affecting millions of women worldwide. They discuss how modern women experience 4x more ovulatory cycles than women 200 years ago (400 vs. 100 lifetime cycles), contributing to higher disease prevalence. The conversation covers diagnostic challenges, the dangerous normalization of female pain, and why early treatment is critical to prevent permanent nervous system changes.

Full Transcript

Transcript of 397 - Endometriosis and adenomyosis: diagnosis, fertility, reproductive aging, & emerging treatments from The Peter Attia Drive Podcast. Auto-generated from episode audio; may contain minor errors.

Hey everyone, welcome to the drive podcast. I'm your host Peter Aia Hanado. Wonderful to see you. Uh thank you for coming to Austin. Um today we're going to talk about two things that are related, but I want to talk about them in sort of this order. Uh the first thing I want to do is talk about the diseases of the uterus. Um and and I think most notably we'll talk about endometriosis but also others. Um 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 let's start with the former. Um 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 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 cerosa. The middle part which is the muscular layer called myometrium and the inner part where the embryo implants and develop the placenta which is called endometrium. endometrium. endometrium.

And this layer is very important because endometriosis is a disease, a chronic disease where an endometrial like tissue very similar to the endometrius is outside the uterus. Right? So instead of being inside that layer, it goes into the fallopian tubes on the ovaries on the bowel, the bladder, sometimes the appendix and even the diaphragm. So that's endometriosis. very important disease around 10% of reproductive women globally have endometriosis which means around 200 million 200 million women and if you look into the data of infertile women it's about 30 to 50% of women they can have endometriosis so so so so just to make sure I understand that 30 to 50% of women who are struggling with fertility have endometriosis and the other way around Like if you have endometriosis, you have a chance of around 40% of being infertile.

So it's causal. Yes. Yes. Yes. Let's dig into this a little bit more. So first of all, you mentioned we have three layers in the uterus. Um 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 the the dur duration of the cycle and of course where you are in the cycle. cycle. cycle. You have a muscular layer and that's presumably functional. So during childirth the uterus needs to contract. So when a woman is experiencing contractions that's what's contracting precisely.

precisely. precisely. Okay. And then the outer layer tell me about that again. Functionally it's just a peronium like the visceral perinium. No, no, like no, no, it doesn't have it doesn't add up much, you know, we just have but we can have endometriosis on that layer and then sometimes it just infiltrates and transform to what we can say we can talk about ad internal and adenomiosis like external adomiiosis. Got it. And I did want to ask you about adenomiosis 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 um environmental triggers for it? Great question. So, we have about 50% of heritability. heritability. heritability. If you have a firstderee relative with endo, you have about seven times higher chance of having endometriosis. So that's the the the meaning mother or sister. Yeah. Yeah. Yeah. Okay. Okay. Okay. And um and we know from twin studies also that of course they 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 is what we call the repetitive ovulatory menstruation. So what what that means every time a woman is uh menstruating part of the the menstrual flow goes back through the fallopian tubes and into the pelvis. So we know that by surgeries 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. Exactly. So remember the fimbra like the the distal part of the tubes they are not directly connected to the ovary.

They are like they are moving around and they can pick up the o sites. This this always amazed me by the way. I I don't understand why that works or how it works. it works. it works. And it's it's actually most of the time the the old side is just on the surface of the ovary. Uhhuh. Uhhuh. Uhhuh. Sometimes it's inside the pelvis in the cold the sack. But the fimbr can pick it up and then permits the fertilization inside the the isimus, right? Inside the the middle part of the tube essentially.

But we know by like old studies that around 90% of women they have this retrograde ministration which is amazing. So you would think why is that then just 10% have endometriosis right because sometimes we just do it's not sufficient to have endometriosis but it's probably necessary in the most in most cases. There are some nuances here but those patients with endometriosis they might have immune disregulation. So the macrofasages can you know can cope with that overload of menstrual flow and endometrial tissue endometrial tissue endometrial tissue they have uh also like if you have many many many years of retrograde ministration that can be bad.

There's an interest interesting story here per if you look um like 200 years ago uh a woman's back a woman back then uh would have around 100 o of cycles in their lifetime. their lifetime. their lifetime. Menarchy was about at the age of 16 now it's 12. it's 12. it's 12. Wow. Wow. Wow. First pregnancy around 20 now 30 or more. Right. Breastfeeding for 2 years per child. Now almost And during that period you're not ovulating. ovulating. ovulating. Yes. And they used to have like five, seven children.

Right. Now you So many times not ovulating. If you compare that women to a modern woman, woman, woman, it's about a four-fold increase in this retrograde of menstruations. And this may be the main cause that we are seeing much more inometriosis not not only diagnosing but probably the prevalence is getting higher and higher right so the Darwinian evolution they anticipate that right this modern woman's reproductive pattern that we have nowadays and that's pro probably the best proxy for us to use and to think about using oral contraceptives or any hormonal treatment to block like to mimic that women back then, right?

So, let me make sure I understand all of that. So, 200 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. Um, she was pregnant more often. So, all the entirety of her pregnancy, she's not cycling. Once she has a baby, she's breastfeeding for very, very long. Again, not cycling. And so, you can sort of do the math that the and by we didn't talk about menopause, but presumably they might not have even lived long enough to have had that many to to get to full menopause.

So, a woman today might have 400 cycles if uninterrupted or if if if not intervened with and every cycle produces the risk of retrograde flow. And and and then going back to what you talked about when you get retrograde get retrograde get retrograde flow of blood into the fallopian tube the macrofasages that need to come and sort of take care of it can't always do the job. So presumably you're creating uh anitis for infection or something that the immune system is upset about. And if you look into the mechanism here, yeah, we have this estrogen dependence.

estrogen dependence. estrogen dependence. The endom endometri endometriic 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 the disease. We have also this progesterone resistance. resistance. resistance. So the the progesterone receptor is downregulated. downregulated. downregulated. So we don't have this you know the the action of progesterone that is very important to counteract the action of the estrogen. the estrogen. the estrogen. Yeah. I 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 hyperlasia 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 estro as she's as she's ovulating estrogen is increasing the thickness the progesterone surge causes the shedding. That's it. So remember the at the follicular like the late follicular phase endometrial people who works with IVF know that a lot right because we are aiming to look at the endometrium at the the final phase of the follicular part right so endometrium is about to like eight at 10 mm at that point but when you have the progesterone it opens the implantation window.

So we we have this so-called decidualization so-called decidualization so-called decidualization the lipids and secrettory phase comes in and then at the ultrasound it endometri is like white not anymore black and this is very important for the pregnancy but if there is no ember inside the uterus the corpus lugan like it has like 12 to 14 days of of life and then it just sheds because you have um a decrease in estrogen and progesterone levels. So it sheds. sheds. sheds. Mhm. Mhm. Mhm. So that is very important for endometriosis too because remember it's like endometrial outside the uterus.

So one of the the treatment uh pillars is giving progesterone or progestines to these patients. But endometriosis lesions they have this progesterone resistance. resistance. resistance. What does that literally mean? You're saying that the actual endometrial cells which I assume are like another endothelium. endothelium. endothelium. Yeah. Yeah. Yeah. Because it's outside the body. Yeah. It's like stroma and glands like that resembles the indometrial lining. Okay. And they have progesterone receptors. receptors. receptors. Yeah. Yeah. Yeah. And when you say they're resistant to progesterone, progesterone, progesterone, do you mean is it you know not like it's the same but insulin resistance where progesterone hits the receptor but kind of kind of.

Yeah. you need much more insulin or progesterone to produce the effect. the effect. the effect. Y Y Y like to actually Why does that happen? It's complicated. I don't I don't think we know for sure. But it it's very interesting because those lesions they also produce they also have somatic mutations. mutations. mutations. Think about that like in encogenic genes like Kas Pik3 Pynise, right? right? right? uh so they resembles they they act like cancer especially in deep infiltrated endometriosis and adenomiosis up to 37% of those lesions they express these enco genes so they grow independently but but but do they have metastatic potential no no no why is that so in sense they're benign tumors they are benign tumors they have the machinery to go like to grow really fast, but probably due to the adions and the fibrosis outside the lesions, they cannot metastasize.

cannot metastasize. cannot metastasize. That's incredible. That's incredible. That's incredible. Yeah, it's like putting a 1,00 horsepower F1 engine into a golf cart, right? You just have the machinery, but you can't go further. This might be a good time to explain adomiosis, which can clinically be confused with endometriosis, but has some distinct pathology. So, maybe tell us what that is. So adenomiiosis I think is the missed disease because everybody talks about or should talk about endometriosis very prevalent but adenomiiosis actually is more prevalent probably probably probably up to 20 or 30% of women have adosis and you're saying about 10% of all women in reproductive age have endometriosis.

