#397 ‒ Endometriosis and adenomyosis: diagnosis, fertility, reproductive aging, and emerging treatments | Renato Tomioka, M.D., Ph.D.

View the Show Notes Page for This Episode https://peterattiamd.com/renatotomioka/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260622-pod-renatotomioka&utm_content=260622-pod-renatotomioka-podfeed Become a Member to Receive Exclusive Content https://peterattiamd.com/subscribe/?utm_source=podcast-feed&renatotomioka%20=referral&utm_campaign=260622-pod-renatotomioka&utm_content=260622-pod-renatotomioka-podfeed Sign Up to Receive Peter's Weekly Newsletter https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260622-pod-renatotomioka&utm_content=260622-pod-renatotomioka-podfeed View our full terms of use https://peterattiamd.com/terms-of-use/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260622-pod-renatotomioka&utm_content=260622-pod-renatotomioka-podfeed Renato Tomioka is a leading expert in reproductive medicine and gynecologic surgery whose unique skills allow him to diagnose and treat some of the most impactful yet frequently overlooked conditions affecting women's health. In this episode, Renato explores endometriosis and adenomyosis, explaining what these conditions are, why they often go undiagnosed for years despite affecting millions of women worldwide, and how advances in MRI and specialized ultrasound are transforming diagnosis beyond traditional surgical laparoscopy. He discusses the decision-making process behind hormonal therapy versus surgery, how treatment strategies change when fertility preservation is a priority, and where IVF fits into the care pathway for women with endometriosis, adenomyosis, or age-related fertility decline. Renato also examines the profound effects of female age on egg quality and quantity, including the accelerating rise in chromosomal abnormalities after age 35, highlights common mistakes in both surgical and fertility management, and shares promising developments on the horizon for treating these conditions and preserving fertility. Follow Dr. Tomioka's work: Instagram: @dr.renatotomioka https://www.instagram.com/dr.renatotomioka; Website: Renato Tomioka, M. D., Ph. D. https://www.renatotomioka.com We discuss: 0:00:00 - Intro 0:00:11 - Endometriosis: definition, prevalence, infertility risk, and theories of disease development 0:09:03 - The biology of endometriosis: estrogen dependence, progesterone resistance, and tumor-like growth mechanisms 0:13:25 - Adenomyosis explained: how it differs from endometriosis, why it develops, and its impact on reproductive health 0:18:52 - Recognizing endometriosis and adenomyosis: the "6 Ds" of endometriosis and key differences in clinical presentation 0:22:09 - Uterine fibroids: classification, symptoms, and the importance of fibroid location for bleeding and fertility 0:24:09 - Understanding endometriosis pain: lesion-driven pain, nerve involvement, central sensitization, and the importance of early treatment 0:28:26 - Endometriosis in young women: rising prevalence, delayed diagnosis, and barriers to care 0:33:11 - Modern diagnosis of endometriosis: specialized ultrasound, MRI, and the decline of diagnostic laparoscopy 0:45:52 - Clinical case example #1: Managing endometriosis in a young woman seeking pain relief while preserving future fertility 0:54:10 - Clinical case example #2: Comparing treatment strategies for symptom control versus fertility 1:01:24 - Endometriosis and fertility: the roles of age, embryo quality, IVF, and surgery 1:11:50 - Clinical case example #3: Managing adenomyosis after failed IVF transfers to improve implantation and pregnancy outcomes 1:20:51 - The funding gap in endometriosis research: disease burden, economic impact, and growing awareness 1:22:01 - Clinical case example #4: Surgical decision-making in endometriosis—balancing pain relief, fertility preservation, and common treatment pitfalls 1:27:43 - Common misconceptions about fertility: maternal age, embryo aneuploidy, the inefficiency of human reproduction, and the limits of IVF 1:34:23 - Elective egg freezing: timing, success rates, the fertility funnel, and the tradeoffs of fertility preservation 1:45:49 - Emerging fertility technologies: mitochondrial replacement, ovarian tissue preservation, stem-cell-derived eggs, and current limitations 1:55:10 - The future of endometriosis treatment: new guidelines, biologic therapies, and unanswered questions about IVF 1:58:30 - Why earlier diagnosis matters: reducing years of suffering from endometriosis and adenomyosis Connect With Peter on Twitter https://twitter.com/PeterAttiaMD, Instagram https://www.instagram.com/peterattiamd/, Facebook https://www.facebook.com/peterattiamd/ and YouTube https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:11Dr. Peter Attia?

