A

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness and we've established a great team of analysts to make this happen. It is extremely important important to me to provide all of this content without relying on paid ads to do this. Our work is made entirely possible by our members and in return we offer exclusive member only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to peterattiamd.com subscribe My guest this week is Dr. Hanato Tomioka, a leading expert in reproductive medicine and gynecologic surgery. Hanato's clinical work sits at the intersection of three closely related reproductive medicine, minimally invasive gynecologic surgery and gynecologic endocrinology, a combination that makes him uniquely equipped to diagnose and treat some of the most consequential and under recognized conditions women face today. Endometriosis affects roughly 10% of reproductive aged women, about 200 million women globally, and contributes to infertility in 30 to 50% of cases. Adenomyosis, its often overlooked counterpart, may be even more prevalent. Yet the average woman waits five to 12 years for a diagnosis, often because her pain has been dismissed as normal. In my conversation with Hanato, we cover what endometriosis and adenomyosis actually are, and why they're so often missed, and how diagnosis has shifted from surgical laparoscopy towards MRI and specialized ultrasound how Hinato decides between hormonal therapy and surgery and how those decisions change when fertility is part of the goal Where IVF fits into the pathway for women with endometriosis and adenomyosis or age related fertility decline how female age shapes egg quality and quantity, including the steep non linear rise in chromosomal abnormalities after age 35 and the most common mistakes in surgical and fertility decisions and what may be on the horizon for both endometriosis treatment and fertility preservation. So without further delay, I hope you enjoy my conversation with Dr. Hanato Tomioka. Hanato, wonderful to see you. Thank you for coming to Austin today. We're going to talk about two things that are related, but I want to talk about them in sort of this order. The first thing I want to do is talk about the diseases of the uterus, and I think most notably, we'll talk about endometriosis, but also others. And then I want to talk about infertility and obviously talk about some of the treatments for infertility. And of course, there's an overlap between those two. So let's start with the former. Orient us to what exactly this term is. I'm sure everybody's heard of endometriosis, but it's likely that not everybody understands exactly what it is.

B

So I believe the first point is to remember the layers of the uterus, right? So we have mainly three layers. The outside layer, it's called serosa, the middle part, which is the muscular layer called myometrium, at the inner part, where the embryo implants and develop the placenta, which is called endometrium. And this layer is very important because endometriosis is a disease, a chronic disease, where an endometrier, like tissue, very similar to the endometriosis outside the uterus, instead of being inside that layer, it goes into the fallopian tubes on the ovaries, the bowel, the bladder, sometimes the appendix, and even the diaphragm. So that's endometriosis. Very important disease. Around 10% of reproductive women globally have endometriosis, which means around 200 million women. And if you look into the data of infertile women, it's about 30 to 50% of women, they can have endometriosis.

A

So just to make sure, I understand that 30 to 50% of women who are struggling with fertility have endometriosis.

B

And the other way around, like, if you have endometriosis, you have a chance of around 40% of being infertile.

A

So it's causal.

B

Yes.

A

Okay, so let's dig into this a little bit more. So first of all, you mentioned we have three layers in the uterus. The endometrial layer is the inner layer. The. That's the part that sheds every month during a woman's reboot.

B

Very dynamic. Very dynamic. Depending on the duration of the cycle and of course, where you are in the cycle.

A

Okay. You have a muscular layer, and that's presumably functional. So during childbirth, the uterus needs to contract. So when a woman is experiencing contractions, that's what's contracting.

B

Precisely.

A

Okay. And then the outer layer. Tell me about that again.

B

Functionally, it's just a peritoneum.

A

Okay.

B

Like the visceral peritoneum. It doesn't have it doesn't add up much. You know, we just have. But we can have endometriosis on that layer and then sometimes it just infiltrates and transform to what we can say. We can talk about Adam internal and adenomyosis, like external adenomyosis, I mean.

A

Got it. And I did want to ask you about adenomyosis because I know that they can often be confused. Before I do, I want to ask another question about endometriosis, which is, do we have a sense of the features or characteristics that predict it? For example, how genetic is it and are there any environmental triggers for it?

B

Great question. So we have about 50% of her TBILI. If you have a first degree relative with Endo, you have about seven times higher chance of having endometriosis. So that's the main meaning.

A

Mother or sister.

B

Yeah.

A

Okay.

B

And we know from twin studies also that of course they share some genes, but of course they are not that penetrant. We have some triggers, maybe pollution. And one thing that's very important bigger is what we call the repetitive ovulatory menstruation. So what that means every time a woman is menstruating, part of the menstrual flow goes back through the fallopian tubes and into the pelvis. So we know that by surgeries, and

A

I'm sorry, it goes into the pelvis by going retrograde towards the ovary. But of course, the fallopian tube doesn't enter the ovary, it enters back into the pelvis correctly.

B

So remember, the fimbra, like the distal part of the tubes, they are not directly connected to the ovary. They are moving around and they can pick up the oocytes.

A

This always amazed me, by the way. I don't understand why that works or how it works.

B

And it's actually most of the time the oocyte is just on the surface of the ovary. Sometimes it's inside the pelvis in the cul de sac. But the fimbrid can pick it up and then permits the fertilization inside the isthmus. Right inside the middle part of the tube, essentially. But we know by old studies that around 90% of women, they have this retrograde menstruation, which is amazing. So you would think, why is that then just 10% have endometriosis? Right. Because sometimes we just the. 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 dysregulation so the macrophages can cope with that overload of menstrual flow and endometrial tissue. They have also, like, if you have many, many, many years of retrograde menstruation, that can be bad. There's an interesting story here, Peter. If you look like 200 years ago, a woman back then would have around 100 ovulatory cycles in their lifetime. Menarche was about at the age of 16. Now it's 12, first pregnancy around 20, now 30 or more, breastfeeding for two years per child now almost.

A

And during that period you're not ovulating?

B

Yes. And they used to have like five, seven children now usually so many times not ovulated. If you compare that woman to a modern woman, it's about a fourfold increase in this retrograde ovulatory menstruations. And this may be the main cause that we are seeing much more endometriosis. Not only diagnosing, but probably the prevalence is getting higher and higher. Right. So the Darwinian evolution didn't anticipate that this modern woman's reproductive pattern that we have nowadays, and that's probably the best proxy for us to use and to think about using oral contraceptives or any hormonal treatment to block, to mimic that women back then.

A

So let me make sure I understand all of that. So 200 years ago, a woman would have had 100 ovulatory cycles in her lifetime. And that would have been driven by many changes. She got her period four years later, she was pregnant more often. So the entirety of her pregnancy, she's not cycling. Once she has a baby, she's breastfeeding for very, very long. Again, not cycling. And so you can sort of do the math that. And by the, we didn't talk about menopause, but presumably they might not have even lived long enough to get to full menopause. So a woman today might have 400 cycles if uninterrupted or if, if, if not intervened with. And every cycle produces the risk of retrograde flow.

B

That's it.

A

And, and then going back to what you talked about, when you get retrograde flow of blood into the fallopian tube, the macrophages that need to come and sort of take care of it can't always do the job. So presumably you're creating a nidus for infection or something that the immune system is upset about.

B

And if you look into the mechanism, period, we have this estrogen dependence, the meteorologic lesions, they produce by themselves estrogen so they overexpress aromatase. There's an upregulation in aromatase. So sometimes just blocking the ovaries is not sufficient to block the disease. We have also this progesterone resistance. So the progesterone receptor is downregulated. So we don't have this. The action of progesterone, that is very important to counteract the action of the estrogen.

A

Now, of course, I only know this in the context of hormone replacement therapy, where to your point? When you give women estrogen unopposed, the endometrial lining gets thicker and thicker and thicker. You can get hyperplasia, which could ultimately become cancer. But tell me more about what's happening in the cycle through that. Is it basically the same thing? You give estrogen as she's ovulating, estrogen is increasing the thickness. The progesterone surge causes the shedding.

B

That's it. So remember the follicular, like the late follicular phase, endometrium. People who works with IVF know that a lot. Right. Because we are aiming to look at the endometrium at the final phase of the follicular part. So endometrium is about like 8, 10 millimeters at that point. But when you have the progesterone, it opens the implantation window. So we have this so called decidualization lipids and secretory phase comes in. And then at the ultrasound, endometrium is like white, not anymore, black. And this is very important for the pregnancy. But if there is no amber inside the uterus, the corpus luteum, it has like 12 to 14 days of life, and then it just sheds because you have a decrease in estrogen and progesterone levels. So it sheds. So that is very important for endometriosis too, because remember, it's like endometriosis outside the uterus. So one of the treatment pillars is giving progesterone or progestins to these patients. But endometriosis lesions, they have this progesterone resistance.

A

What does that literally mean? You're saying that the actual endometrial cells, which I assume are like another endothelium.

B

Yeah.

A

Cause it's outside the body.

B

Yeah, it's like stroma and glands. That resembles the endometrial lining.

A

Okay. And they have progesterone receptors.

B

Yeah.

A

And when you say they're resistant to progesterone, do you mean is it not like it's the same, but insulin resistance, where progesterone hits the receptor, but kind of.