Okay. Okay. Okay. Yes. So adom meiosis is essentially the presence of this endometrial like tissue inside the myometrium. So inside the muscular wall right. So back then they used to call this internal endometriosis. Understood. endometriosis. Understood. endometriosis. Understood. But now we are we are calling this the disease differently because they they have they share some mechanisms but they are different. uh if you look into the the studies of single cell transcripttoics Linda Judis last year published one beautiful paper about this they are they don't have the same molecular pathway so they are different diseases and the the the mechanisms in what's the overlap I'm sorry to interrupt you interrupt you interrupt you so they have the same encogenic mut somatic mutations adenomiosis also have u also has this u progesterone resistance and estrogen dominance So they also produce an or overexpress aromatase.

So it's pretty much the same but there are different diseases and of course you have cure and adomiiosis. If you do a hyerectomy you take out the disease it's just a disease in the uterus endometriosis it's outside the uterus. uterus. uterus. And what is the um overlap in women who have one the other and both? So obviously 20% have one, 10% have the other. How many have both? Difficult to be precise here Peter, but we think up to 70%. Up to 70% of 70% of endometriosis patients, they might have some type or some degree of adenomiiosis and that's very important for the infertile couple.

Right? So the mechanism in adomiiosis is the so-called T I A. So it's tissue injury and repair. So essentially the the endometrium is going inside the uterus like breaking that junctional zone which is a thin layer between the endometrium and the myometrium and it's going inside and disrupting and like breaking the lines and producing those islands of cysts and echogenic buds that like increase the volume of the uterus and make it makes it very soft to the touch like during surgery can palpate the uterus. the uterus.

the uterus. Why is there a defect in the junction between the endometrium and the myometrium? myometrium? myometrium? Yes. And probably that somatic mutations that aggressiveness that they go inside but we we're not sure about why but they can't get through the myometrium. myometrium. myometrium. They can get through the myometrium and we have some like risk factors. For example, when you do a when you have a miscarriage, when you have C-section, so you break the line mechanically, when you do curage, right? You you break that or even hyster hysteroscopy for leyomas or polyps, you can break that acutely and uh the endometri can invade the myometrium.

the myometrium. the myometrium. Okay. So again just to orient everyone myself included myself included myself included adnomiiosis is a disease where endometrial tissue spreads outward from the inner part of the uterus into the muscular layer of the uterus. We have u another type of adenomiiosis. There's not like a it's not consensus but some authors they call it external adenomiosis in which the endometriosis the deep infiltrated endometriosis is going inside the myometrium from the cerosa to the myometrium and now we have not only endometriosis but adenomiiosis but there are some authors that think they are this it's not correctly to say that it's aden So mainly adomiosis that what you're talking about talking about talking about from a demographic standpoint how does it overlap?

Is it young women? Is it a disease of the fertile years? Do do women experience this denovo after menopause or is it all the same sort of presentation? So traditionally adomiiosis adomiiosis adomiiosis was called a disease of the women at 40s because she had like pregnancies sometimes c-sections and you know corage and miscarriage but now we are seeing patient younger patients with adenomiosis adenomiosis adenomiosis 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 in a minute.

But um 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 those women they have pain like pelvic pain. Sometimes they they just organize their their lives around their pain. And tell me what that means. Is pelvic pain akin to a UTI? Is it akin like what what would be the closest thing that that that that someone would understand who doesn't have it?

I like the framework of the sixds of endometriosis. Like the first D would be the dismenora which is pain during menstrual period. So they have this lower abdominal pain and this is not cramping this is actual pain pain pain pain okay that sometimes the just pain medications don't resolve it completely sometimes those patients they go to the ER to receive u intra intra intravenous medications intravenous medications intravenous medications introvenous medications and they have the second is deep disparunia which means uh pain during intercourse course especially in the profound um posterior wall of the vagina.

Third D would be disquasia or pain during bowel movements. Mh. Mh. Mh. Right. Right. Right. Especially during the uterus is how close to the rectum? It's it's close. It's adjacent immediately. Right. Right. Right. Yeah. And sometimes we can have lesions right there. Yep. In the septum, right? Fourth D would be disaria like pain during urination especially cyclic pain usually uh during the menstrual period we can have also like bleeding but that's not very common. 50 would be difficulty in getting pregnancy getting pregnant right so difficulty in conceiving infertility and uh the last one would be I will put the D like just for a hook for memory hook but it's dysfunctional chronic pelvic pain so those women can present with pain for more than six months without uh any relation with the cycle so it 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 admiiosis based on symptoms. Is that possible? Yeah. Yeah. Adomiiosis mainly uh sometimes the patients are asymptomatic. By the way around 10% of women with endometriosis might be asymptomatic. So their only symptom would be for infertility potentially infertility potentially infertility potentially potentially or they just normalize the pain which is a problem. They think that it's normal or they're tell that they're told that it's normal but adenomiiosis mainly presents with bleeding uterine bleeding like sometimes th those patients they get anemic and they bleed a lot during her per their their periods.

Um 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 adnomiiosis. So fibroids they are very common. Up to 70 or 80% of women will have one fibroid. Mostly asymptomatic. They are benign nodules inside the uterus. can be just right at the endometrium so-called submucosum submucosum submucosum uh inside the mometrium intramuscular or on the sarosa like subcerosis right and they can be 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 provokes miscarriage provokes miscarriage and they can bleed Especially the submacosis.

Yeah, submacosis. Yeah, submacosis. Yeah, we we classify them by the uh international federation of gynecologist and obstetricians and obstetricians and obstetricians by zero up to seven depending on the classification up to eight and the zero one and two they are submucosis. So they are the the problematic for fertility and for bleeding. And that's counterintuitive to me. Why would the sub mucosal ones cause more issue than the ones that are closer to the lining? the lining? the lining? Actually the sub mucosal they they are the closest to the lining like ah okay ah okay ah okay so zero will be like just inside inside the cavity.

the cavity. the cavity. Okay. Yeah. Okay. Yeah. Okay. Yeah. One is mainly inside the cavity but a part is in the myometr and two is like mostly in the myometran and a part is inside the the uterus. And then number three would be like just touching the endometrium. endometrium. endometrium. Okay, got it. And then as you go all the way out to the sarosa, it gets lower and lower or higher and higher number but lower and lower severity. Yeah. Yeah. Yeah. Okay. Okay. Okay. Probably not severity, but yeah.

Clinical implications, right? Okay. So the woman with uh you said 10% of women with endometriosis could be asymptomatic or their only presentation could be infertility. So that would suggest that when we start talking about infertility, one thing that should be in the differential diagnosis is un untreated endometriosis. untreated endometriosis. untreated endometriosis. Um but otherwise most women are going to experience some pain with something. Pain with intercourse, pain with her cycle, urination, everything. Okay. Um then on adnomiiosis, what percentage of those are asymptomatic? uh I don't have the number in my head but I would say that probably one/ird oneird because depends on the phenotype and the intensity of the disease right so we have if you just have one leo cyst myometro cyst which a presentation of adenomiosis probably these patients they don't have any symptoms at all but if you have like a very diffuse adenomiiosis or even an adenomyoma which is a nodule of adomiiosis.

They yeah they bleed out a lot. They it it's it's very painful. The the especially the period is very painful. Well, and again might sound like a dumb question. What is causing the actual pain? pain? pain? Great question. Great question. Actually, we have three types of pain in endometriosis, Peter. That's I think that's the the most complicated part for us gynecologists to understand because we're not trained for we're not trained for that right but there is the so-cal no sceptive pain y y y pain uh from the lesion directly so it's just hurts and here surgery and treatment hormonal treatment can help second layer is the so-cal no plastic pain where the nerves are infiltrated by the the lesions and you can have burning sensations, you know, sometimes on their their legs and the back and here medications can help sometimes gabapenting and SR SNRI right surgery can remove can remove some of those lesions.

We do this technique called S nerve sparing. Very difficult, sometimes impossible to do but we can try. And the third layer and most difficult to to treat is the noiplastic pain when we have central sensization. sensization. sensization. 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, right? So surgery can remove the burglar. Hormones can lock the door. But once you have this alarm system ringing and ringing years after years, the wiring changed and now even a wind can you know triggers the alarm and even removing without the burglar without you know the the doors are locked but you need to you need a different specialist here.

We need a physiootherapist, physiootherapist, physiootherapist, a pelvic floor physiootherapist and also a pain specialist to treat those patients. And that's why the the delay in diagnosis and treatment of endometriosis endometriosis endometriosis is one of the main causes of this central sensitization. It's very important for us to treat even uh empirically empirically empirically uh nowadays u the ACOG just published this March 2025 26 new guidance on endometriosis diagnosis and it allows us to not only diagnose clinically but treat it treat it treat it because if you have a just based on clinical symptoms right if you have a patient that has pelvic pain dismenoria disper Corona and so on.