  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 to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription.

• 0:54Dr. Peter Attia?

  If you want to learn more about the benefits of our premium membership, head over to peterattia MD dot com forward slash subscribe. My guest this week is Dr. Hanato Tomioka, a leading expert in reproductive medicine and gynecologic surgery. Hanato's clinical work sits at the intersection of three closely related fields: reproductive medicine, minimally invasive gynecologic surgery, and gynecologic endocrinology, a combination that makes him uniquely equipped to diagnose and treat some of the most consequential and under-recognized conditions women face today. Endometriosis affects roughly 10% of reproductive-aged women, about 200 million women globally,

• 1:39Dr. Peter Attia?

  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 Hanato decides between hormonal therapy and surgery, and how those decisions change when fertility is part of the goal.

• 2:20Dr. Peter Attia?

  Where IVF fits into the pathway for women with endometriosis, adenomyosis, or age-related fertility decline. How female age shapes egg quality and quantity, including the steep nonlinear 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.

• 2:59Dr. Peter Attia?

  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.

• 3:37Speaker 01

  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. And 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 endometrial-like tissue, very similar to the endometriose, is outside the uterus. Instead of being inside that layer, it goes into the fallopian tubes on the ovaries, on the bowel, the bladder, sometimes the appendix, and even the diaphragm.

• 4:22Dr. Peter Attia?

  Hmm.

• 4:23Speaker 01

  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.

• 4:43Dr. Peter Attia?

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

• 4:51Speaker 01

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

• 4:58Dr. Peter Attia?

  So it's causal?

• 4:59Speaker 01

  Yes.

• 5:00Dr. Peter Attia?

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

• 5:13Speaker 01

  Very dynamic, very dynamic, depending on the duration of the cycle, of course, where you are in the cycle.

• 5:20Dr. Peter Attia?

  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?

• 5:31Speaker 01

  Precisely.

• 5:32Dr. Peter Attia?

  Okay. And then the outer layer, tell me about that again functionally.

• 5:35Speaker 01

  It's just a peritoneum.

• 5:37Dr. Peter Attia?

  Okay.

• 5:37Speaker 01

  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 adenomyosis, like external adenomyosis, I mean.

• 5:59Dr. Peter Attia?

  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?

• 6:20Speaker 01

  Great question. So we have about 50% of heritability.

• 6:25Speaker 01

  If you have a first degree relative with endo, you have about seven times higher chance of having endometriosis. So that's the the.

• 6:38Dr. Peter Attia?

  So meaning mother or sister?

• 6:40Speaker 01

  Yeah.

• 6:41Dr. Peter Attia?

  Okay.

• 6:41Speaker 01

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

• 7:14Dr. Peter Attia?

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

• 7:23Speaker 01

  Correctly. So remember the fibra, like the 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.

• 7:35Dr. Peter Attia?

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

• 7:40Speaker 01

  And it's it's actually most of the time the the oocyte is just on the surface of the ovary.

• 7:46Dr. Peter Attia?

  Uh huh.

• 7:47Speaker 01

  Sometimes it's inside the pelvis and the called the sac. But the fibra can pick it up and then permits the fertilization inside the the isthmus, right? Inside the the the middle part of the tube, essentially. But we know by old studies that around ninety percent of women, they have this retrograde menstruation, which is amazing. So you would think, why is that then just ten percent have endometriosis, right? Because sometimes we just it's not sufficient to have endometriosis, but it's probably necessary in the most in most cases. There are some nuances here.

• 8:30Speaker 01

  But those patients with endometriosis, they might have immunosregulation. 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.

• 9:14Speaker 01

  First pregnancy around 20, now 30 or more. Breastfeeding for two years per child, now almost-

• 9:22Dr. Peter Attia?

  And during that period, you're not ovulating.

• 9:24Speaker 01

  Yes. And they used to have like five, seven children. Now you-

• 9:29Dr. Peter Attia?

  So many times of not ovulating.