B

Kind of yeah, you need much more insulin or progesterone to produce the effect. Yeah, like 12.

A

So why does that happen?

B

It's complicated. I don't think we know for sure. But it's very interesting because those lesions, they also produce, they also have somatic mutations. Think about that. In oncogenic genes like KRAS, PIK3, PIK kinase. Right. So they resembles, they act like cancer. Especially in deep infiltrated endometriosis and adenomyosis. Up to 37% of those lesions, they express these oncogenes. So they grow independently.

A

Do they have metastatic potential?

B

No. No. Why is that?

A

So in a sense, they're benign tumors.

B

Yeah, benign tumors. They have the machinery to go like to grow really fast, but probably due to the adhesions and the fibrosis outside the lesions, they cannot metastasize.

A

That's incredible.

B

Yeah, it's like putting a 1000 horsepower F1 engine into a golf cart. You just have the machinery, but you can't go further.

A

This might be a good time to explain adenomyosis, which can clinically be confused with endometriosis, but has some distinct pathology. So maybe tell us what that is.

B

So adenomyosis, I think is the missed disease because everybody talks about, or should talk about endometriosis, very prevalent, but adenomyosis actually is more prevalent. Probably up to 20 or 30% of women have endometriosis.

A

And you're saying about 10% of all women in reproductive age have endometriosis? Yes. Okay.

B

Yes. So adenomyosis is essentially the presence of this endometrial like tissue inside the myometrium, so inside the muscular wall. So back then they used to call this internal endometriosis.

A

Understood.

B

But now we are calling this disease differently because they share some mechanisms, but they are different. If you look into the studies of single cell transcriptomics, Linda Judis last year published one beautiful paper about this. They don't have the same molecular pathway, so they are different diseases. And the, the mechanisms, what's the overlap?

A

I'm sorry to interrupt you.

B

So they have the same oncogenic somatic mutations. Adenomyosis also have this progesterone resistance and estrogen dominance, so they also produce their overexpressed aromatase. So it's pretty much the same, but they are different diseases. And of course we have cure. And adenomyosis, if you do a hysterectomy, you take out the disease. It's just a disease in the uterus. Endometriosis, it's outside the uterus.

A

And what is the Overlap in women who have one, the other and both. So obviously 20% have one, 10% have the other. How many have both?

B

Difficult to be precise here, Peter, but we think up to 70%.

A

Up to 70% of 70% of endometriosis

B

patients, they might have some type or some degree of adenomyosis, and that's very important for the infertile. A couple. So the mechanism in adomyosis is the so called tiar. So it's tissue injury and repair. So essentially 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 makes it very soft to the touch during surgery, can palpate the uterus.

A

Is there a defect in the junction between the endometrium and the myometrium?

B

Yes, and probably that somatic mutations, that aggressiveness that they go inside, but we're not sure about why.

A

But they can't get through the myometrium.

B

They can get through the myometrium. And we have some risk factors. For example, when you have a miscarriage, when you have C section, so you break the line mechanically. When you do curettage, you break that. Or even hysteroscopy for leiomyomas or polyps, you can break that acutely and the endometrium can invade the myometrium.

A

Okay, so again, just to orient everyone, myself included, adenomyosis is a disease where endometrial tissue spreads outward from the inner part of the uterus into the muscular

B

layer of the uterus mainly is that sort of interior. But we have another type of adenomyosis. There's not like a, it's not consensus, but some authors, they call it external adenomyosis in which the endometriosis, that deep infiltrated endometriosis, is going inside the myometrium, from the serosa to the myometrium. And now we have not only endometriosis, but adenomyosis. But there are some authors that think it's not correctly to say that it's adenomyosis. So mainly adenomyosis that we are talking

A

about from a demographic standpoint, how does it overlap? Is it young women? Is it a disease of the fertile years? Do women experience this de novo after menopause, or is it all the same sort of presentation?

B

So traditionally, adenomyosis was called a disease of the women at 40s because she had, like, pregnancies, sometimes C sections and, you know, corettage and miscarriage. But now we are seeing younger patients with adenomyosis, even without pregnancies.

A

And again, this must be very confusing because it would be easy to confuse this for endometriosis. I assume. We haven't even talked about the presentation, so we can do that in a minute, but. Well, let's actually do that. Let's talk about presentation. So maybe we can start with the traditional presentation and then the nuanced. So what is the. If you were taking a board exam and it was trying to show you a woman with endometriosis, how would she present?

B

So, typically those. Those women, they have pain, like pelvic pain. Sometimes they. They just organize their. Their lives around their pain.

A

And tell me what that means. Is pelvic pain akin to a uti? Is it akin. Like, what would be the closest thing that someone would understand who doesn't have it?

B

I like the framework of the six Ds of endometriosis. The first D would be dysmenorrhea, which is pain during menstrual period. So they have this lower abdomen.

A

And this is not cramping. This is actual pain.

B

Pain.

A

Okay.

B

That. Sometimes the. Just pain medications don't resolve it completely. Sometimes those patients, they go to the ER to receive intra. Intra.

A

Intravenous medications.

B

Intravenous medications, and they have. The second D is deep dyspareunia, which means pain during intercourse, especially in the profound posterior wall of the vagina. 3rd D would be dyschezia, or pain during bowel movements, especially during the uterus.

A

Is how close to the rectum? It's close. It's adjacent immediately, right?

B

Yeah. And sometimes we can have lesions right there in the septum. 4th D would be dysuria, like pain during urination, especially cyclic pain, usually during the menstrual period. We can have also bleeding, but that's not very common. 50 would be difficulty in getting pregnant, so difficulty in conceiving, infertility. And the last one would be. I will put the D just for a hook, for a memory hook. But it's dysfunctional chronic pelvic pain. So those women can present with pain for more than six months without any relation with the cycle. So you have a lot of this myriad of pain, you know?

A

Okay. And then help us understand how that differs. If, as a clinician, you were trying to make the distinction between endometriosis and adenomyosis based on symptoms Is that possible?

B

Yeah, adenomyosis mainly. Sometimes the patients are asymptomatic. By the way, around 10% of women with endometriosis might be asymptomatic.

A

So their only symptom would be infertility. Potentially.

B

Potentially. Or they just normalize the pain, which is a problem. They think that it's normal or they're told that it's normal. But adenomyosis mainly presents with bleeding, uterine bleeding. Like, sometimes those patients, they get anemic and they bleed a lot during their periods.

A

Let's take one quick detour to understand another condition that produces bleeding, which is fibroids. Maybe explain what fibroids are and how it's different from adenomyosis.

B

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 submucosal, inside the myometrium, intramuscular, or on the cirrhosa, like subserosis. And they can get very, very large right. Nodules. Sometimes it disrupts the. It can disrupt the anatomy of the uterus, especially the endometrial cavity, and provokes miscarriages. And they can bleed too, especially the submacosis. Yeah, we. We classify them by the International Federation of Gynecologists and obstetricians by 0, up to 7, depending on the classification, up to 8. And the 0, 1 and 2, they are submucosal. So they are the problematic for fertility and for bleeding.

A

And that's counterintuitive to me. Why would the submucosal ones cause more issue than the ones that are closer to the lining?

B

Actually, the submucosal, they are the closest to the lining. Okay, so zero will be like just in the endometrium inside the cavity. Okay.

A

Yeah.

B

One is mainly inside the cavity, but a part is in the myometer, and then two is like mostly in the myometrium, and a part is inside the uterus. And the number three would be like just touching the endometrium.

A

Okay, got it. And then as you go all the way out to the serosa, it gets lower and lower or higher and higher number, but lower and lower severity.

B

Yeah.

A

Okay.

B

Probably not severely, but. Yeah. Clinical implications. Right.

A

Okay. Okay. So the woman with. You said 10% of women with endometriosis could be asymptomatic or their only presentation could be infertility. So that would suggest that when we start talking about Infertility. One thing that should be in the differential diagnosis is untreated endometriosis. But otherwise most women are going to experience some pain with something. Pain with intercourse, pain with her cycle, urination, everything. Then on adenomyosis, what percentage of those are asymptomatic?

B

I don't have the number in my head, but I would say that probably one third because it depends on the phenotype and the intensity of the disease. So if you just have one leocyst, myometral cyst, which is a presentation of adenomyosis, probably these patients, they don't have any symptoms at all. But if you have like a very diffuse adenomyosis or even an adenomyoma, which is a nodule of adenomyosis, they bleed out. It's very painful, especially the period is very painful.

A

And again, might sound like a dumb question, what is causing the actual pain?