You can give her a medication to avoid this disease burden you know year after years years later. later. later. What's the typical age of presentation today for endometriosis? Uh we are I I don't think we have a typical presentation anymore. We are seeing endometriosis in teenagers. Look at this data. Up to 50 and 75% of teenagers with pelvic pain, they have endometriosis. endometriosis. endometriosis. Threearters they have endometriosis. And what percentage of teenagers have pelvic pain? pelvic pain? pelvic pain? I'm not sure. Not sure. Presumably it's like 5% or I think a little bit more.

A little bit more. Yeah. So we are seeing teenagers presenting with endometriosis and if just normal again how going back to the ideology of this this this anytime you see an increase in the prevalence of something you have to assume there's some environmental trigger and it would be hard to explain just the number of periods because if she's a teenager she's still well below 100. 100. 100. So what else 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.

What is there anything else that you think could be uh increasing the prevalence of this? We we don't have definitive data here but probably even microplastics we have some studies about that pollution. pollution. pollution. Oh you mentioned pollution. Yeah, diet probably the the you know this sad diet that you talk uh poor sleep because remember poor sleep can immune yeah immune system regulation the macrofasages they just jump from one to the other type and this may increase the the risk of endometriosis. So we are not sure about this uh question but question but 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 the with the burglar analogy is you need to treat as soon as possible because the longer you wait the more you rewire in a negative fashion. Um Um Um so so so let's talk about treatment options for well let's actually talk more about the diagnosis. Let's go down the formal p. So, so a woman presents to you or to a gynecologist and with a story and actually um actually um actually um how um how uniform is the understanding of this amongst primary care doctors and gynecologists or is everybody attuned to making the diagnosis based on a presentation or do women slip through the cracks?

Oh yeah. Unfortunately not because if if you look like the diagnosis delay per is 5 to 12 years depending on the country. I believe in the US is around six years. So Brazil around seven years. So from the first symptom up to the diagnosis can you imagine like five up to 10 years. So no I can't understand that. So that means that for a period of 5 years a woman is saying to somebody I'm having symptom X Y and Z and they're not able to make the diagnosis mainly because of uh three 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 they miss school they sometimes they miss work they cannot like u properly uh work so we have the the estimate cost is around 80 to 120 billion per year and twothirds 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 biioarker like a simple biomarker like a blood biomarker right we we need a very good imaging system that's actually very simple not that complex like a transvaginal ultrasound but with a specialist or even an MRI an MRI an MRI and yeah I think that's and the third one would be that traditionally the diagnosis uh is has been made with diagnostic laparoscopy 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, insiflate the abdomen, put cameras inside and this is a surgical procedure. It requires general anesthesia. Um, anesthesia. Um, anesthesia. Um, and and and I guess the rationale for doing that was we are looking for endometrial tissue inside the abdomen. So that's as good a place to look as any. And it's easier to look with your eyes, which is what you're able to do with a camera in an insiflated abdomen than it is to look with a CT scan.

But now you mentioned MRI and then obviously ultrasound. So um when when did the shift of diagnostic uh acumen or uh success start to move towards non-invasive uh or non-surgical treatment? treatment? treatment? That's a good point around 25 years ago. Okay. Okay. Okay. So if you for for us in Brazil the specialized ultra sonography is a very good exam. We have uh we have Dr. Luciana Shamier which who's now in Boston Boston Boston the Mass General Man Orlando 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 sigmoid octop yeah like much more like simple okay okay okay u you have this anema in like one hour before the the exam and no residue diet.

But that simple protocol with gel inside vagina so you can look into small lesions in the bowel bladder and you can even see the layers of the bowel. So it's it's a beautiful exam but that started around 25 years ago and that's not widespread yet. I know that I I was just talking to Luciana this day and she told me that in I think in Mayo Clinic Arizona there's a one doctor doing that Scott Young but not for everybody. I think in the US mainly is uh MRI but MRI and ultrasonography they are they have very high sensitivity about 95 98% yeah very high and very high specificity too but for superficial lesions just let let me go step back we have three types of three phenotypes right the superficial lesions the deep infiltrative endometriosis and the endometriomomas the cysts of endometri rosis.

So for those superficial lesions ultrasound sometimes it needs when you say superficial you mean superficial away from the endometrium closer to the parinium. Actually yeah parinium but the definition will be deep within the parneium just sitting right on top on top of the parinium. Yeah but less than 5 mm. 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, right? And what do you see? Well, you see nothing cuz it's all collapsed.

But so let's assume you can put air into there and blow it up and separate everything. You have um you have bowels surrounded by parinium, you have the kidneys behind the the blood vessels, etc. It's basically just a potential space. And what would be and and by the way included on top of that paranium you would see the uterus you would see the ovaries ovaries ovaries the fallopian tubes between them the ligaments the ligaments the ligaments and is the most common place you're going to see these endometrial deposits situated on top of uterus fallopian tubes and ovaries right behind it.

Ah yeah right right behind the uterus the li the ligaments like the so-cal uteros sacral ligaments sacral ligaments sacral ligaments because just of the anatomy and gravity you know most lesions they just stay there but sometimes they can travel. Yeah you said it could get up to the diaphragm so that's a big transit. Yeah, 80% on the right side because of the anatomy of the the the sigmoid. So it blocks the left side mainly. But yeah, the like bladder around 10 to 12% of endometriosis patients, they might have urinary tract lesions, but mostly it's and what about between the rectum and the uterus?

the uterus? the uterus? That's rare That's rare That's rare because the space is too tight. the so it needs to go inside from the uterus sacral ligaments from the like behind the uterus and go to the septum. Y Y Y so that's rare but that's very very hard to treat because sometimes it goes deep into the muscle the the the muscle floor you know of the pelvis and invades the nerves and those patients present with lots of fibrosis. If you're doing an ultrasound, it's 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? posterior? posterior? Very important question, Peter. If you do a normal ultrasound and you don't have an endometriosis in the report, doesn't mean that you don't have an endometriosis. That's one of the most important things uh I think on in this episode. So if you complain about pain, you have dismenoria, disparunia and so on and you do a normal ultrasound. Yeah, that that's one of the problem very low sensitivity normal ultrasound.

Yeah, we we see that a lot. But we have a we have three layers of ultrasound. This is the normal one, the regular the augmented ultrasound with this lighting sign. So you can uh use the probe to you know to push the posterior wall of the vagina and see if there is any addition there. So uh and sometimes we even without b prep it's better than the normal ultrasound but the best will be for the detailed protocol with an expert with this bow prep to to look into the the pelvis.

Uh and who does this a radiologist or the gynecologist? radiologist sometimes as a gynecologist is 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 larger no larger no larger how how how big in diameter would be something yeah close to this arm okay so basically an inch in diameter 2 centimeters in diameter okay And And And you mentioned that the second thing you want to be able to do is push the probe into the posterior or the the furthest part of the uterus.

Now, are you doing that because you're trying to get the probe to look further or are you trying to elicit to elicit to elicit to move the Yeah. To move the uterus? Okay. Okay. Okay. So, you can see this line sliding sign, right? right? right? Okay. Okay. Okay. And MRI cannot do that. Right. Because Right. It's static. It's static. Yeah. And the probe can see 180 degrees plus in front. Yeah. Yeah. Yeah. Okay. So then when you're and and again I'm still a bit unclear as to why the bowel prep is needed.

So you can check for endometriosis in the bowel especi especially in the rectum. rectum. rectum. I see. And if you have stool in the rectum you can't get you need air on the other side. Okay. Or liquid. Yeah we need liquid. Okay. Um, air is not good for ultrasound. Yep. Yep. Yep. Okay. So, is this a different device? Is the ultrasound a different type of device? device? device? Good question. No, actually the difference the difference is just the experience and the protocol, but it takes time, right?

And what is the official name of the protocol? protocol? protocol? It's called a detailed protocol for endometriosis with bowel prep. It depends on the 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. Uh is it possible that there's someone who lives in a city where there's nobody that does this this this in the US? Definitely. I was talking to my friend and she told me that in the US uh uh uh this is the woman at MGH.

Yeah. Yeah. Yeah. Yeah. One of the best. Yeah. And but in the US it's mainly uh MRI but they do the augmented ultrasography. Okay. Okay. Okay. So you can do that the second layer but just a few um I think few clinics in the US probably Mayo Clinic uh they are doing the the protocol for endometriosis and why is that? Because it takes lots of time like one hour exam. Y exam. Y exam. Y so you need to allocate the person and also you need of course the the machine is not available like all the time right so we because we in this country obviously have so many MRI machines it's it's easier to do that it sounds to me like the MRI is very good high sensitivity high specificity the drawback is you don't get the dynamic phase phase phase but you don't yeah but you it's not that good for bowel endometriosis and is it a safe assumption that a woman who's having pain with stool is more likely to have bowel endometriosis.

Definitely. Definitely. 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. Yeah. Yeah. Okay. Okay. Okay. Probably sufficient. Probably sufficient. Probably sufficient. Okay. Okay. Okay. But if you are planning a surgery, the ultrasound is for me is essential. You would never operate without the without the ultround. Yeah. We have the privilege in S. Paulo to have access to probably five or six very good uh radiologists that do this type of type of type of you have five or six people in one city that can do this.