• 9:31Speaker 01

  So if you compare that women 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.

• 10:15Dr. Peter Attia?

  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 that, we didn't talk about menopause, but presumably they might not have even lived long enough to get to full menopause. So a woman today might have 400 cycles if uninterrupted or if not intervened with. And every cycle produces the risk of retrograde flow.

• 10:57Speaker 01

  That's it.

• 10:58Dr. Peter Attia?

  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.

• 11:19Speaker 01

  And if you look into the mechanism here, we have this estrogen dependence. The endometrial 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.

• 11:55Dr. Peter Attia?

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

• 12:25Speaker 01

  That's it. So remember the follicular, like the late follicular phase in the middle, people who works with IVF know that a lot, right? Because we are aiming to look at the endometrium at the final phase of the follicular part. So endometrium is about to like eight, 10 millimeters at that point.

• 12:46Speaker 01

  But when you have the progesterone, it opens the implantation window. So we have this so-called des individualization. Lipids and secretor phase comes in. And then at the ultrasound, endometriology 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 shuts because you have a decrease in estrogen and progesterone levels. So it shuts. So that is very important for endometriosis too.

• 13:27Speaker 01

  Because remember, it's like endometrial 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.

• 13:44Dr. Peter Attia?

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

• 13:54Speaker 01

  Yeah.

• 13:55Dr. Peter Attia?

  Because it's outside the body?

• 13:56Speaker 01

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

• 14:01Dr. Peter Attia?

  Okay, and they have progesterone receptors?

• 14:03Speaker 01

  Yeah.

• 14:04Dr. Peter Attia?

  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?

• 14:13Speaker 01

  Kind of, kind of, yeah. You need much more insulin or progesterone to produce the effect.

• 14:18Dr. Peter Attia?

  Yep. So why does that happen?

• 14:21Speaker 01

  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 resemble, 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.

• 14:57Dr. Peter Attia?

  But do they have metastatic potential?

• 14:59Speaker 01

  No, no. Why is that?

• 15:02Dr. Peter Attia?

  So in a sense, they're benign tumors?

• 15:03Speaker 01

  They are 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.

• 15:17Dr. Peter Attia?

  That's incredible.

• 15:18Speaker 01

  Yeah, it's like putting a 1,000 horsepower F1 engine into a golf cart. You just have the machinery, but you can't go further.

• 15:27Dr. Peter Attia?

  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.

• 15:36Speaker 01

  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 adenomyosis.

• 15:53Dr. Peter Attia?

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

• 15:57Speaker 01

  Yes.

• 15:58Dr. Peter Attia?

  Okay.

• 15:58Speaker 01

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

• 16:12Dr. Peter Attia?

  Understood.

• 16:12Speaker 01

  But now we are, we are calling this disease differently. Because they, they share some mechanisms, but they are different. If you look into the, 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, the mechanisms in-

• 16:35Dr. Peter Attia?

  What's the overlap? I'm sorry to interrupt you.

• 16:37Speaker 01

  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, you have cure in adenomyosis. If you do a hysterectomy, you can take out the disease. It's just a disease in the uterus. Endometriosis, it's outside the uterus.

• 17:07Dr. Peter Attia?

  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?

• 17:17Speaker 01

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

• 17:23Dr. Peter Attia?

  Up to 70% of endometriosis patients?

• 17:26Speaker 01

  Patients, they might have some type or some degree of adenomyosis. And that's very important for the infertile couple. So the mechanism in adenomyosis is the so-called T I A R. So it's tissue injury and repair. So essentially, the endometriol 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 ecogenic buds that like increase the volume of the uterus

• 18:09Speaker 01

  and makes it very soft to the touch. During surgery, it can palpate the uterus.

• 18:16Dr. Peter Attia?

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

• 18:20Speaker 01

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

• 18:29Dr. Peter Attia?

  But they can't get through the myometrium?

• 18:32Speaker 01

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

• 18:58Dr. Peter Attia?

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

• 19:13Speaker 01

  Mainly is that surgery, endometriopathy. 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, the deep infiltrated endometriosis is going inside the myometrium, from the serosa to the myometrium. And now we have not only endometriosis, but adenomyosis.