B

Great question, great question. Actually, we have three types of pain in endometriosis. Peter that's, I think that's the most complicated part for us gynecologists to understand because we're not trained, we're not trained for that. But there's the so called nociceptive pain, pain from the lesion directly. So it just hurts. And here surgery and treatment, hormonal treatment can help. Second layer is the so called nociplastic pain where the nerves are infiltrated by the lesions and they can have burning sensations, you know, sometimes on their legs and the back. And here medications can help sometimes gabapentin and snris. Right. Surgery can remove some of those lesions. We do this technique called nerve sparing. Very difficult, sometimes impossible to do, but we can try. And the third layer and most difficult to treat is the nociplastic pain when we have central sensitization. So you can have a beautiful surgery. Your pelvis is clean, but you can still have pain. It's like, imagine this analogy. Imagine like endometriosis. Lesion is a burglar. So surgery can remove the burglar, hormones can lock the door. But once you have this alarm system ringing and ringing, years after years, the wiring changed and now even a wind can, you know, triggers the alarm and even removing without the burglar, without, you know, the doors are locked, but you need to, you need a different specialist here. We need a physiotherapist, a pelvic floor physiotherapist, and also a pain specialist to treat those patients. And that's why the delay in diagnosis and treatment of endometriosis is one of the Main causes of this central sensitization. And it's very important for us to treat, even empirically, nowadays. The ACOG just published this March 2025, 26, a new guidance on endometriosis diagnosis. And it allows us to not only diagnose clinically, but treat it. Because if you have. Just based on clinical symptoms, Right. If you have a patient that has pelvic pain, dysmenorrhea, dyspareunia and so on, you can give her a medication to avoid this disease burden, you know, years later.

A

What's the typical age of presentation today for endometriosis?

B

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. Three quarters they have endometriosis.

A

And what percentage of teenagers have pelvic pain?

B

Not sure, not sure.

A

Presumably it's like 5% or.

B

Yeah, I think a little bit more. A little bit more, yeah. So we are seeing teenagers presenting with endometriosis and if just normal.

A

Again, going back to the etiology of this, anytime you see an increase in the prevalence of something, you have to assume there's some environmental trigger. And it would be hard to explain just the number of periods, because if she's a teenager, she's still well below 100. So what else do you think? Do you think there are some health factors? Do you think it's like. So, for example, we see more PCOS today, presumably linked to more insulin resistance and lifestyle factors that drive that. Is there anything else that you think could be increasing the prevalence of this?

B

We don't have definitive data here, but probably even microplastics. We have some studies about that. Pollution.

A

Oh, you mentioned pollution. Yep.

B

Yeah. Diet, probably this sad diet that you talk. Poor sleep. Because remember, poor sleep.

A

The immune system.

B

Immune. Yeah, immune. The macrophages, 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 question, but it's probably many things, which

A

is what makes it so complicated.

B

Yes.

A

So the implication, of course, of what you just said with the burglar analogy is you need to treat as soon as possible because the longer you wait, the more you rewire in a negative fashion. So let's talk about treatment options for. Well, let's actually talk more about the diagnosis. Let's go down the formal path. So a woman presents to you or to a gynecologist. With a story. And actually how uniform is the understanding of this amongst primary care doctors and gynecologists? Or is everybody attuned to making the diagnosis based on a presentation or do women slip through the cracks?

B

Oh, yeah, unfortunately not. Because if you look like the diagnosis delay, Peter is five to 12 years, depending on the country. I believe in the US is around six years and in Brazil, Brazil around seven years. So from the first symptom up to the diagnosis, can you imagine like five up to 10 years?

A

No, I can't understand that. So that means that for a period of five years, a woman is saying to somebody, I'm having symptom X, Y and Z. And they're not able to make the

B

diagnosis, mainly because of, I think three factors here. The first one is this cultural normalization of pain. Right. Female pain especially. So they are told that, oh, that's normal, just have a medication, have an anti inflammatory and go. But some teenagers, they just can't go to school. They miss school. Sometimes they miss work, they cannot properly work. So we have the estimate cost is around 80 to 120 billion per year. And two thirds of that is productivity loss, not only medications and hospitalizations and surgeries. So that means that we have this big culture, unfortunately of normalization. Right. And misleading. The second one is that we don't have a biomarker, like a simple biomarker, like a blood biomarker. Right. We need a very good imaging system that's actually very simple. Not that complex like a transvaginal ultrasound, but with a specialist or even an mri. And yeah, I think that's. And the third one would be that traditionally the diagnosis has been made with diagnostic laparoscopy, which is a big step to take. Yeah, we shouldn't do that anymore.

A

Okay, so let's talk a little bit about that. So for folks unfamiliar with the term diagnostic laparoscopy, laparoscopy, of course is when you put actual cameras and air insufflate the abdomen, put cameras inside. And this is a surgical procedure, it requires general anesthesia. And I guess the rationale for doing that was we are looking for endometrial tissue inside the abdomen. So that's as good a place to look as any. And it's easier to look with your eyes, which is what you're able to do with a camera in an insufflated abdomen, than it is to look with a CT scan. But now you mentioned MRI and then obviously ultrasound. So when did the shift of diagnostic acumen or success start to move towards non Invasive or non surgical treatment.

B

That's a good point. Around 25 years ago. Okay, so if you. For us in Brazil, the specialized ultrasonography is a very good exam. We have Dr. Luciana Chamier, who's now in Boston, the Mass General Manuel 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.

A

Like not just like a colonoscopy or sigmoid.

B

Yeah, like much more like simple.

A

Okay.

B

You have this enema in like one hour before the exam. And no residue diet. But that simple protocol with gel inside vagina so you can look into small lesions and the bowel bladder and you can even see the layers of the bowel. So it's a beautiful exam. But that started around 25 years ago and that's not widespread yet. I know that. I was just talking to Luciana this day and she told me that I think in Mayo Clinic, Arizona, there's one doctor doing that, Scott Young. But not for everybody. I think in the US mainly is MRI, my MRI and ultrasonography, they have very high sensitivity, about 95, 98% and very high specificity too. But for superficial lesions. Just let me go. Step back. We have three types of three phenotypes. The superficial lesions, the deep infiltrative endometriosis, and the endometriomas, the cysts of endometriosis. So for those superficial lesions, ultrasound. Sometimes it needs to.

A

When you say superficial, you mean superficial away from the endometrium, closer to the peritoneum?

B

Actually, I peritoneum. But the definition would be deep within

A

the peritoneum, just sitting right on top.

B

On top of the peritoneum. Yeah, but less than 5 millimeters.

A

Okay. And so just to orient everybody, because the anatomy here is actually a little confusing, this means imagine you could go inside a woman's abdomen and what do you see? Well, you see nothing because it's all collapsed. But so let's assume you can put air into there and blow it up and separate everything. You have bowel surrounded by peritoneum, you have the kidneys, behind the blood vessels, et cetera. It's basically just a potential space. And what would be. And by the way, included on top of that perineum, you would see the uterus, you would see the ovaries, fallopian tubes. The fallopian tubes, between them, 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.

B

Right behind it? Yeah, right behind the uterus. The ligaments, like the so called uterosacral ligaments, because just of the anatomy and gravity, you know, most lesions they just stay there, but sometimes they can travel.

A

Yeah, you said it could get up to the diaphragm. So that's a big. That's a big transit.

B

Yeah, 80% on the right side because of the anatomy of the sigmoid. So it blocks the left side mainly, but yeah, the bladder. Around 10 to 12% of endometriosis patients, they might have urinary tract lesions, but mostly it's.

A

And then between. What about between the rectum and the uterus? That's rare because the space is too tight.

B

So it needs to go inside from the uterus, sacral ligaments from the, like behind the uterus and go to the septum. Yeah, so that's rare, but that's very hard to treat because sometimes it goes deep into the muscle, the muscle floor of the pelvis, and invades the nerves. And those patients present with lots of fibrosis.

A

Okay, so if you're doing an ultrasound, how is this different from any normal transvaginal ultrasound? Is the difference that you're doing the enema and the bowel prep so you can get a better look posterior?

B

Very important question, Peter. If you do a normal ultrasound and you don't have endometriosis in the report, doesn't mean that you don't have an endometriosis. That's one of the most important things, I think, in this episode. So if you complain about pain, you have dysmenorrhea, dyspareunia and so on, and you do a normal ultrasound, that's one of the problems.

A

That's very, very low sensitivity, Very low sensitivity, normal ultrasound.

B

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

A

And who does this, a radiologist or the gynecologist?

B

Radiologist. Sometimes it's a gynecologist specialized in radiology.

A

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?

B

No, a little larger.

A

How big in diameter would be something.

B

Yeah, Close to this arm.

A

Okay. So basically an inch in diameter. Two centimeters in diameter. Okay. And you mentioned that the second thing you want to be able to do is push the probe into the posterior or the furthest part of the uterus. Now, are you doing that because you're trying to get the probe to look further, or are you trying to elicit the.

B

Yeah. To move the uterus.

A

Okay.

B

So you can see this slight sliding sign. Right.

A

Okay.

B

And MRI cannot do that. Right. Because.

A

Right. It's static.

B

It's static. Yeah.

A

And the probe can see 180 degrees plus in front.

B

Yeah.

A

Okay, so then when you're. And again, I'm still a bit unclear as to why the bowel prep is needed.

B

So you can check for endometriosis in the bowel, especially. Especially in the rectum.

A

I see. And if you have stool in the rectum, you can't get stool. You need air on the other side.

B

Yeah.

A

Okay. Or liquid.

B

Yeah, we need liquid.

A

Okay.

B

Air is not good for ultrasound.