Yeah, S. Paulo is one of the best city to do probably the best city. Italy is also a good country for that but it depends on people right. Yeah. So man Orlando Luc Shamier and Alan Nikola there are few radiologists that are very experienced not only in diagnosing but also the followup of those patients. So for instance, Luciana, she used to not only do the the the ultrasound, but then she would go inside the O with the surgeon surgeon surgeon to look to look to look to correlate what she mean.

That's that that's brilliance. that's brilliance. that's brilliance. Brilliance. Brilliance. Brilliance. Yeah, that's the brilliance. Yeah, but that's very rare unfortunately. unfortunately. unfortunately. Okay. So you made a very interesting point point point which is which is which is you can make the diagnosis with MRI with one blind spot which is rectal. Now let's talk about treatment. Just to be clear, MRIs is better for extra pelvic lesions such as diaphragm. Yep. Yep. Yep. And for the lateral part of the pelvis where the ultrasound loses its echogenicity. echogenicity.

echogenicity. Yes. Y Yes. Y Yes. Y so for instance for to to see the uriter and to look for the deep pelvis the nerve infiltration it's better than the ultrasound. ultrasound. ultrasound. 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 gatalinium? gatalinium? gatalinium? No. No. No. No. So non-contrast T1 T2. They just usually put some gel inside vagina. T1 T2. That's it. Okay. It's a relatively easy MRI. Yeah. Yeah. Yeah. Probably a 20 minute scan.

Yeah. But there are some pitfalls like movements, you know, bowel movements. Y if the patient cannot stand too much, you know, sometimes you just get some artifacts. So now let's assume you have the diagnosis. diagnosis. diagnosis. What are the treatment options? How do you think about non-surgical and surgical treatment options? So it depends a lot on on the object, right? If the patient is trying to conceive, yes, yes, yes, is we have another section. If she's trying just to get a better life without pain and not wanting to conceive, now we have much more options.

Okay, so let's start with that. Let's start with start with start with um 20 yearear-old woman not trying to conceive but having pain and just wants symptom resolution but wants to preserve the option of conceion in 5 years. So we have a list of questions. First one is u do you want to get pregnant in the future? How many children do you do you want? It's hard to to answer that if you are 20. Um how is your ovarian reserve? AMH entropollical count very important important important disease phenotype.

What I mean here do you have endometrioma the cyst because this is a a very special phenotype which can leads to lower ovarian reserve and also the surgery can impair uh can impair the entropollical count and even the M AMH and how's the pain right like if she has she's presenting with pain we mainly start with a pill like a birth control pill because those patient uh they usually are not trying to conceive so they want contraception right and if the patient doesn't have endometrioma we can use an IUD like a merina or a kylina just just just in addition to an oral contraception no just just we we tend to use just one okay okay okay right so merina is not good for cysts because it doesn't suppress the ovulation right so but if the patient is like no endometrioma.

You can use either a marina benefit is like 5 years of treatment. treatment. treatment. And what I mean a marina is progesterone coded. Why would you use a marina over any IUD? any IUD? any IUD? Because you need the progesterone action. action. action. You're trying to suppress endometrial hyperlasia. hyperlasia. hyperlasia. That's it. And to like to avoid menstruation. menstruation. menstruation. Okay. Okay. Okay. Yeah. So, so in other words, a regular IUD doesn't necessarily suppress. No. No. No. Whereas a marina will. It's just an inflammatory event for concept.

It prevents conception. Yeah. Um Um Um Okay. And do you all things equal in this example I gave you? So, 20-year-old woman who wants to preserve her right to fertility but at the moment is just trying to deal with pain. She has pelvic symptoms. Are how are you deciding between the merina and the oral contraceptive? That's a good question. Is if she doesn't have myofascial pain which is like a contractions in the muscle pel in the pal the muscle part of the pelvis and marina is a good option.

So no endometrioma no myofacial pain marina is a good option but sometimes they just don't want to insert a marina right. So you can start with a pill a progesterine only pill like norindone or dionest or dissol or you can use uh combined contraceptive pill like the traditional ones right estrogen progesterone. estrogen progesterone. estrogen progesterone. Yeah ethanol estradi or just estradi plus progesterine plus progesterine plus progesterine and you don't use a low dose you don't use a low low estin or you do yes we we we prefer using the lowest effective dose.

Yeah, because remember estrogen canate yeah can activate the lesions. So it's better to use the low dose but the data points to like they are pretty much similar. Right. So if we do that and three three months or six months later the the patient doesn't 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 anometriosis like in 5 years or even 10 years and she'll need more surgeries.

surgeries. surgeries. And the surgery here is a laparoscopic procedure. It's a blunt force tool. You're going in and you're literally laparoscopically laparoscopically laparoscopically cutting out cutting out cutting out excising. excising. excising. And you're and are they that visible to the eye? the eye? the eye? Yeah, most of legions they are visible but there are some tiny legions that we cannot see and that's why probably the recurrence rate it's not actually recurrence. Think about how different this is from cancer, right? Like endometriosis endometriosis endometriosis presents like metastatic parinal cancer and no one in there's no treatment that would ever involve surgery for that, right?

Like you you treat this systemically once the cancer is at that level. It's only systemic treatment. And and the reason of course in part is because you can never get it all. even you 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 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, that's that's the point. Yeah. Sometimes you even with a good surgery excising all the lesions if you don't use a medication after surgery recurrence rate is around 10% per year especially in endometriomomas. So it might be that surgery doesn't cause recurrence. It's just that surgery is a sign of recalcitrant disease that it's disease that doesn't respond to medication. That's it. And that's why those patients need repeated surgery.

And that's where the the progesterone resistance come in, you know. And you do you have an assay to measure this or is it uh it's just it's a clinical diagnosis. clinical diagnosis. 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. endometriosis. endometriosis. we just have this ovulatory blockage, you know, we just suppress ovulation suppress ovulation suppress ovulation and by doing that we of course we increase uh we we decrease the risk of recurren recurrence.

There's a study published that show that if you insert a marina after a surgery, recurrence rate is 88% lower to placebo. So, it's better to use something after surgery. So, coming back to that patient with uh the patient 20 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 this concept that was published in nature reviews 70 years ago by sharab French uh French group that calls the endometriosis life.

What that means that we should not only treat the 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 1 diabetes and so on. But we we are mainly doing just one appointment, one surgery or one medication and go. We're not thinking about the life like what's going to be like in 5 10 years. Right? So, we should change the mindset on that. on that. on that. Let's now consider um um a woman who's uh in her late 30s.

She's had two kids. Uh AMH is declining. So, she's technically still fertile, but is not trying to conceive again and is um mostly just trying to deal with her symptoms. um um um and she has uh significant lesions in her uh in her pelvis. Uh how do you approach her? So first line medical therapy we would because remember if she doesn't want to conceive she needs contraception. So we could we could use a a combined pill or a progesterine. In Brazil we have this dionogest which is a very good progressing for endometriosis.

In the US we have the natisa. Natiza is like estrogen estradi plus dionogest but you need to use only the active with dionogest. There are 22 pills inside a box. box. box. And if she responds well that's 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. 36y 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 the objective is have a baby, right? It's not just controlling pain. pain. pain. That's right. That's right. That's right. But sometimes they present with both pain plus uh infertility. So this patient we we we have a a series of questions that remember infertility is a couple's disease probably the only disease that I know in medicine that involves two people right it's defined by the incapacity to 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 right so you need to to ask request a carotype and some other exams like hysteroggram like hysteroggram like hysteroggram so let's say you do the fertility workup and and and you do not see any evidence in the male for for for with motility count or anything like that.

that. that. Um, Um, Um, 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 misarrying at four weeks, six weeks, eight weeks, like she's never getting past. Is that does that is that consistent more with maternal age? Yes. Yes. Yes. Okay. So how does how does the how does the infertility of endometriosis present structurally? Is it they don't even they can't implant. can't implant. can't implant.

Very good question. Actually we now we mainly think of uh the mechanism about a mechanical mechanism. We think that it's mainly mechanical not biological. Okay. Okay. Okay. So the tubes are compromised. So they can't pick up the oides or they can't permit the the fertilization inside the tube and transport the embryo back into the uterus. Got it. Right. And surgery can fix that sometimes if the tubes are not too damaged but we have some adhesions not too much but you know you can can do that by laparoscopy or robotic surgery.

But it depends a lot on the couple right? If the if male factor is okay, if age is okay and the the couple just want like one child, probably this 36 year old woman, she has time to do that. And if she doesn't get pregnant after one year of surgery, and just to make sure I understand, Hado, the surgery you're proposing is an uh uh is a laparoscop laparoscopic procedure where you attempt to remove any at all adhesions. And just doing that, the hope is that the fallopian tubes become less dysfunctional, can 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? obstructions? obstructions? Yeah, primarily yes. But of course we have plenty of data showing that we have molecular um differences between endometriosis and non-endometriosis pelvis. For instance, we have C reactive protein IL6, TNF alpha, but clinically it's mainly an anatomical problem, right? right? right? This is uh it's so hard to believe that it's that uh crude, if you will, that it's it's it's it's plumbing basically.