• 19:41Speaker 01

  There are some authors that think they are this, it's not correctly to say that it's adenomyosis. So mainly adenomyosis that we're talking about.

• 19:51Dr. Peter Attia?

  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?

• 20:06Speaker 01

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

• 20:25Dr. Peter Attia?

  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?

• 20:51Speaker 01

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

• 21:02Dr. Peter Attia?

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

• 21:13Speaker 01

  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.

• 21:26Dr. Peter Attia?

  And this is not cramping, this is actual pain?

• 21:28Speaker 01

  Pain.

• 21:29Dr. Peter Attia?

  Okay.

• 21:29Speaker 01

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

• 21:41Dr. Peter Attia?

  Intravenous medication.

• 21:42Speaker 01

  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.

• 21:57Speaker 01

  Third D would be dyskesia or pain during bowel movements. Especially during the period.

• 22:04Dr. Peter Attia?

  And the uterus is how close to the rectum? It's close, it's adjacent immediately, right?

• 22:08Speaker 01

  Yeah, yeah. And sometimes we can have lesions right there.

• 22:11Dr. Peter Attia?

  Yep.

• 22:11Speaker 01

  In the septum. Fourth D would be dysuria, like pain during urination, especially cyclic pain, usually during the menstrual period.

• 22:22Speaker 01

  We can have also like bleeding, but that's not very common. Fifth D would be difficulty in getting pregnant, so difficulty in conceiving, infertility. And the last one would be, I will put the D like just for a hook, for a memory hook, but it's dysfunctional chronic pelvic pain. So those women can present with pain for more than six months without any relation with the cycle. So you have a lot of this myriad of pain, you know?

• 22:55Dr. Peter Attia?

  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?

• 23:07Speaker 01

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

• 23:18Dr. Peter Attia?

  So their only symptom would be for infertility potentially?

• 23:21Speaker 01

  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.

• 23:41Dr. Peter Attia?

  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.

• 23:51Speaker 01

  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 submucos.

• 24:09Speaker 01

  Inside the myometrium, intramuscular or on the serosa, 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 miscarriage. And they can bleed too, especially the submucosis. Yeah. We classify them by the International Federation of Gynecologists and Obstetricians, by zero up to seven, depending on the classification, up to eight. And the zero, one and two, they are submucosis. So they are the problematic for fertility and for bleeding.

• 24:53Dr. Peter Attia?

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

• 25:01Speaker 01

  Actually, the submucosa, they are the closest to the lining.

• 25:04Dr. Peter Attia?

  Ah, okay.

• 25:05Speaker 01

  So zero would be like just

• 25:07Dr. Peter Attia?

  In the endometrium?

• 25:08Speaker 01

  Inside the cavity.

• 25:09Dr. Peter Attia?

  Okay.

• 25:10Speaker 01

  Okay. One is mainly inside the cavity, but a part is in the myometrium. 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.

• 25:25Dr. Peter Attia?

  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?

• 25:31Speaker 01

  Yeah.

• 25:32Dr. Peter Attia?

  Okay.

• 25:33Speaker 01

  Probably not severe, but yeah, clinical implications, right?

• 25:36Dr. Peter Attia?

  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.

• 26:03Dr. Peter Attia?

  Then on adenomyosis, what percentage of those are asymptomatic?

• 26:07Speaker 01

  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, myometrocyt, 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, it's very painful, especially the period is very painful.

• 26:45Dr. Peter Attia?

  And again, it might sound like a dumb question. What is causing the actual pain?

• 26:52Speaker 01

  Great question, great question. Actually, we have three types of pain in adenomyosis. That's, I think that's the most complicated part for us gynecologists to understand, because we're not trained for that. But there's the so-called nociceptive pain.

• 27:12Dr. Peter Attia?

  Yep.

• 27:12Speaker 01

  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, in 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.

• 27:54Speaker 01

  And the third layer, and most difficult to treat, is the nociplastic pain, when we have central sense exation. 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.

• 28:37Speaker 01

  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 twenty twenty five, twenty six, a new guidance on endometriosis diagnosis. And it allows us to not only diagnose clinically, but treat it.

• 29:22Speaker 01

  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, year after years, years later.

• 29:42Dr. Peter Attia?