A

Okay, so is this a different device? Is the ultrasound a different type of device?

B

Good question. No, actually, the difference is just the experience and the protocol. But it takes time. Right.

A

What is the official name of the protocol?

B

It's called a detailed protocol for endometriosis with bowel prep. It depends on the.

A

Okay, so if someone's listening to this now and they want to do this, it sounds like you've already mentioned Mass General Mayo in Arizona. Is it possible that there's someone who lives in a city where there's nobody

B

that does this in the US Definitely. I was talking to my friend, and she told me that in the U.S.

A

this is the woman at MGH.

B

Yeah, yeah. One of the best. Yeah. And in the US it's mainly mri, but they do the augmented ultrasonography. Okay. So you can do that. The second layer. But just a few clinics in the US Probably Mayo Clinic, Cleveland Clinic, they are doing the protocol for endometriosis. And why is that? Because it takes lots of time. Like one hour exam.

A

Yeah.

B

So you need to allocate the person. And also you need. Of course, the machine is not available all the time. Right.

A

So we. Because we in this country obviously have so many MRI machines, it's easier to do that. It sounds to me like the MRI is very good. High sensitivity, high specificity. The drawback is you don't get the dynamic Phase, but you don't.

B

Yeah, but it's not that good for bowel endometriosis.

A

And is it a safe assumption that a woman who's having pain with stool is more likely to have bowel endometriosis?

B

Definitely.

A

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?

B

Yeah, probably sufficient. Okay. But if you are planning a surgery, the ultrasound is, for me, is essential.

A

You would never operate without the surgery.

B

Yeah. We have the privilege in Sao Paulo to have access to probably five or six very good radiologists that do this type of.

A

You have five or six people in one city that can do this?

B

Yeah, Sao Paulo is one of the best city to do. Probably the best city. Italy is also a good country for that. But it depends on people. Right. So Manuel Orlando, Luciana Chamier and Aluisa Nicola. There are a few radiologists there, very experienced, not only in diagnosing, but also the follow up of those patients. So for instance, Luciana, she used to not only do the ultrasound, but then she would go inside the OR with the surgeon to look to correlate what she.

A

I mean, that's brilliance.

B

Brilliance.

A

Yeah, that's the brilliance.

B

But that's very rare, unfortunately.

A

So you made a very interesting point, which is you can make the diagnosis with MRI with one blind spot, which is rectal. Now, let's talk about treatment.

B

I would just. Sorry to interrupt. Peter, just to be clear, MRIs is better for extra pelvic lesions such as diaphragm, and for the lateral part of

A

the pelvis where the ultrasound loses its echogenicity.

B

Yes. So for instance, to see the ureter there and to look for the deep pelvis, the nerve infiltration. It's better than the ultrasound.

A

So do you do both?

B

Sometimes? Mostly both, yeah.

A

And what's the sequence of mri by the way? Is it special? Does it require gadolinium? No, no. So non contrast, T1, T2, they just

B

usually put some gel inside vagina. T1, T2, that's it.

A

Okay, so relatively easy MRI.

B

Yeah.

A

Probably a 20 minute scan.

B

Yeah. But there are some pitfalls, like movements, you know, bowel movements.

A

Yep.

B

If the patient cannot stand too much, you know, sometimes you just get some artifacts. Yep.

A

Okay, so now let's assume you have the diagnosis. What are the treatment options? How do you think about non surgical and surgical treatment options?

B

So it depends a lot on the object. Right. If the patient is trying to Conceive?

A

Yes.

B

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.

A

Okay, so let's start with that. Let's start with 20 year old woman not trying to conceive but having pain and just wants symptom resolution, but wants to preserve the option of conception in five years.

B

So we have a list of questions. First one is do you want to get pregnant in the future? How many children do you, do you want? It's hard to answer that if you are 20. How is your ovarian reserve? Amh, enter follicle count, Very important disease phenotype. What I mean here, do you have endometrioma, the cyst, because this a very special phenotype which can lead to lower ovarian reserve. And also the surgery can impair the anthropological count and even the 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 patients, they usually are not trying to conceive. So they want contraception. Right. And if the patient doesn't have endometrioma, we can use an iud like a Mirena or a Kyleina in addition to an oral contraception. No, just, just we, we tend to use just one. Okay, so Mirena is not good for cysts because it doesn't suppress the ovulation. Right. So but if the patient has like no endometrioma, you can use either Amirena benefit is like five years of treatment

A

and Amirena is progesterone coded. Why would you use a Mirena over any iud?

B

Because you need the progesterone action.

A

You're trying to suppress endometrial hyperplasia.

B

That's it. And to like to avoid menstruation.

A

Okay, yeah. So in other words, a regular IUD doesn't necessarily suppress.

B

No.

A

Whereas a Mirena will.

B

It's just an inflammatory event for conception.

A

It prevents conception. Yeah. Okay. And do you all things equal in this example I gave you? So 20 year old woman who wants to preserve her right to fertility, but at the moment is just trying to deal with pain. She has pelvic symptoms. How are you deciding between the Mirena and the oral contraceptive?

B

That's a good question. If she doesn't have myofascial pain, which is like a contractions in the muscle part of the pelvis. And Mirena is a good option. So no endometrioma, no myofascial pain. Mirena is a good option, but sometimes they just don't want to insert Mirena. Right. So you can start with a pill, a progestin only pill like norethindrone or Diana Jest or desogestrel. Or you can use combined contraceptive pill like the traditional ones.

A

Right. Estrogen, progesterone.

B

Yeah. Ethinyl, estradiol or just estradiol plus progestin.

A

And you don't use a low dose, you don't use a low. Low Estin or you do?

B

Yes, we prefer using the lowest effective dose. Yeah. Because remember, estrogen can activate. 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. So if we do that three months or six months later, the patient is not better. We can change the method or we can plan surgery, but mainly we try to use medications. And why is that? Because if you do surgery right from the beginning, it's very probable that this patient is going to recur endometriosis like in five years or even 10 years, and she'll need more surgeries afterwards.

A

And the surgery here is a laparoscopic procedure. It's a blunt force tool. You're going in and you're literally laparoscopically cutting out, excising, and you're. And are they that visible to the eye?

B

Yeah, most of lesions they are visible, but there are some tiny lesions that we cannot see. And that's why probably the recurrence rate, it's not actually recurrence.

A

Think about how different this is from cancer. Right. Like endometriosis presents like metastatic peritoneal cancer and no one in, there's no treatment that would ever involve surgery for that. You treat this systemically. Once the cancer is at that level, it's only systemic treatment. And the reason, of course, in part is because you can never get it all. Even if you only took what you can see, you know, you're missing things that are below the threshold of your vision. And so is that not the case here or is it the case that you're, 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?

B

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 endometriomas.

A

So it might be that surgery doesn't cause recurrence. It's just that surgery is a sign of recalcitrant disease. It's disease that doesn't respond to medication.

B

That's it.

A

And that's why those patients need repeated surgery.

B

And that's where the progesterone resistance come in, you know?

A

And you. Do you have an assay to measure this, or is it. It's just. It's a clinical diagnosis.

B

We don't have it. Yeah, we don't have it. And remember, they produce aromatase, they produce their own estrogen, like their own fuel to keep growing even. So we don't have like a chemo for endometriosis. We just have this ovulatory blockage. You know, we just suppress ovulation. And by doing that, we, of course, we decrease the risk of recurrence. There's a study published that showed that if you insert a merina 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 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 concept that was published in Nature reviews 7 years ago by Charles Chopron, a French group that calls the endometriosis life. What that means that we should not only treat the main symptom, but we should think about the life of this patient that has this disease that is chronic, like type 2 diabetes, type 1 diabetes, and so on. But we are mainly doing just one appointment, one surgery or one medication, and go. We're not thinking about the life, like what's going to be like in five, 10 years. Right. So we should change the mindset on that.

A

Okay, let's now consider a woman who's in her late 30s. She's had two kids, AMH is declining, so she's technically still fertile, but is not trying to conceive again and is mostly just trying to deal with her symptoms. And she has significant lesions in her pelvis. How do you approach her?

B

So first line medical therapy. Because remember, if she doesn't want to conceive, she needs contraception. So we could use a combined pill or progestin. In Brazil, we have this dienogest, which is a very good progestin for endometriosis. In the US we have the Natiza. Natiza is like estrogen, estradiol plus dienogest, but you need to use only the active. With Dienogest, there are 22 pills inside a box. And if she responds well, that's it. We are controlling the disease. Right.

A

And if not, you go to surgery

B

or we can use a Mirena.

A

Okay, so now let's go, same question. 36 year old, everything I said is the same, except now she wants to conceive, but her AMH is, as I said, declining and therefore the clock is running out.

B

So probably the objective is have a baby, right?

A

Yes, she wants a baby controlling pain. That's right.

B

But sometimes they present with both pain plus infertility. So this patient, we have 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. It's defined by the incapacity to achieve pregnancy after one year of trying to do that. So you need to investigate the male factor, like a sperm analysis, and you need to investigate other factors that not only endometriosis can impair in fertility. Right. So you need to ask to request a karyotype and some other exams like hysterosopingogram.