Yeah. But there there are some authors that may argue that u implantation so the the Utop gendometrum is also dysfunctional dysfunctional dysfunctional molecularly molecularly molecularly but clinically not that much. Why is that? Because we have like beautiful uh data and papers published like 20 years ago that compared women with or without endometriosis donor roides so good quality embryos and they transferred the embryos the implantation rate miscarriage rate and life birth rate were pretty much similar. So which means that clinically endometriosis probably doesn't impair implantation and that's very important for IVF too because if you have a frozen embryo, right?

You you you did IVF and you freeze all the the embryos. If the patient has endometriosis, does she benefit from surgery before doing the frozen transfer? Probably not. But if she has adenomiiosis, she will probably benefit from doing the hormonal suppression because you cannot operate on adenomiiosis mainly just just the adenomyomas with 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 adinomiiosis are women who no longer want to conceive because you're going to do a hyctomy.

Do you do thectomy as well and the self in depends on depends on her age and over and reserve but we always do the self inject. inject. inject. You always take the tubes out when you take the over the uterus now. Yeah. Great. Yeah. Does is that standard of care? Oh yeah. There's no gynecologist that would ever leave tubes. Yeah. Okay. You know that that's 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 with failure as the woman with endometriosis's own egg.

Correct? No. Oh, No. Oh, No. Oh, if you if you are looking just for recipients of donor rags, one group has endometriosis, the other one is no endometriosis confirmed by laparoscopy. This is very important because because because mainly those those studies they are very heterogeneous. heterogeneous. heterogeneous. Yeah. Yeah. Yeah. And they mix and they they just don't know if the patient has adenomiosis too. So my opinion is that the missing factor is adenomiiosis. It this can confound implantation rate and miscarriage rate. So what I'm saying is that if you transfer a good embryo in a uterus of a patient with or without endometriosis, endometriosis, endometriosis, we have pretty much same results.

But you understand that? Yep. So, but if a patient with endometriosis is doing IVF, she will probably have probably have probably have m m m less oytes, less mature oytes and less embryos to transfer, which means that she needs much more cy much more cycles to do than the patient without endometriosis. endometriosis. endometriosis. But that doesn't mean that the quality is impaired. is impaired. is impaired. It's very subtle. We have also molecular data showing that all sides with in patients with endometriosis they are not normal but clinically if you look into the data just ask I've have patients with endometriosis or without endometriosis is there any difference in quality probably not h h h okay okay okay even any play rates they are similar because you're matching for age.

That's it. That's it. That's it. Yeah. Yeah. Yeah. Age is proxy for for for abnormalities. Yeah. abnormalities. Yeah. abnormalities. Yeah. Okay. So, in the case of this woman who's in her late 30s, are you going to treat her surgically and give her a year? Are you going to harvest eggs to give her a year? Like what is your algorithm? So probably we're going to offer both um options but IVF is the the way to go here because up to 34 to 34 to 34 the difference in between a blastoyist with 31 or 34 years old like in a patient that that is 31 or 34 is not that different.

It's about 35% of annuploy. About that if you are 30. Is it that high? Yeah. Yeah. Yeah. A 31 year old woman has a 35% chance of annuployy. annuployy. annuployy. 30 to 35. Yeah. Almost onethird of blastoes they are annoying. I I mean I just don't think of 31 as old. old. old. Yeah. I know. I think I almost think of that as prime um reproductive age. Yeah, prime time would be like 25 up to 30 because it's very so it falls off very quickly at 30 especially after 35 and 35 annuploy is is around 40% around 40 and 38 around 60%.

40 around 70%. 40 to around 80 85%. So it ramps up, right? And uh 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. Annuploity 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 tricom you know down syndrome which is what tricom 21. 21. 21. Yeah. Yeah. Yeah. So the definition is like anybody is an abnormality in the number of chromosomes. chromosomes. chromosomes. So we have 46 XX a female or XY a male. But so the the like the normal way would be like 33 chromosomes from the egg X and 33 from the sperm X or Y, right? So if you do the the math will be 46. But 23 and 23. Yeah.

23. Sorry. Yeah. 23 and 23. Yeah. So 46 in the end. But if you have like problems in the egg because essentially um anybody they come from the old the old the old maternal side maternal side maternal side maternal like 93 and 95% they are they come from their old side due to errors in meiosis. in meiosis. in meiosis. So they don't split the chromosomes and now you can get monosomi one less or tricomy as you said they are the most quoteunquote dangerous because those babies can live right they can have the disease monostomy is not we don't have a compatibility with life just the monostomy of x which is ter so mainly we are having an implantation failure problem so infertility And that's invisible to the exams, right?

So a 30 year old woman with normal XMs can get pregnant. Why is that? Because she is 38. Most u most ambros they are not normal at that time. And u we can have also miscarriage uh risk here. 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. So, yeah, just coming back to the case. So, we could do potentially two to two like two ways to to routes here. First one would be direct go directly to IVF then freeze the or the oides 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 cm because they can they can get that big. Yeah, Yeah, Yeah, that seems massive. Yeah, I have a patient now she has 12 cm in one side and 8 cm in the other side. Is the size proportional to the symptoms? symptoms? symptoms? No. 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. Yeah, that's of the the classification system that we have. We we tend to use the ASRM. That's the American Society for Reproductive Medicine classification, classification, classification, but it doesn't capture it all because it doesn't match the the 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 uh pain, neither fertility. So, that's a problem. So ASRM4 would be like very severe disease but she can can be asymptomatic be asymptomatic be asymptomatic while uh a stage one pay patient could be like at their homes just having pain and so on right so that's a problem we have but we have um like talking about classification and scoring we have this endometriosis fertility index which is a a score based in some you know you you give like zero to four depending on the quality of the tubes and the fibria and the ovaries after surgery.

after surgery. after surgery. So you can predict the rates the pregnancy rates after surgery. So if the score is high like nine or 10 they have almost 65% of chances of getting pregnant naturally after surgery. So that's that's useful. uh which means that if the tubes are not okay, they are dilated they or you you did had to proc to you you need to to do a self injectomy probably the chances are not that high after surgery so you can walk them through IVF directly. So just coming back to that patient.

So if if you freeze the the embryos then you can operate on the endometriosis. If there is indication mainly indications are large endometriomas pain pain pain if the quality of life is not good you can operate on them and small bowel lesions that can obstruct and sometimes ureal involvement which can lead to kidney function loss. Actually I have I had a patient with she had a nephrectomy left nephrectomy due to endometriosis in the uriter like silent disease mostly mostly mostly and she developed hydronosis hydron nepherosis and the urologist performed a nephrectomy so that those are the red flags those are the red flags to to perform surgery even without symptoms.

Yeah, like appendix is important too because sometimes it just mimics neurindocrine tumors. tumors. tumors. Yep. Yep. Yep. Essentially the same phenotype. Wow. Wow. Wow. And small bowel and your turn. You need to operate on them. Okay. Okay. Okay. Let's talk about a 32-year-old woman comes to you. She has had uh difficulty conceiving, two failed IVF transfers. You're seeing her for the first time. You do a workup. You find she has adnomiiosis. adnomiiosis. adnomiiosis. What can you do to help this woman? That's very common. Very, very good example, Peter.

So, if she still have uh embryos frozen. embryos frozen. embryos frozen. Yes. Let's assume she still has uh so 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 that they don't want to waste anymore without knowing what's going on. So that's why they came. So she has uh ambro amber that are frozen and you can perform if she didn't do that yet um a G&R analog or agonist use before the the transfer.

What that means that [snorts] you can treat adenomiosis with medication suppressing the ovulation and suppressing the estradiol levels. So it can produce like a menopause symptoms. That's the side effects. But we have data showing that this can increase implantation rate but decrease miscarriage rate and increase lip rates. So So So you are treating the uterus, right? So estrogen can triggers adomiosis lesions can can can just like endometriosis. Just like in metrosis and if you use generage antagonist we have now in the US what are the preferred ones we prefer like we have much more data with analoges the agonist Lupron it's called the goerline they are injectable yeah subcutaneously monthly right so two to four months with this and then we transfer the the embryo using just tiny levels smallest amount of estrogen Yes.

And high amounts of progesterone. Okay. Okay. Okay. So that's the strategy. Now day uh nowadays we have the antagonist the oral antagonist in the US. They are very expensive. They are called allegolix and relig relig relig oral medications. We had just one paper published last year that compared the use of antagonist versus agonist and they're pretty much the same. Here we have less side effects. They're very expensive. I think around $1,000 per month. per month. per month. Okay. Okay. Okay. Yeah. So in Brazil we don't have these medications.