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

• 29:46Speaker 01

  I don't think we have a typical presentation anymore. We are seeing endometriosis in teenagers. Look at this data. Up to fifty and seventy five percent of teenagers with pelvic pain, they have endometriosis. Three quarters, they have endometriosis.

• 30:03Dr. Peter Attia?

  And what percentage of teenagers have pelvic pain?

• 30:05Speaker 01

  I'm not sure, not sure.

• 30:07Dr. Peter Attia?

  Presumably it's like five percent or.

• 30:10Speaker 01

  Yeah, I think a little bit more, a little bit more, yeah. So we are seeing teenagers presenting with endometriosis.

• 30:17Speaker 01

  And if just normal-

• 30:20Dr. Peter Attia?

  Which 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 in young-

• 30:52Speaker 01

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

• 31:01Dr. Peter Attia?

  Mm-hmm. Oh, you mentioned pollution, yep.

• 31:03Speaker 01

  Yeah. Diet, probably the, you know, this sad diet. It's all poor sleep. Because remember, poor sleep-

• 31:12Dr. Peter Attia?

  The immune system.

• 31:13Speaker 01

  Immune, yeah. Immune system regulation, the macrophages, they just jump from one to the other type. And this may increase the risk of anemia terrosis. So we are not sure about this question, but-

• 31:26Dr. Peter Attia?

  It's probably many things, which is what makes it so complicated.

• 31:29Speaker 01

  Yes.

• 31:30Dr. Peter Attia?

  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?

• 32:11Speaker 01

  Oh, yeah. Unfortunately, no. Because if you look like the diagnosis delay period is five to 12 years, depending on the country. I believe in the US is around six years.

• 32:22Dr. Peter Attia?

  And in Brazil?

• 32:24Speaker 01

  Brazil, around seven years. So from the first symptom-

• 32:29Speaker 01

  Up to the diagnosis, can you imagine like five up to 10 years?

• 32:35Dr. Peter Attia?

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

• 32:47Speaker 01

  Mainly because of, I think, three factors here. The first one is this cultural normalization of pain, right? Female pain especially. So they are told that, oh, that's normal. Just have a medication, have an anti-inflammatory and go. But some teenagers, they just can't go to school. They miss school. Sometimes they miss work. They cannot like properly work. So we have, the estimate cost is around 80 to 120 billion per year, and two thirds of that is productivity loss, not only medications and hospitalizations and surgeries.

• 33:28Speaker 01

  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 is, has been made with diagnostic laparoscopy.

• 34:03Dr. Peter Attia?

  Which is a big step to take.

• 34:04Speaker 01

  Yeah, we shouldn't do that anymore.

• 34:06Dr. Peter Attia?

  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 and syflate the abdomen, put cameras inside, and this is a surgical procedure. It requires general anesthesia and

• 34:26Dr. Peter Attia?

  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 encephalated 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?

• 35:00Speaker 01

  That's a good point. Around 25 years ago.

• 35:03Dr. Peter Attia?

  Okay.

• 35:04Speaker 01

  So if you, for us in Brazil, the specialized ultrasonography is a very good exam. We have, we have Dr. Luciana Chamier, who's now in Boston, Mass General. Manoel Orlando, they are like one of the best radiologists in the world for endometriosis. And they developed this protocol in which you have bowel prep, like not-

• 35:31Dr. Peter Attia?

  Just like a colonoscopy or a sigmoidoscopy?

• 35:33Speaker 01

  Yeah, like much more like simple.

• 35:35Dr. Peter Attia?

  Okay.

• 35:36Speaker 01

  You have this enema in like one hour before the exam and no residue diet. But that's simple protocol with a gel inside vagina. So you can look into small lesions in the bowel, bladder, and you can even see the layers of the bowel. So it's, it's a beautiful exam. But that started around 25 years ago. And that's not widespread yet. I know that, I was just talking to Luciana today and she told me that in, I think in Mayo Clinic, Arizona, there's a one doctor doing that, Scott Young, but not for everybody.

• 36:19Speaker 01

  I think in the US mainly is MRI. My MRI and ultrasonography, they have very high sensitivity, about ninety-five, ninety-eight percent, and very high specificity too. But for superficial lesions, just let me go step back. We have three phenotypes, right? The superficial lesions, the deep infiltrative endometriosis, and the Endometriosis, the cysts of endometriosis. So for those superficial lesions, ultrasound, sometimes it misses.