A

So let's say you do the fertility workup and you do not see any evidence in the mail with motility count or anything like that. And I'm making this up because I don't know if this is how it would present. They don't seem to have difficulty with a chemical pregnancy. But it never. She's always miscarrying at four weeks, six weeks, eight weeks. She's never getting past. Is that consistent more with maternal age?

B

Yes.

A

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.

B

Very good question. Actually. We now we mainly think of the mechanism, about a mechanical mechanism. We think that it's mainly mechanical, not biological.

A

Okay.

B

So the tubes are compromised, so they can't pick up the oocytes, or they can't permit the, the fertilization inside the tube and transport the embryo back into the uterus. Right. And surgery can fix that sometimes if the tubes are not too damaged, but we have some 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. 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.

A

And just to make sure I understand the surgery you're proposing is a laparoscopic. 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,

B

restore the anatomy and the functionality of the pelvis.

A

And is that because it is such a mechanical issue where the adhesions can literally kink the fallopian tubes or create obstructions?

B

Yeah, primarily, yes. But of course we have plenty of data showing that we have molecular differences between endometriosis and non endometriosis pelvis. For instance, we have C reactive protein IL6TNF alpha. But clinically it's mainly an anatomical problem. Right.

A

This is. It's so hard to believe that it's that crude, if you will, that it's plumbing. Basically, yeah.

B

But there are some authors that may argue that implantation. So the U top endometrium is also dysfunctional molecularly, but clinically not that much. Why is that? Because we have beautiful data and papers published like 20 years ago that compared women without endometriosis donor or oocytes. So good quality embryos. And they transferred the embryos. The implantation rate, miscarriage rate and live birth rate were pretty much similar. So which means that clinically endometriosis probably doesn't impair implantation. And that's very important for IVF too, because if you have a frozen embryo, you do IVF and you freeze all the embryos. If the patient has endometriosis, does she benefit from surgery before doing the frozen embryo transfer? Probably not. But if she has adenomyosis, she will probably benefit from doing the hormonal suppression because you cannot operate on adenomyosis. Mainly just the adenomyomas. They are not that common. But we cannot treat the uterus unless

A

you do a hysterectomy.

B

Yes.

A

So in other words, the only women who can be relieved surgically from adenomyosis are women who no longer want to conceive because you're going to do a hysterectomy. Do you do the oophorectomy as well? And the cell depends on.

B

Depends on her age. Ovarian reserve. But we always do the SALP injectomy.

A

You always take the tubes out when you take the. Over the uterus now.

B

Yeah.

A

Great.

B

Yeah.

A

Does is that standard of care?

B

Oh yeah.

A

There's no gynecologist that would ever leave tubes.

B

Yeah.

A

Okay. You Know that that's.

B

They should. Yeah, they should. Yeah.

A

Okay, so I didn't understand something you said a minute ago. You said that when you took 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 endometriosis own egg, correct?

B

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

A

Yep.

B

But if a patient with endometriosis is doing ivf, she will probably have less oocytes, less mature oocytes, and less embryos to transfer. Which means that she needs much more cycles to do than the patient without endometriosis. But that doesn't mean that the quality is impaired. It's very subtle. We have also molecular data showing that all sites in patients with endometriosis, they are not normal. But clinically, if you look into the data, just ask IVF patients with endometriosis or without endometriosis, is there any difference in quality? Probably not.

A

Okay.

B

Even aneuple rates, they are similar because

A

you're matching for age.

B

That's it?

A

Yep.

B

Age is the proxy for chromosomal abnormalities. Yeah.

A

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?

B

So probably we're going to offer Both options, but IVF is the way to go here because up to 34, the difference between a blastocyst with 31 or 34 years old in a patient that is 31 or 34 is not that different. It's about 35% of aneuploidy about that. If you are 30. Is it that high? Yeah.

A

A 31 year old woman has a 35% chance of aneuploidy.

B

30 to 35. Almost 1/3 of blastocyst. They are aneuploidy.

A

I mean, I just don't think of 31 as old.

B

Yeah, I know.

A

I almost think of that as prime reproductive age.

B

Yeah, prime time would be like 25 up to 30 because it's very.

A

So it falls off very quickly at

B

30, especially after 35 and 35. Aneuploidy is around 40%, around 40 and 38, around 60%, 40 around 70%, 40 to around 80, 85%. So it ramps up and so that's very important. So if you draw, I want to

A

make sure you and I are talking about this very casually, but I want to make sure the listener understands what we mean. Aneuploidy is when the egg is split. Split and you don't get an equal number of chromosomes, so you get either 2 or 0 instead of the one chromosome you want. And that's almost uniformly fatal. Those almost always result in miscarriages. There are a few notable exceptions like trisomy, you know, down syndrome, which is what? Trisomy. 21. Yeah, yeah.

B

So the definition is like aneuploidy is an abnormality in the number of chromosomes. So we have 46xx a female or XY a male. But so the normal way would be like 33 chromosomes from the egg, X and 33 from the sperm, X or Y. Right. So if you do the Math will be 46.

A

But 23 and 23, yeah, 23, sorry.

B

Yeah, 23 and 23, yeah. So 36 again. But if you have like problems in the egg because essentially any employee, they come from the old side, the maternal side. Yep, maternal like 93 and 95% they are they coming from the old side due to errors in meiosis. So they don't split the chromosomes. And now you can get monosomy one less or trisomy. As you said, they are the most dangerous because those babies can live, they can have the disease. Monosomy is not. We don't have compatibility with life, just the monosomy of X, which is Turners. 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 exams can get pregnant. Why is that? Because she's 38. Most embryos, they are not normal at that time. And we can have also miscarriage risk here.

A

Okay, so you're going to pursue both paths in parallel with her, but given her age, you're going to harvest some eggs and have them handy.

B

Yeah, Just coming back to the case. So we could do potentially to like two ways, two routes here. First one would be to go directly to ivf, then freeze the. Or the oocytes 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 5-6 cm, because they can.

A

It can get that big. Yeah, that seems massive.

B

Yeah. I have a patient now. She has 12 cm in one side and 8 cm in the other side.

A

Is the size proportional to the symptoms?

B

No. No.

A

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.

B

Yeah, that's the problem of the classification system that we have. We tend to use the asrm, that's the American Society for Reproductive Medicine classification. But it doesn't capture it all because it doesn't match the severity of the disease. It's classified from 1 to 4, like mild, minimal, moderate and severe disease. But it's just like a map, like a surgical description. It doesn't match with pain, neither fertility. So that's a problem. So ASRM4 would be very severe disease, but she can be asymptomatic, while a stage one patient could be at their homes just having pain and so on. So that's the problem we have. But we have, like, talking about classification and scoring. We have this endometriosis fertility index, which is a score based in some. You give like 0 to 4, depending on the quality of the tubes and the fimbra and the ovaries after surgery. So you can predict the rates, the pregnancy rates after surgery. So if the score is high, like 9 or 10, they have almost 65% of chances of getting pregnant naturally after surgery. So that's. That's useful. Which means that if the tubes are not okay, they are dilated, or you did have to proceed to. You need to do a salpingectomy, probably the chances are not that high after surgery. So you can walk them through IVF directly. So just coming back to that patient. So if you freeze the embryos, then you can operate on the endometriosis if there is indication. Mainly indications are large endometriomas, pain. If the quality of life is not good, you can operate on them. And small bowel lesions that can obstruct and sometimes urethral involvement, which can lead to kidney function loss. Actually, I had a patient with. She had a nephrectomy, left nephrectomy due to endometriosis in the ureter. Like silent disease, mostly. She developed hydronephrosis hydronephrosis. And the urologist performed a nephrectomy. Oh, yeah. So those are the red flags. Those are the red flags. To perform surgery even without symptoms like appendix is important too, because sometimes it just mimics neuroendocrine tumors. It's essentially the same phenotype. Wow. And small bowel and ureterm. You need to operate on them.

A

Okay, let's talk about a 32 year old woman comes to you. She has had difficulty conceiving, two failed IVF transfers. You're seeing her for the first time, you do a workup, you find she has adenomyosis. What can you do to help this woman?

B

That's very common. A very good example, Peter. So if she still have embryos frozen.

A

Yes, let's assume she still has. So she has three embryos still frozen. Two of them. She got a lot. She had a decent reserve. But two have failed and now they don't want to waste anymore without knowing what's going on. So that's why they came to.

B

So she has embryos that are frozen and you can perform if she didn't do that yet. GnRH, analog or agonist use before the transfer. What? That means that you can treat adenomyosis with medication suppressing the ovulation and suppressing the estradiol levels. So it can produce like a menopause symptoms. That's the side effect. But we have data showing that this can increase implantation rate but decrease miscarriage rate and increase live birth rate. So why does that work? You are treating the uterus. Right. So estrogen can trigger adenomyosis. Lesions can.

A

Just like endometriosis.

B

Just like endometriosis. And if you use generation antagonists, we have now in the.

A

What are the preferred ones?