We mainly use uh the agonist. And by doing that we can achieve achieve achieve similar rates of pregnancy and miscarriage as patients if she didn't have endometriosis. Adomiosis. 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. Do they both produce a lower level of estrogen? estrogen? estrogen? So mainly is the the the 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 leads to ovulation. But after two to four weeks of medication you then you downregulate the receptor and then you you have this this suppression hormonal suppression. So you produce the menopause essentially chemically. chemically. chemically. Mhm. Mhm. Mhm. But the antagonist the action is right in the first medication. So you don't have this flare up effect but essentially the like the the the objective is the same. So, 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? changing? changing? Good question. Not much, but yeah, sometimes we just see the the uterus shrinking a little bit, like reducing in volume, but sometimes the lesions they they are there. And why did this woman have a hard time conceiving? You said this is a common presentation but what is it that in this woman with and let's assume that this is IVF so we know that these are good eggs right these are chromosomally normal eggs what prevented the implantation in her her her actually is a problem in pregnancy maintenance maintenance 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 oh wow oh wow yeah sometimes even even further.

Okay. And why? Because there there are contractions in the that junctional zone. Yep. Yep. Yep. And the uterus is just trying to kind of expel the embryos. Then you you you give her four months of treatment, but you said you don't really shrink the the the adnomiiosis. Morphologically, not that much, but chemically you change Yes. Yeah. And then you can give her the embryo back. Low dose of estrogen, lots of progesterone, of progesterone, 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 adnomiiosis or any form of contraction be a problem?

Does this increase her risk of premature labor if it starts to contract too soon? Like how 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. complications. complications. But we know that endometriosis and adomiiosis they can increase the risk of preterm birth like preeacclamp preeclampsia preeacclamp preeclampsia preeacclamp preeclampsia and small for gestational age c-section uh rates. So if you're speaking to this woman before you'd go through all of this, you would say to her, look, if you were a 32-year-old with none of these issues, you had no admiosis, you had nothing, and we were just doing IVF because there was some reason you were struggling to conceive, your success, your rates of success would be X.

Now, because of this condition, how much less are your chances of chances of chances of around 30% less? Okay. with admiosis. Wow. Wow. Wow. But depends on the phenotype. If you have the involvement of the junction ozone, ozone, ozone, you have a three times uh higher risk of miscarriage miscarriage miscarriage because it's more likely to contract. Yes. It sits right on top of this like the surface where the embryo is going to implant. implant. implant. And remind me again, did you did you tell me already why you think adnomiiosis is occurring?

We think there's a disruption in the bound in the basically in the boundary layers placent. Yeah. The the decidualization, the progesterone resistance, the contractions in the junctional zone and the ura sometimes they just you can see Yeah. Yeah. The hypertrophy. You can see the contraction sometimes ultrasound. ultrasound. ultrasound. Are there drugs in the pipeline that are trying to address the progesterone resistance? resistance? resistance? No. Not going to say no. It seems like that would be an interesting area of of study. study. study. Yeah. Yeah. Yeah.

Um 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 we have a sense what that is and there's even a drug that can target that directly. So it's it's conceivable that with enough understanding of what happens when the progesterone molecule hits the progesterone receptor inside the cell, what creates the resistance. Uh seems that that would be one opportunity. Yeah. Yeah.

Probably. But we are now just just just you're just giving more and more progesterone. progesterone. progesterone. Progesterone. If that woman who was 32 had had been diagnosed immediately, could she have been treated with highdosese progesterones highdosese progesterones highdosese progesterones and other hormonal therapies to have not arrived where she is like during pregnancy? No, pre-reg. In other words, could she have been maintained on some sort of birth control routine for 3 years prior to trying to conceive? And would that have increased her odds? That's the point, Peter.

We think that if we diagnose an adolescent or even a young woman u earlier, we can avoid 40% of the legions or the the disease burden. burden. 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 NIH NIH like invests 15 times more dollars on diabetes than endometriosis. But endometri an endometriosis patients might cost around $16,000 per year per year per year while a diabetic patient would cost $12,000 per year.

So we don't have much u funding for that. Yeah. Why do you think that is? It's It's It's that that's a complicated question. 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. that's it. that's it. I I think that's it's just a a question of time probably like menopause, right? Yeah. That we are seeing this revolution. Are there any other good case examples you can think of that um well actually let's let me give you one more.

So let's let's take another one where one where one where um a woman is 30 years old. She would like to conceive, but she's not trying to at the moment. But her symptoms are horrific. So, she has the worst symptoms you've ever seen. Truly debilitating. Truly debilitating. 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. Um, you you will always try chemical therapy first. You'll always try hormone therapy first.

in that patient. No, because she's she's going to try to conceive. So, we have data showing that if you do that, you control the the symptoms, but you don't have a cumulative effect after stopping the medication. So, you are treating the disease while you are using the medications and the medications they are mainly contraceptives by nature, right? So, after you stop the medication, you just lost some time, you know? So that patient probably will benefit from surgery because you can treat the pain and then she can try to conceive naturally.

conceive naturally. conceive naturally. What is the biggest mistake that happens with respect to surgical intervention? Like what's the biggest like patient selection mistake? Uh I would say that if you if you have a patient that has central sensitization central sensitization central sensitization and you think that this surgery is going to resolve that that's a biggest mistake because surgery doesn't uh attack that layer of pain the noslastic pain right so we need sometimes physiootherapy 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 seeds that you know that you see like the endometrioma because that can impair fertility by reducing the not fertility per se but IVF outcomes because you reduce AMH reduce AMH reduce AMH because each of those cysts explain why that's the case because they are not actually very defined cysts. They're like pseudo cysts. 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 to the cortical part of the ovary. Uhhuh. Uhhuh. Uhhuh. Where the primordial follicles are. So when you take out the cyst, you you do a cystectomy, you can reduce AMH by 40%, sometimes 50%. So you don't want to take the cysts out if you're trying to preserve fertility. preserve fertility. preserve fertility. Yeah. That but that's a double-edged sword. Why? Because the presence of the cyst cyst cyst decrease decrease decrease the the the drain.

It drain. It drain. It can decrease the AMH. So shouldn't you harvest the eggs first? That's it. Yep. That's it. And the mechanism is is beautiful explained by this phantom reaction, the same one that we know. And it produce hydroxil um you know molecules that are very toxic to the DNA. So they ended up 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 this this now that this lower V reserve.

So it's I think that's one one big mistake. And uh I think maybe the third mistake would be like to leave a damaged tube a hydropppings just to preserve the tubes. But we know that this can reduce the IVF chances by half. So if you have a dilated tube dilated tube dilated tube because the the mechanism is like washing the embryos like the they are connected to the uterus. So this you're saying even if you implant Yeah. Yeah. Yeah. in the in the uterus just having the damaged fallopian tube can decrease the success of that.

Yes. By half by half. So there's that widely known. Yeah. Yeah. We have Cochran review on that. that. that. Okay. So we have this mechanical effect and also the it's embryotoxic. Yeah. Yeah. Yeah. Cytoines Cytoines Cytoines secreted down into Yeah. We need to take out that you need to do a self injecttomy. Mhm. Um how often are you how in your practice how much time are you spending on endometriosis? on endometriosis? on endometriosis? Uh inclusive of discussions around fertility like how often are you operating for this?

Operating? Operating? Operating? Yes. Yes. Yes. Like you mean surgery, right? Uh probably 20%. probably 20%. probably 20%. 20% of your cases are removing endometriosis. endometriosis. endometriosis. Yeah. But but you know I'm I'm I have a fertility clinic so I have the you know this bias. People tend to come to me to do IVF. do IVF. do IVF. Okay. So let's pivot and talk a little bit about that. Um you have you know arguably the premier um fertility clinic in in Sa Paulo and Brazil. Um, and this is a huge clinical interest of yours.

Um, 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, uh, you've also shared numbers that are even worse than I imagined with respect to annuployy and age. Um, what else do you think is just not fully realized by a person or a couple out there that are trying to conceive? I 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 if if sometimes you just see the patient with the doctor trying like they operate on them and they try to conceive naturally naturally naturally at 42 years old, you know.

So that's a big mistake because you're just uh 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 they nobody knows that a lot. So what I do in our my clinic during the appointment [snorts] I show a table we can put in the show notes of the annloy rates by year after year and it's very interesting to know that it's not a uh it's not linear no it's exponential and it's not only explanation but it's like this we have a sweet spot it's a J curve very young patients they can have monostomy monostomy monostomy oh I didn't know that Yeah.