• 36:53Dr. Peter Attia?

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

• 37:00Speaker 01

  Actually, I have peritoneum, but the definition will be...

• 37:03Dr. Peter Attia?

  Not deep within the peritoneum, just sitting right on top?

• 37:05Speaker 01

  On top of the peritoneum, yeah, but less than five millimeters.

• 37:10Dr. Peter Attia?

  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, etc. It's basically just a potential space. And what would be, and by the way, included on top of that peritoneum, you would see the uterus, you would see the ovaries.

• 37:44Speaker 01

  Fallopian tubes.

• 37:44Dr. Peter Attia?

  The fallopian tubes between them.

• 37:46Speaker 01

  The ligaments.

• 37:47Dr. Peter Attia?

  And is the most common place you're going to see these endometrial deposits, situated on top of uterus fallopian tubes and ovaries?

• 37:56Speaker 01

  Actually, right behind it.

• 37:58Dr. Peter Attia?

  Ah.

• 37:58Speaker 01

  Yeah, right, behind the uterus, the ligaments, the so-called uterosacroligaments. Because just of the anatomy and gravity, you know?

• 38:11Dr. Peter Attia?

  Yeah.

• 38:12Speaker 01

  Most lesions, they just stay there, but sometimes they can travel.

• 38:17Dr. Peter Attia?

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

• 38:20Speaker 01

  Yeah, eighty percent on the right side because of the anatomy of the sigmoid, so it blocks the left side mainly. But yeah, the bladder, around 10 to 12% of enometriosis patients, they might have urinary tract lesions. But mostly it's on the perineum.

• 38:40Dr. Peter Attia?

  And then what about between the rectum and the uterus?

• 38:43Speaker 01

  That's rare.

• 38:43Dr. Peter Attia?

  Because the space is too tight?

• 38:45Speaker 01

  Yeah, so it needs to go inside from the uterus sacral ligaments, from the like behind the uterus and go to the septum.

• 38:54Dr. Peter Attia?

  Yep.

• 38:54Speaker 01

  So that's rare, but that's very hard to treat because sometimes it goes deep into the muscle, the muscle floor, you know, of the pelvis and invades the nerves. And those patients present with lots of fibrosis.

• 39:12Dr. Peter Attia?

  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?

• 39:25Speaker 01

  Very important question, Pierre. If you do a normal ultrasound and you don't have enometriosis, and the report doesn't mean that you don't have enometriosis. 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.

• 39:52Dr. Peter Attia?

  That's very, very low sensitivity for a normal ultrasound.

• 39:55Speaker 01

  Very low sensitivity, yeah. We see that a lot. But we have, 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. So, and sometimes even without bowel prep, it's better than the normal ultrasound. But the best will be the detailed protocol with an expert. With this bowel prep to look into the pelvis like.

• 40:32Dr. Peter Attia?

  And who does this? A radiologist or the gynecologist?

• 40:34Speaker 01

  A radiologist. Sometimes it's a gynecologist specialized in radiology.

• 40:40Dr. Peter Attia?

  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?

• 40:51Speaker 01

  No, a little larger.

• 40:53Dr. Peter Attia?

  How, how, how big in diameter?

• 40:54Speaker 01

  Would be something, yeah, close to this arm.

• 40:57Dr. Peter Attia?

  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 pain?

• 41:17Speaker 01

  Yeah, to move the uterus.

• 41:19Dr. Peter Attia?

  Okay.

• 41:19Speaker 01

  So you can see this is line, sliding sign, right?

• 41:22Dr. Peter Attia?

  Okay.

• 41:23Speaker 01

  And MRI cannot do that, right?

• 41:25Dr. Peter Attia?

  Right, it's static.

• 41:26Speaker 01

  It's static, yeah.

• 41:27Dr. Peter Attia?

  And the probe can see 180 degrees plus in front?

• 41:32Speaker 01

  Yeah.

• 41:33Dr. Peter Attia?

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

• 41:39Speaker 01

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

• 41:46Dr. Peter Attia?