B

We prefer like, we have much more data with analogs, the agonists, Lupron, it's called Goserulline. They are injectable subcutaneously monthly. Right. So two to four months with this. And then we transfer the embryo using

A

just tiny smallest amount of estrogen.

B

Yes. And high amounts of progesterone. Okay, so that's this strategy nowadays. Nowadays we have the antagonist, the oral antagonists. In the US they are very expensive. They are called Elagolix and Religolix. But they are oral medications. We had just one paper published last year that compared the use of antagonists versus agonists and they are pretty much the same here we have less side effects, they're very expensive. I think around $1,000 per month. So in Brazil, we don't have these medications. We mainly use the agonists. And by doing that we can achieve similar rates of pregnancy and miscarriage as patients. If she didn't have endometriosis. Adomyosis. Sorry.

A

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.

B

So mainly 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, then you downregulate the receptor and then you have this suppression, hormonal suppression. So you produce the menopause essentially chemically. But the antagonist, the action is right in the first medication. So you don't have this flare up effect. But essentially the objective is the same.

A

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?

B

Good question. Not much, but yeah, sometimes we just see the uterus shrinking a little bit, like reducing in volume. But sometimes the lesions, they are there.

A

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?

B

Actually it's a problem in pregnancy maintenance.

A

I see. So she implanted, but something happened in the first week or two weeks or. Where is she typically failing?

B

Six to eight weeks.

A

Oh, wow.

B

Yeah, sometimes even further.

A

Okay, and why?

B

Because there are contractions, that junctional zone and the uterus is just trying to kind of expel the embryus and.

A

Okay, so then you give her four months of treatment. But you said you don't really shrink the adenomyosis.

B

Morphologically not that much.

A

But chemically you shrink.

B

Chemically, yes. Yeah.

A

And then you can give her the embryo back, low dose of estrogen, lots of progesterone, the embryo implants. And is there a critical window in which she just needs to make it through to then not have the adenomyosis or any form of contraction be a problem? Does this increase her risk of premature labor if it starts to contract too soon? Like how does it play out through their nine months of Pregnancy.

B

If you do the treatment, you have higher chances of implantation and lower chances of miscarriage. But we don't have data on pregnancy complications. But we know that endometriosis and adenomyosis, they can increase the risk of preterm birth, like preeclampsia and small for gestational age, C section rates.

A

So if you're speaking to this woman, before you'd go through all of this, you would say to her, look, if you were a 32 year old with none of these issues, you had no adenomyosis, you had nothing. And we were just doing IVF because there was some reason you were struggling to conceive, your rates of success would be X. Now, because of this condition, how much less are your chances of.

B

Around 30% less with adiomyosis. Wow. But depends on the phenotype. If you have the involvement of the junctional zone, you have a three times higher risk of miscarriage.

A

Because it's more likely to contract.

B

Yes. It's right on top of this surface where the embryo is going to implant.

A

And remind me again, did you tell me already why you think adenomyosis is occurring? We think there's a disruption basically in the boundary layer.

B

Yeah. The decidualization, the progesterone resistance, the contractions in the junctional zone and the urus. Sometimes it just. You can see even. Yeah, yeah. The hypertrophy, you can see the contraction, sometimes ultrasound.

A

Are there drugs in the pipeline that are trying to address the progesterone resistance?

B

No. Not gonna say no.

A

It seems like that would be an interesting area of study.

B

Yeah.

A

Because if the. For example, we know that insulin resistance is largely mediated by a failure inside the cell when the insulin molecule hits the receptor and it triggers the kinase in the cell. And we have a sense of what that is. And there's even a drug that can target that directly. So it's conceivable that with enough understanding of what happens when the progesterone molecule hits the progesterone receptor inside the cell, what creates the resistance? Seems that that would be one opportunity.

B

Yeah, probably. But we are now just.

A

You're just giving more and more progesterone.

B

Progesterone.

A

If that woman who was 32 had been diagnosed immediately, could she have been treated with high dose progesterones and other hormonal therapies to have not arrived where she is, like during pregnancy? No, pre pregnancy. In other words, could she have been maintained on some sort of birth control routine for three years prior to trying to conceive and Would that have increased her odds?

B

That's the point, Peter. We think that if we diagnose an adolescent or even a young woman earlier, we can avoid 40% of the lesions or the disease burden. So, yeah, probably, yes, but we don't have much data on that.

A

So why don't we have much data given the prevalence of this condition?

B

Because if you look at the economic side, NIH, like, invests 15 times more dollars on diabetes than endometriosis. But endometriosis, an endometriosis patients might cost around $16,000 per year, while a diabetic patient would cost $12,000 per year. So we don't have much funding for that.

A

Why do you think that is?

B

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 then. So I think that's just. It's coming up, you know, that's it. I think that it's just a question of time, probably like menopause, right, that we're seeing this revolution.

A

Are there any other good case examples you can think of that. Well, actually, let me give you one more. So let's take another one where a woman is 30 years old, she would like to conceive, but she's not trying to at the moment. But her symptoms are horrific. So she has the worst symptoms you've ever seen. Truly debilitating. When you look at the ultrasound and the mri, you don't see a very high burden of disease. You see a very diffuse disease, but nothing big. You will always try chemical therapy first, you'll always try hormone therapy first.

B

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

A

What is the biggest mistake that happens with respect to surgical intervention? What's the biggest patient selection mistake?

B

I would say that if you have a patient that has central sensitization and you think that this surgery is going to resolve that, that's the biggest mistake, because surgery doesn't attack that layer of pain, the nociplastic pain. So we need sometimes physiotherapy eight weeks before surgery to prepare the pelvis, and then you operate on them. And after surgery, two to four weeks, you can restart the physical therapy. So that would be the optimal approach. The second mistake is to take out all the cysts that you know that you see, like the endometriomas, because that can impair fertility by reducing not fertility per se, but IVF outcomes. Because you reduced amh.

A

Because each of those cysts explain why

B

that's the case, because they are not actually very defined cysts like pseudocysts. So when we strip them out, you end up by taking some follicles and oocytes that are healthy adjacent to the cyst. So we have data showing that.

A

Wait, you're saying that endometrial cysts are dragging follicles with them?

B

No, they are very attached to the cortical part of the ovary where the primordial follicles are. So when you take out the cyst, you do a cystectomy, you can reduce AMH by 40%, sometimes 50%.

A

So you don't want to take the cysts out if you're trying to preserve fertility.

B

Yeah, but that's a double dashed sword. Why? Because the presence of the cystic decrease the amh.

A

Because it's draining.

B

Yeah, it can decrease the amh.

A

So shouldn't you harvest the eggs first?

B

That's it.

A

Okay.

B

Yep, that's it. And the mechanism is beautiful, explained by this phantom reaction, the same one that we know, and it produce hydroxyl 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 now that this low ovarian reserve. So I think that's one big mistake. I think maybe the third mistake would be to leave a damaged tube hydrosalpinx just to preserve the tubes. But we know that this can reduce the IVF chances by half. So if you have a dilated tube, because the mechanism is like washing the embryos like they are connected to the uterus.

A

So this you're saying even if you implant in the uterus, just having the damaged fallopian tube can decrease the success of that?

B

Yes, by half. By half. So there's that.

A

Is that widely known?

B

Yeah, yeah, we have Cochrane review on that.

A

Okay.

B

So we have this mechanical effect and also it's embryo toxic cytokines being secreted down into. Yeah, we need to take out that you need to do a salpingectomy in your practice.

A

How much time are you spending on endometriosis, inclusive of discussions around fertility? Like, how often are you operating for this?

B

Operating?

A

Yes.

B

Like, you mean surgery, right? Yes. Probably 20% of cases.

A

20% of your cases are removing endometriosis.

B

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, so.

A

Okay, so let's pivot and talk a little bit about that. You have arguably the premier fertility clinic in Sao Paulo in Brazil, and this is a huge clinical interest of yours. What do you think is the most misunderstood thing about fertility that we haven't already discussed? Now, you've already made a very important point, which is it's a disease of two people, not one. But as it pertains to the female side of the equation, you've also shared numbers that are even worse than I imagined. With respect to aneuploidy and age, what else do you think is just not fully realized by a person or a couple out there that are trying to conceive?

B

I want just to emphasize that age is the most important factor. And even doctors, they just don't realize it, because sometimes you just see the patient with the doctor trying, like, they operate on them and they try to conceive naturally at 42 years old. So that's a big mistake, because you're just feeding this desire of natural pregnancy that it's not that common at that age, and the risks are very high. So age is probably. Nobody knows that a lot. So what I do in my clinic during the appointment, I show a table. We can put in the show notes of the annual rates by year after year. And it's very interesting to know that it's not linear. It's not linear.

A

No, it's exponential.

B

And it's not only exponential, but it's like this. We have a sweet spot.

A

It's a J curve.

B

It's a J curve. Very young patients, they can have monosomy.

A

Oh, I didn't know that.

B

Yeah. And we see that in other primates. We don't know why, but that's not that risky for the couple. Right. Because monosomy, they don't live. Right?

A

Yep.

B

But the sweet spot would be around 25. And even at.