And we see that in other primates like Yeah. But we we don't know why, but that's not that risky for the the the couple, right? Because monosom they don't live, right? Y Y Y but the sweet spot would be around 25 and even at you're saying at 20 you have a worse chance than you do at 25 because the egg is more likely to be missing a chromosome. chromosome. chromosome. Yeah. I would say that the risk of annual plotting is probably higher at 20 than 25.

than 25. than 25. But of course, that's incredible. that's incredible. that's incredible. Yeah, it's incredible. And do you think, I mean, this is a silly theoretical question. Do you think that's because evolution is trying to optimize for 25 year olds having babies? Yeah, that's why more than 20 year olds or 18 year olds and obviously 30 year olds. It's really saying, I want this. that 25-year-old woman is the perfect fitness to carry, deliver, and raise a child. That's exactly what I think. But we don't we are not sure yet about that.

Uh but that's interesting because do we think that that's drifted? Like do you think 200 years ago if we could go back in time do you think it it would have been lower? You think it's I don't think so because the mechanisms they they should be the same, right? That's that's unbelievable. Yeah. So that means that if you are going to do an IVF with um like if you are 25 and going to IVF not all the embryos they're going to be uployly about 20% or 25% will be anuplo even at 25 20 to 25% of your eggs are already anuploid.

So you never are walking around fully around fully around fully uploed. So what I say to my patients bigger is that uh reproduction in humans it's very inefficient right so if you think about it you need one egg you you have just you lose a thousand eggs every month you obviously you make one you lose a thousand yeah you lose a thousand a pop apoptosis but you just have cohort of like 10 15 and of them just one ovulate Okay. And you have th millions and thousands and 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. If you're not pregnant, you have infertility. No, you need to try much more. That's because our reproductions uh reproduction system it's not that efficient. Right? If you look into the data of like mouse or rabbits, annipity rate is very low. They're very efficient at producing good embryos. H H H and that means that when we do IVF, we are just grouping. We're just like making more embryos, but we are not increasing their quality.

So if a woman is 40, you sometimes need to do much more cycles, you know, but all things equal, if you take the 40year-old versus the 25 year old, once you have um uploid eggs, are the qualities the same or are there other nonvisible nonvisible nonvisible changes? So for example, we know with sperm they're not the same. Even though chromosomally they appear the same between 25 and 50, we know that genetically they're different. And so older fathers are more likely to produce children with more neurossychiatric polygenic conditions.

But what do we know on the egg side? Yeah, that's a good point. We have data on that. uh there's a beautiful table uh showing that the clinical pregnancy with uploid embryo at 30 35 40 and so on it's pretty similar but we know from the lab the i if you ask an embryologist she would say that the amber is not that um quote unquote beautiful you know sometimes morphologically they are different different different the morphocinetics they are not similar But clinically it's not that big difference.

difference. difference. Interesting. Yeah. Um would you advise a woman who's listening to this who's 25 years old who is in graduate school, business school, law school, medical school, pick your favorite. favorite. favorite. um 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. Uh maybe she hasn't even met her partner yet. Um but she deep down thinks she wants to have a child. Um but it's possible she's not going to be thinking about it for another 10 years till she's 35.

So she's 25. 25. 25. she come and you're her regular gyn just you're you're doing your regular sort of exam she tells you all of this are would you advise her to freeze eggs right now at 25 at 25 at 25 not for all the patients uh but I would say that it's reasonable to do an AMH like check your reserve right but let's say she's normal she's not defic she's not she's not ahead of time she's not behind time she's just a normal 25-year-old but thinking about the J curve right which is the difference between being 25, 30, and 35 is significant.

And she's not just from an optionality perspective, she's she can't tell you. I definitely going to do it by 30, in which case maybe you could say, okay, it doesn't change much. Yeah. If she if she's not if she's sure that she she want uh she wants child children in the future, I would talk to her. But her. But her. But the the chances, you know, look at this statistic, Peter. statistic, Peter. statistic, Peter. What do you think is the the rate of patients that come back to use their own o sites like globally?

All the women who freeze eggs? Yes. Yes. Yes. You're saying how many of them never come back and touch them? Yes. Of 100 women that froze the their eggs, like how many come back are coming back to back to back to to do something with them? Yeah. Yeah. Yeah. 75 75 75 actually around 10%. What? What? What? Yes. Yes. Yes. 90% of women who freeze eggs never touch them. them. them. Yeah. Or because they get pregnant maybe they got pregnant and sometimes they just don't want to use that.

And but the sweet spot would be around 30 something 32 35 32 35 32 35 because the cost effectiveness of doing that is better than at 25. Right. So biologically of course does it makes sense to freeze earlier. Yeah, but the chances of like the time you spend on it, the cost you Let's help me understand the costs and I know it's different in Brazil from in the US, but I assume in Brazil this is all paid by out of pocket. This is so I think in the same in in the US I don't even understand.

even understand. even understand. Yeah, US I think there there are some differences uh depend price of doing it in in Brazil. So, if this 25-year-old came and said, "I want to go ahead and do this." What is the cost of harvesting of doing one harvest cycle cycle cycle in Brazil? She would spend about $5,000 US dollars. US dollars. US dollars. US dollars because uh our currency is like like like five to five. Yeah. Yeah. Okay. So, she spends $5,000 to do one harvest cycle. And then how much does she spend per year to keep them in storage?

Safe storage? It's like It's like It's like $150. $150. $150. Okay. Okay. Okay. compared to the so she's going to incur that. And again, I'm just being devil's advocate. My view is if you could afford $5,000, why not do it at 25 instead of 30 just because you've capped your downside? Your downside is you're out $5,000. Your upside is how many would you expect? How many uploid eggs do you expect to get out of a 25year-old per cycle? We were talking about blastoyst or embryos in day five to day seven about 80%.

Around 80 80 75 80% of the embryos they're eupoid. they're eupoid. they're eupoid. But since this is not embryos you're not going to be fertilizing these. You're just getting an egg. Yes. So we have a like you don't touch them. You don't you just freeze the the M2 oite the mature oid mature oid mature oid and you won't know until you fertilize. about 75% uh 75% of the all sides they are mature. So we freeze just the mature eggs and we have some calculators to like to estimate the pregnancy rate and not only that but the live birth rate depending on the age and number of eggs.

So at that age probably if you have like 15 eggs your chances are higher than 80% of having one at least one baby which still seems not that high but yeah but remember uh a fertile 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 etc. Yeah. etc. Yeah. etc. Yeah. Okay. So Okay. So Okay. So so biologically of course that makes sense but sense but sense but economically it doesn't. I think that yeah that's just economics.

Okay. Okay. Okay. The risk is pretty low like the risk of overintor torsion and bleeding and you know infections it's about 1%. And the main driver of that cost is the medication the procedure is it split about equally? about equally? about equally? Yeah. Oneird medication the procedure one third like clinic and one third like lab. lab. lab. What is the median age of women who are coming to you to have eggs frozen, but they're not planning to fertilize? Mine is 37, 38. Yes, very high. Why so high?

Why are they coming so late for eggs? for eggs? for eggs? Because I think that's just a new treatment. kind of new treatment and and because I have bias because we're in you're treating the hardest cases. Yeah, probably. Yeah, probably. Yeah, probably. So, when a 37year-old woman comes to you, I assume she's been trying for a while to get pregnant because she's 37, she's probably had many annuploitic miscarriages. miscarriages. 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 oyes in her? So my infertile patient is even older like 40 like 40 like 40 like a social freezing is around 37. So it depends a lot on her ovarian reserve. So if the reserve is like normal for 40 40 year old woman what's a typical AMH for a 40-year-old will be around one okay nanog per ml and that corresponds to roughly how many eggs left eggs left eggs left depends a lot a lot on the cohort on that cycle which uh can u can be different between the follicular phase and the ludial phase and that's very important for from a practical standpoint because sometimes we check the ovaries, we do the entropollical count, that's not fine.

We wait and recheck another phase because it varies a lot but um we would expect around eight eggs something like this. Okay. And eight eggs at 40 is not sufficient uh mostly to produce a new ploy embryo. ploy embryo. ploy embryo. Oh my god. Because eight eggs you're going to fertilize them and at more than half of them are are going to be annoyed. annoyed. annoyed. Yeah. Yeah. Yeah. So you might get seven 80% of them. Yeah. Yeah. Yeah. Okay. So you might get one to two uploid uploid uploid to implant.

to implant. 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 oite. oite. oite. Every oite has a chance of being matured 75%. 75%. 75%. Every mature egg can be fertilized and on day one present this pr-uclei. We say that it's it's fine. That's the M2 phase. Yeah. after the M2 phase and then from day one to day five or day six which is a blastoyst around 30 up to 60% of the those day one can develop into a blastoyst it depends a lot on the sperm quality too in the lab of course and on top of that you have the aniplo rate right so it's it's so hence the inefficiency you're just multiplying negative numbers after you're multiplying so many small numbers numbers together that the the outcome is very difficult.

very difficult. very difficult. So when the patient is freezing her own eggs, it's very important for her to know that the you know the the funnel is deep. very important because sometimes it's very sad to to see a patient that that is coming back like she froze her eggs with at 34 and she's coming back at 40 and she had just eight eggs and now you thaw them and then you produce just one blastoyst and doesn't implant. So that's it and now she's 40. Yeah. Which again goes back to my question of why isn't every 25 year old woman who is unclear on her timeline I I I guess you know it's funny like I wonder if in countries where population growth is not high enough.