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

• 41:51Speaker 01

  Yeah.

• 41:51Dr. Peter Attia?

  Okay. Or liquid?

• 41:53Speaker 01

  Yeah, we need liquid.

• 41:54Dr. Peter Attia?

  Okay.

• 41:55Speaker 01

  Air is not good for ultrasound.

• 41:56Dr. Peter Attia?

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

• 42:03Speaker 01

  Good question, no. Actually, the difference is just the experience and the protocol. But it takes time, right?

• 42:11Dr. Peter Attia?

  And what is the official name of the protocol?

• 42:13Speaker 01

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

• 42:19Dr. Peter Attia?

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

• 42:32Speaker 01

  In the US, definitely. I was talking to my friend and she told me that in the US.

• 42:38Dr. Peter Attia?

  This is the woman at MGH?

• 42:40Speaker 01

  Yeah, yeah, yeah. One of the best, yeah. And in the US, it's mainly MRI. But they do the augmented ultrasoundography.

• 42:49Dr. Peter Attia?

  Okay.

• 42:50Speaker 01

  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.

• 43:05Dr. Peter Attia?

  Yep.

• 43:05Speaker 01

  So you need to allocate the person and also you need, of course, the machine is not available like all the time, right?

• 43:14Dr. Peter Attia?

  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.

• 43:27Speaker 01

  But you don't, yeah, but it's not that good for bowel endometriosis.

• 43:32Dr. Peter Attia?

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

• 43:41Speaker 01

  Definitely.

• 43:41Dr. Peter Attia?

  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?

• 43:51Speaker 01

  Yeah, probably sufficient.

• 43:53Dr. Peter Attia?

  Okay.

• 43:54Speaker 01

  But if you are planning a surgery, the ultrasound is, for me, is essential.

• 44:00Dr. Peter Attia?

  You would never operate without the ultrasound?

• 44:02Speaker 01

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

• 44:11Dr. Peter Attia?

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

• 44:13Speaker 01

  Sao Paulo is one of the best cities to do, probably the best city. Italy is also a good country for that. But it depends on people, right?

• 44:21Dr. Peter Attia?

  Yeah.

• 44:22Speaker 01

  So Manolo Orlando, Luciana Chamier, and Luisa Nicola, there are a few radiologists that are very experienced, not only in diagnosing, but also the follow-up of those patients. So for instance, Luciana, she used to not only do the ultrasound, but then she would go inside the OR with the surgeon to look.

• 44:44Dr. Peter Attia?

  To correlate what she, I mean, that's brilliance.

• 44:47Speaker 01

  Brilliant.

• 44:47Dr. Peter Attia?

  Yeah, that's the brilliance.

• 44:48Speaker 01

  But that's very rare, unfortunately.

• 44:51Dr. Peter Attia?

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

• 45:04Speaker 01

  I was just sorry to interrupt you, Peter. Just, just to be clear, MRI is better for extra pelvic lesions such as diaphragm.

• 45:14Dr. Peter Attia?

  Yep.

• 45:15Speaker 01

  And for the lateral part of the pelvis.

• 45:19Dr. Peter Attia?

  Where the ultrasound loses its ecogenicity.

• 45:21Speaker 01

  Yes.

• 45:22Dr. Peter Attia?

  Yep.

• 45:22Speaker 01

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

• 45:33Dr. Peter Attia?

  So do you do both?

• 45:34Speaker 01

  Sometimes, mostly both, yeah.

• 45:37Dr. Peter Attia?

  And what's the sequence of MRI, by the way? Is it special? Does it require gadolinium?

• 45:41Speaker 01

  No.

• 45:42Dr. Peter Attia?

  Note, so non-contrast?

• 45:43Speaker 01

  No contrast.

• 45:44Dr. Peter Attia?

  T1, T2?

• 45:44Speaker 01

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

• 45:50Dr. Peter Attia?

  Okay, so relatively easy MRI.

• 45:52Speaker 01

  Yeah.

• 45:53Dr. Peter Attia?

  Probably a 20-minute scan.

• 45:55Speaker 01

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

• 45:59Dr. Peter Attia?

  Yep.

• 45:59Speaker 01

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

• 46:06Dr. Peter Attia?

  Yep, okay.