A

So you're saying at 20, you have a worse chance than you do at 25 because the egg is more likely to be missing a chromosome.

B

Yeah, I would say that the risk of Aneuploidy is probably higher at 20 than 25, but of course that's incredible. Yeah, it's incredible.

A

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?

B

Yeah, that's why.

A

More than 20 year olds or 18 year olds and obviously 30 year olds, it's really saying, I want this. A 25 year old woman is the perfect fitness to carry, deliver and raise a child.

B

That's exactly what I think. But we don't, we are not sure yet about that. But that's interesting because do we think

A

that that's drifted like do you think 200 years ago, if we could go back in time, do you think it would have been lower?

B

I don't think so. Because the mechanisms, they should be the same. Right?

A

That's unbelievable.

B

Yeah. So that means that if you're, if you are 25 and going to IVF, not all the embryos, they are going to be euploid, about 20% or 25% will be anuploid.

A

Even at 25.

B

Yeah.

A

20 to 25% of your eggs are already. So you never are walking around fully Euploid.

B

So what I say to my patient speaker is that reproduction in humans is, it's very inefficient. So if you think about it, you need one egg. You lose a thousand eggs every month.

A

You ovulate, you make one, you lose a thousand.

B

Yeah, you lose a thousand. Apoptosis, but you just have cohort of like 10, 15 and of them just one ovulate and you have 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 reproduction system, it's not that efficient. If you look into the data of like mouse or rabbits, any polarity rate is very low. They are very efficient at producing good embryos. And that means that when we do ivf, we are just grouping, we're just like making more embryos, but we are not increasing their quality. So if a woman is 40, you sometimes need to do much more cycles.

A

But all things equal, if you take the 40 year old versus the 25 year old, once you have euploid eggs, are the qualities the same or are there other non visible changes? So for Example, we know with sperm they're not the same, even though chromosomally they appear the same between 25 and 50, we know that genetically they're different. And so older fathers are more likely to produce children with more neuropsychiatric polygenic conditions. But what do we know on the egg side?

B

Yeah, that's a good point. We have data on that. There's a beautiful table showing that the clinical pregnancy with euploid embryo at 30, 35, 40 and so on, it's pretty similar. But we know from the lab, if you ask an embryologist, she would say that the amber is not that quote unquote beautiful. You know, sometimes morphologically they are different. The morphokinetics they are not similar. But clinically it's not that big difference.

A

Interesting.

B

Yeah.

A

Would you advise a woman who's listening to this, who's 25 years old, who is in graduate school, business school, law school, medical school, Pick your favorite who still has five, six, seven years ahead of her in really, really working hard and does not want to have a child in that period of time. Maybe she hasn't even met her partner yet. But she deep down thinks she wants to have a child. But it's possible she's not going to be thinking about it for another 10 years till she's 35. So she's 25 and you're her regular gyn, just you're doing your regular sort of exam. She tells you all of this. Would you advise her to freeze eggs right now at 25?

B

Not for all the patients, but I would say that it's reasonable to do an amh, like check your reserve. Right.

A

But let's say she's normal, she's not defeat. 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 can't tell you, Hanato, I'm definitely going to do it by 30. In which case maybe you could say, okay, it doesn't change much.

B

Yeah. If she's sure that she won 30, she wants child children in the future. I will talk to her. But the chances, you know, look at this statistic, Peter. What do you think is the, the rate of patients that come back to use their own oocytes, like globally, all

A

the women who freeze eggs.

B

Yes.

A

You're saying how many of them never come back and Touch them?

B

Yes. Of 100 women that froze their eggs, like how many come back, are coming

A

back to, to do something with them?

B

Yeah.

A

75.

B

Actually around 10%.

A

What?

B

Yes.

A

90% of women who freeze eggs never touch them.

B

Yeah. Or because they, because they get pregnant. Maybe they got pregnant. Sometimes they just don't want to use that. But the sweet spot would be around 3, 30 something. 32, 35. Because the cost effectiveness of doing that is better than at 25. So biologically, of course, does it make sense to freeze earlier? But the chances of the time you spend on it, the cost you spend,

A

help me understand the costs. And I know it's different in Brazil from in the US but assume in Brazil this is all paid by out of pocket. So I think in the same in the US I don't even understand us.

B

I think there, there are some differences.

A

Some.

B

Yeah.

A

But let's talk about the cash 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

B

in Brazil, she would spend about $5,000 US dollars. US dollars. Because our currency is like five to one.

A

Okay, so she spends US$5,000 to do one harvest cycle and then how much does she spend per year to keep them in storage?

B

It's like $150 compared to the.

A

Okay, so the big cost is she's going to incur that. And again, I'm just being devil's advocate. My view is if you could afford $5,000, why not do it at 25 instead of 30? Just because you've capped your downside? Your downside is you're out $5,000. Your upside is how many would you expect? How many euploid eggs do you expect to get out of a 25 year old per cycle?

B

We are talking about blastocyst or embryos in day five to day seven. About 80%. Around 80, 75, 80% of the embryos, they are Euploy.

A

But since this is not embryos, you're not going to be fertilizing these. You're just getting an egg.

B

Yes. So we have a.

A

So you don't much gram.

B

You don't just freeze the, the M2 oocyte, the mature oocyte, you won't know until you fertilize about 75%, 75% of the oocytes, they are matured. So we freeze just the mature eggs. And we have some calculators to like to estimate the pregnancy rate and not Only that, but the 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

A

least one baby, which still seems not that high. But.

B

Yeah, but remember a fertile but that's

A

all the way to baby. Meaning. Yeah, yeah. So how many embryos and then each implantation has a rate of fall off, et cetera. Okay, so.

B

So biologically of course that makes sense,

A

but economically it doesn't.

B

Yeah, that's just economics.

A

Okay.

B

The risk is pretty low. Like the risk of overintortion and bleeding and, you know, infections. It's about 1%.

A

And the main driver of that cost is the medication. The procedure. Is it split about equally?

B

Yeah, one third medication, 1/3 procedure, 1/3 like clinic and 1/3 lap.

A

Yep. What is the median age of women who are coming to you to have eggs frozen but they're not planning to fertilize?

B

Mine is 37. 38. Yes. Very high.

A

Why so high? Why are they coming so late for eggs?

B

Because I think that's just a new treatment kind of new treatment. And because I have bias as wearing so taller.

A

Like you're treating the hardest cases.

B

Yeah, probably.

A

So when a 37 year old woman comes to you, I assume she's been trying for a while to get pregnant because she's 37, she's probably had many aneuploidic miscarriages. So she comes to you and says, look, we can't leave this to chance anymore. You're going to do a cycle. You will typically get how many oocytes in her?

B

So my infertile patient is even older, 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 a 40 year old woman, what's

A

a typical AMH for a 40 year

B

old would be around 1 nanogram per milliliter.

A

And that corresponds to roughly how many eggs left.

B

Depends a lot on the cohort on that cycle, which can be different between the follicular phase and the luteal phase. And that's very important for from a practical standpoint, because sometimes we check the ovaries, we do the anthropological count, that's not fine, we wait and recheck another phase because it varies a lot. But we would expect around eight eggs, something like this. Okay. And eight eggs at 40 is not sufficient mostly to produce aneuploid embryo.

A

Oh my God. Because eight eggs, you're going to fertilize them and More than half of them are going to be aneuploid.

B

Yeah. So you might get 2, 80% of them. Yeah.

A

Okay. So you might get 1 to 2 euploid to implant.

B

Yeah. We say that it's like a funnel. It's very important for the layperson to understand that you have the follicles. Each follicle might have one oocyte. Every oocyte has a chance of being matured.75%. Every matured egg can be fertilized and on day one, present this pronuclei. We say that it's fine, that's the M2 phase. Yet after the M2 phase, and then from day one to day five or day six, which is a blastocyst, around 30, up to 60% of those, day one can develop into a blastocyst. It depends a lot on the sperm quality too, and the lab, of course. And on top of that you have the aneuploidy rate.

A

So hence the inefficiency. You're just multiplying negative numbers. After you're multiplying so many small numbers together that the outcome is very difficult.

B

So when the patient is freezing her own eggs, it's very important for her to know that, you know, the funnel is deep. Very important because sometimes it's very sad to see a patient that is coming back. Like she froze her eggs at 34 and she's coming back at 40 and she had just eight eggs and now you thaw them and then you produce just one blastocyst and doesn't implant. So that's it. And now she's 40. Yeah.

A

Which again goes back to my question of why isn't every 25 year old woman who is unclear on her timeline? I guess, you know, it's funny, like, I wonder if in countries where population growth is not high enough. So if you look at a country where the reproductive rate is below 2.1 and that turns out to be a lot of countries and immigration alone won't solve your demographic problem, you actually need de novo reproduction. This strikes me as a reasonable cost for the government to bear.

B

Yeah. Japan is facing this right now. So in Israel you can do how many cycles you want. You need to produce your family. Yeah. So I think from a longevity perspective, you're right. You can avoid this disease called infertility, but you can prevent that by freezing oocytes earlier. But I think that's a problem of access right now we have the technology.