So if you look at a country where the reproductive rate is below 2.1 and that turns out to be a lot of countries um and immigration alone won't solve your demographic problem. you actually need denovo reproduction. This strikes me as a reasonable cost for the government to bear. Yeah. Japan is is facing this right now. Yeah. Yeah. Yeah. So Israel in in Israel you can do how many cycles you want you need to produce your family. your family. your family. Yeah. Yeah. Yeah. So I think from a longevity perspective you you're right.

You can avoid this disease called infertility but you can prevent that by freezing oides earlier but I think that's a problem of excess right now. Yeah, Yeah, Yeah, we have the technology. Yeah. Okay. Now let's talk about something very extreme at the other end of this spectrum. So um you now talk about that woman who's 40. She's come back um only to realize that, you know, I 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. donor. Correct. donor. Correct. Mhm. Mhm. Mhm. Okay. In which case, she will use the egg of a young woman. She'll use the egg of a 25-year-old woman. Uh likely with her partner's sperm. Um and that's fine. That's a great treatment, right? that works that that works very very well. But I have now heard about an emerging technology where technology where technology where that woman who is 40 can use her genetic material material material with the with the 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 s the the donor is only providing the scaffolding and she could even use a surrogate. So so help me understand that technology. Yeah, that technology is called mitochondrial mitochondrial mitochondrial replacement therapy. So that doesn't solve the problem because the problem is the in the nucleus, right? Yeah. Yeah. Yeah. So the problem is chromos chromosomal, right? And that is we had two I think two papers published last year in New England Journal of Medicine by a UK group Newcastle group Newcastle group Newcastle and but 22 patients with mitochondrial disease because remember we have like 20,000 up to 25,000 genes and 37 genes in the the mitochondria the the so-called mitochondrial DNA and For those very specific cases, they basically uh took out the the pr-uclei from the the parents embryo fertilize after fertilization.

So they have in day one the pr-uclei they take out and they insert in a inucleated oite new oite that has this uh new mitochondria that are normal that are supposed to be healthy. So this solves just the problem of the cycloplas the mitochondria. Ah I see. So it is not solving the age problem. problem. problem. No. No. No. Got it. Got it. Got it. As far as I know it's not um available for infertility but there are some clinics I think in north Cyprus or Greece and they are like selling this as a egg rejuvenation.

That that's misleading in my opinion. But you are just trying to replicate like it's like a battery swap for the for the egg, but you're not changing the engine, right? Yeah. Yeah. Yeah. The engine is the main problem. So, is there currently anything on the horizon for the 40year-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. They're I think yeah not for that situation but they are there there's a clinic in uh UK in the UK that is uh trying to freeze ovaries like cortex.

Mhm. Mhm. Mhm. Like long years before menopause like to prevent or to postpone menopause. Yep. Yep. Yep. Very interesting idea but we don't have publications on that. actually have a a huge uh line like a huge weight list of patients trying to to do that makes sense but we don't have data. Sorry, just make sure I understand that. That means um so the the analogy would be somebody with type 1 diabetes that gets implanted [snorts] pancreatic or beta cells that secrete insulin. Autotogus. Yeah. Autotogus. Yeah.

Autotogus. Yeah. Yes. Autotogus. Um, is this her own ovarian tissue that was set aside earlier in life like at 30s? At 30s. At 30s. At 30s. So they do a partial ofctomy. Yeah. And you can then uh transplant like 45 when you are 45 and then you can postpone. There is actually a like a math math math behind that. They can postpone menopause like 10, 15 years, sometimes even more. Where do they reimplant? In the same in the paranormal. Yeah. Perneur. Or you could put in the subcutaneous too.

subcutaneous too. subcutaneous too. And so you're not only postponing menopause from a hormone perspective, you're postponing fertility. Yeah. Actually, that's mainly for menopause. Like to produce her own. That's just to produce estrogen and progesterone. Yeah, but uh for all sides we have data on ovarian cortex freezing but but but the better outcomes they they come from egg freezing. egg freezing. egg freezing. And why would this um autotogus ovarian implantation or transfer be superior to just standard menopausal hormone therapy? therapy? therapy? That's the question. I just gave a lecture uh last year about that.

So why I think because of the the cultural thing about menopause, right? About hormone replacement therapy after uh 2002 July 2002, right? I think there's just this big misconception about menopause hormone therapy. It's much more it's much easier to like just give estrogen, progesterone, and sometimes testosterone than freezing the the ovary and then transplanting transplanting transplanting and probably getting like premenstrual syndrome, you know, symptoms doing that. Yeah. Yeah. Yeah. Yeah. But we don't have the but to your question, uh, we probably in the future we're going to have like stem cells producing new oytes.

We're not there yet. I read an article very recently suggesting that that could be five years away. What's your view on that? Are you optimistic? Not that much. I I think more like 10 years. years. 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. sperm. sperm. Mhm. Mhm. Mhm. And u 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. healthy. healthy. And so are they doing this in primates yet? yet? 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 pur potent 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 chromosomally and genetically normal in the long event.

That has been uh there's a a publication about that. Yeah. That you can make the egg out of a stem cell. cell. cell. Yeah. But uh we are not sure about the consequences and the the clinical benefits of the the like the safety of that. that. that. Has it been done in mice? Yeah. And in mice because their lifespan is short enough does it produce a normal phenotype? phenotype? phenotype? Yeah. Yeah. Yeah. Okay. So that's promising but not guaranteeing. guaranteeing. guaranteeing. But that's going to be like a game changer for us.

Yeah. I think when we do that we are going to going to going to like not do any more vitrification like frozen we are not freezing eggs anymore. Right. Right. Right. So just imagine that. So you're saying in 10 years any couple of any age could potentially reproduce? reproduce? reproduce? Probably. I don't know if that's safe, that's [snorts] going to be safe. Like if you ask me, you are you are 30. U me and my wife, we are healthy. Um 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. I mean, but but look, if if you if you struggled for a year, we wouldn't hesitate to do IVF, right? IVF, right? IVF, right? But for me, I think we are like IVF is the first baby was born in 78. 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 we don't know what are the consequences. So if the the couple had if the couple h has this natural chance I would try naturally and the stem cell takes it to a whole new level. The the problem is yes. Oh, you can count on stem cells. Okay. But wouldn't it be better to use my own o size that I just froze like at 35? Yeah. Yeah. 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? Epigenetics. Epigenetics. Epigenetics. Yeah. Like Yeah. Like Yeah. Like And how do you think that shows up phenotypically? phenotypically? phenotypically? probably uh some malf forations, some u neuro um neuro um neuro um neurological neurological neurological consequences consequences consequences um heart disease. Do we see this in the epidemiology? I mean these so again people born of IVF are still very young. They're Yeah. They're Yeah. They're Yeah. You know they're they're not Louis Brown is like 40 something or 48. She's 48.

She's 48. She's 48. 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 access. There's infertility. There's so many confounders. confounders. confounders. Yeah. Yeah. Yeah. 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.

technology itself. technology itself. Mhm. Mhm. Mhm. And yeah but it's it's a new a new technology. Right. technology. Right. 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 adenomiiosis especially in those vulnerable adolescents and not only treat the disease but as like statin in longevity. You can modify the disease progression early early early earlier. earlier. earlier. Yeah. and uh avoid infertility and I'm very excited about this.

So we should spread this word right and there there's one molecule called HMI115. It's It's It's antibi monoconal antibbody that targets the receptor of prolactin. Mhm. [clears throat] probably this leads to it's in phase three trial now and this leads to less pain and less uh dis disease progression and metrosis because those lesions can express prolactin receptors. Very interesting. Maybe that's going to be the first biologic treatment for endometriosis that it's not using hormones. M so like to your point that some why don't we have like medications that target target target target the disease directly yeah probably we're getting that like soon and and and yeah and I think the diagnosis Peter yeah yeah I think with this widespread you know ultraography and MRI and just the awareness of the disease we're going to yeah not only diagnose and treat more effectively.

Okay. So, basically the final and closing thought here should be if you're listening to this and you're struggling with any symptoms that may be even remotely suggestive of endometriosis or adnimiosis 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 the cases that stay with me are not the most complex surgeries, not the difficult IVF cycles. They are those uh women that cry not from pain, but during the appointment from relief.

That's they finally have a diagnosis. When I tell them you, you know, you are suffering. I I know that's real. It has a name. We have a a plan for that. And if you're listening to this and you have pain and you know you're suffering, please uh don't uh don't take like this is normal. This is just your regular period. Please have a second opinion and we have we have technology for that. We have treatment for that. And we should do that, right? Perfect way to end it.

Hanado, thank you very much and really appreciate you getting this message out. Great to be here. Thank you, man.