A

Yeah. Okay. Now let's talk about something very extreme at the other end of this spectrum. So you now talk about that woman who's 40. She's come back only to realize that nothing worked. But she still wants to have a baby. So right now her only option is to use an egg donor. Correct. Okay. In which case she will use the egg of a young woman. She'll use the egg of a 25 year old woman, likely with her partner's sperm. And that's fine. That's a great treatment. Right. That works very, very well. But I have now heard about an emerging technology where that woman who is 40, can use her genetic material with the remainder of the egg from a donor so that she has all of the benefits of the young egg, except she gets her genetic material in there so that the donor is only providing the scaffolding and she could even use a surrogate. So help me understand that technology.

B

Yeah, that technology is called mitochondrial replacement therapy. So that doesn't solve the problem because the problem is in the nucleus, right?

A

Yep.

B

So the problem is chromosomal. And we had, I think two papers published last year in New England Journal of medicine by a UK group, Newcastle, but 22 patients with mitochondrial disease, because remember we have like 20,000, up to 25,000 genes and 37 genes in the mitochondria, the so called mitochondrial DNA. And for those very specific cases, they basically took out the pronuclei from the parent embryo, fertilized after fertilization. So they have in day one, the pronuclei they take out and they insert in a enucleated oocyte, new oocyte that has this new mitochondria that are normal, they are supposed to be healthy. So this solves just the problem of the cytoplasm, the mitochondria.

A

Ah, I see, so it is not solving the age problem.

B

No, got it. And this, as far as I know is not available for infertility, but there are some clinics, I think in North Cyprus or Greece and they're like selling this as a egg rejuvenation. That's misleading in my opinion. But you are just trying to replicate. It's like a battery swap for the egg. But you're not changing the engine, right? Yep, the engine is the main problem.

A

So is there currently anything on the Horizon for the 40 year old woman who wants to conceive and would like it to be her genetic material even though she no longer has eggs or if she has any eggs, they're not dividing correctly.

B

They're, I think, yeah, not for that situation, but there's a clinic in the UK that is trying to freeze Ovaries, like cortex, like long years before menopause. Like to prevent or to postpone menopause. Yep, Very interesting idea. But we don't have publications on that. Actually, you have a huge line, like a huge wait list of patients trying to do that. Makes sense. But we don't have data.

A

Sorry. Just make sure I understand that. So the analogy would be somebody with type 1 diabetes that gets implanted pancreatic or beta cells that secrete insulin.

B

Autologous.

A

Yes, autologous. Is this her own ovarian tissue that was set aside earlier in life, like at 30s. At 30s. And so they do a partial oophorectomy.

B

Yeah. And you can then transplant like 45 when you are 45, and then you can postpone. There is actually a, like a math behind that. You can Postpone Menopause like 10, 15 years, sometimes even more.

A

Where do they reimplant?

B

In the same.

A

In the peritoneum.

B

Yeah, peritoneum.

A

Okay.

B

Or you could put in the subcutaneous soup.

A

And so you're not only postponing menopause from a hormone perspective, you're postponing fertility.

B

Yeah, Actually, that's mainly for menopause. Like to produce her own.

A

That's just to produce estrogen and progesterone.

B

Yeah. But for all sites, we have data on ovarian cortex freezing. But the better outcomes, they. They come from egg freezing.

A

And why would this autologous ovarian implantation or transfer be superior to just standard menopausal hormone therapy?

B

That's the question. I just gave a lecture last year about that. So I think because of the cultural thing about menopause. Right. About hormone replacement therapy after 2002. July 2002. Whi. Right. I think there's just this big misconception about menopause hormone therapy. It's much more. It's much easier to just give estrogen, progesterone, and sometimes testosterone than freezing the ovary and then transplanting and probably getting like, premenstrual syndrome, you know, symptoms doing that. Yeah, but we don't have data. But to your question, we probably in the future we're going to have like, stem cells producing new oocytes. We are not there yet.

A

I read an article very recently suggesting that that could be five years away. What's your view on that? Are you optimistic?

B

Not that much. I think more like 10 years.

A

Why? Why so difficult? What has to be done? Explain what it is.

B

First of all, I think I'm not the right person to answer that, but it's Very hard to produce an egg. It's easier to produce a sperm and we don't know the consequences of that. So we need data after doing fertilization and transferring to see if those babies are healthy. They still healthy.

A

And we're doing this in animals right now?

B

Yeah.

A

Which animals? How?

B

I think cattle, probably. Yeah.

A

And so are they doing this in primates yet?

B

I'm not sure, but probably, yes. Yeah.

A

Okay, so what has to be done is you have to demonstrate that you can take a pluripotent stem cell and somehow turn it into an egg. And that hasn't been done yet, but if you can do that, you have to ensure that that becomes chromosomally and genetically normal. In the long event that has been.

B

There's a publication about that. Yeah.

A

That you can make the egg out

B

of a stem cell, but we are not sure about the consequences and the clinical benefits of the, like, the safety of the egg.

A

Has it been done in mice?

B

Yeah.

A

And in mice, because their lifespan is short enough, does it produce a normal phenotype?

B

Yeah.

A

Okay, so that's promising, but not guaranteeing.

B

Yeah, but that's going to be like a game changer for us. Yeah. I think when we do that, we are going to not do any more vitrification, like frozen. We are not freezing eggs anymore. Right.

A

So just imagine that. So you're saying in 10 years, any couple of any age could potentially reproduce?

B

Probably. I don't know if that's safe. That's going to be safe. Like, if you ask me, you are 30. Me and my wife, we are healthy. We don't have any fertility problems. Would you do IVF or try naturally?

A

Always start naturally.

B

And why is that?

A

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 look, if you struggled for a year, we wouldn't hesitate to do ivf, right?

B

Yes. But for me, I think we are like, IVF is. The first baby was 78 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 don't know what are the consequences. So if the couple has this natural chance, I will try naturally and

A

the stem cell takes it to a whole new level.

B

The problem is, yes, you can count on stem cells. Okay. But wouldn't be better to use my own oocytes that I just froze, like at 35?

A

Yeah.

B

I don't know. Probably. Yes.

A

Is there anything about IVF that we don't know that worries you? Like what are the unknown unknowns about ivf?

B

The genetics. Yeah.

A

And how do you think that shows up phenotypically?

B

Probably some malformations, some neuro. Neurological consequences. Heart disease.

A

Do we see this in the epidemiology? I mean, so again, people born of IVF are still very young.

B

They're.

A

Yeah, you know, they're, they're not even.

B

Louis Brown is like 40 something. Yeah, 48.

A

She's 48.

B

Yeah. Yeah. But we see definitely some signs. We, we're not sure about whether it's bias. A selection bias.

A

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 sort of infertility, there's certain. So many confounders. And we're never going to do a randomized controlled trial for ivf, but there's

B

data showing that if that same couple that needed IVF and then now they are getting pregnant naturally. Because sometimes it happens. Right. It's mainly a bias, a selection bias problem, not the technology itself. Yeah, but it's a new technology. Right.

A

So what are you most excited about in your field today?

B

Actually I was very excited about this new guidance from acog. Very simple because probably you are going to avoid complications of endometriosis and adenomyosis, especially in those vulnerable adolescents, and not only treat the disease, but as like statin in longevity, you can modify the disease progression early, earlier and avoid infertility. And I'm very excited about this. So we should spread this word. Right. And there, there's one molecule called HMI115. It's antibody, monoclonal antibody that targets the receptor of prolactin. Probably this leads to. It's in phase three trial now and this leads to less pain and less disease progression. Endometriosis, because those lesions can express prolactin receptors. Very interesting. Maybe that's going to be the first biologic treatment for endometriosis that it's not using hormones. So like to your point that some. Why don't we have like medications that

A

target the disease directly?

B

Yeah, yeah, probably we're getting that like soon and. Yeah. And I think the diagnosis, Peter. Yeah, yeah. I think with this widespread, you know, ultrasonography, an MRI and just the awareness of the disease, we're gonna not only diagnose and treat more effectively.

A

Okay, so basically the final and closing thought here should be. If you're listening to this and you're struggling with any symptoms that may be even remotely suggestive of endometriosis or adenomyosis or your partner is experiencing them, the biggest single win is getting that diagnostic window from six years in the US or seven years in Brazil down to six months. That's it. So you just have to be a bull in a china shop and demand a diagnosis and say, I'm not going to take no for an answer. I want an MRI and if necessary, I want an ultrasound done with this correct protocol.

B

That's it.

A

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.

B

And you know, Peter, just to close that, the cases that stay with me are not the most complex surgeries, not the difficult IVF cycles. They are those women that cry not from pain, but during the appointment from relief.

A

They finally have a diagnosis.

B

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

A

Perfect way to end it. Hinato, thank you very much. I really appreciate you getting this message out.

B

Great to be here. Thank you, man.

A

Thank you for listening to this week's episode of the Drive. Head over to peterattiamd.com shownotes if you want to dig deeper into this episode, you can also find me on YouTube, Instagram and Twitter, all with the handle P. Peter Attia md. You can also leave us review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit Peter Attia, where I keep an up to date and active list of all disclosures.