• 46:08Dr. Peter Attia?

  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?

• 46:18Speaker 01

  So it depends a lot on the object, right? If the patient is trying to conceive.

• 46:23Dr. Peter Attia?

  Yes.

• 46:23Speaker 01

  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.

• 46:34Dr. Peter Attia?

  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.

• 46:49Speaker 01

  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, to answer that if you are 20. How is your ovarian reserve AMH antraphollic count? Very important.

• 47:07Speaker 01

  Disease phenotype, what I mean here, do you have endometrioma? The cyst, because this is a very special phenotype, which can lead to lower ovarian reserve and also the surgery can impair the intrafollicle count and even the AMH. And how's the pain? 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 Merina or a Kailena.

• 47:49Dr. Peter Attia?

  In addition to an oral contraceptive?

• 47:50Speaker 01

  No, just, just, we, we tend to use just one.

• 47:53Dr. Peter Attia?

  Okay.

• 47:54Speaker 01

  So Merina 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 a Merina. Benefit is like five years of treatment.

• 48:09Dr. Peter Attia?

  And a Merina is progesterone-coded. Why would you use a Merina over any IUD?

• 48:14Speaker 01

  Because you need the progesterone action.

• 48:17Dr. Peter Attia?

  You're trying to suppress endometrial hyperplasia?

• 48:20Speaker 01

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

• 48:24Dr. Peter Attia?

  Okay. Yeah, so in other words, a regular IUD doesn't necessarily suppress.

• 48:29Speaker 01

  No.

• 48:30Dr. Peter Attia?

  Whereas a Merina will.

• 48:30Speaker 01

  It's just an inflammatory event for contraception.

• 48:34Dr. Peter Attia?

  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 Merina and the oral contraceptive?

• 48:54Speaker 01

  That's a good question. If she doesn't have myofascial pain, which is like 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 wanna insert a Mirena, right? So you can start with a pill, a progesterone-only pill, like Noradrenдрone or Diana Jazz or Desogestrel. Or you can use a combined contraceptive pill, like the traditional ones, right?

• 49:27Dr. Peter Attia?

  Estrogen, progesterone.

• 49:28Speaker 01

  Yeah, ethinyl estradiol or just estradiol plus progesterone.

• 49:33Dr. Peter Attia?

  And you don't use a low dose? You don't use a low low estin or you do?

• 49:36Speaker 01

  Yes, we prefer using a low dose. Yeah, because remember estrogen can

• 49:43Dr. Peter Attia?

  Activate.

• 49:44Speaker 01

  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 gonna recur endometriosis like in five years or even 10 years. And she'll need more surgeries afterwards.

• 50:23Dr. Peter Attia?

  And the surgery here is a laparoscopic procedure. It's a blunt force tool. You're going in and you're literally laparoscopically removing, cutting out.

• 50:33Speaker 01

  Excising.

• 50:34Dr. Peter Attia?

  And are they that visible to the eye?

• 50:37Speaker 01

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

• 50:47Dr. Peter Attia?

  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 and the reason, of course, in part is because you can never get it all. Even you, if you only took what you can see, you know, you're missing things that are below the threshold of your vision. And so is that not the case here? Or is it the case that you're you're missing things? And that when you say the problem with surgery is she's going to recur in five years. Is it that she recurred in five years? Or it's she's just going to present with what you didn't see?

• 51:32Speaker 01

  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 Endometriosis.

• 51:49Dr. Peter Attia?

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

• 52:03Speaker 01

  That's it.

• 52:03Dr. Peter Attia?

  And that's why those patients need repeated surgery.

• 52:05Speaker 01

  And that's where the progesterone resistance come in. You know?

• 52:10Dr. Peter Attia?

  And you, do you have an assay to measure this? Or is it, it's just, it's a clinical diagnosis?

• 52:14Speaker 01

  We don't have, 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.

• 52:28Dr. Peter Attia?

  Yeah.

• 52:28Speaker 01

  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 show that if you insert a marina after a surgery, recurrence rate is 88% lower to placebo. So it's better to use something after surgery. So coming back to that patient with the patient 20 years old, probably she's going to respond to medication. If not, we can change the medication or we can plan surgery. But always we should think about this as a chronic disease. And there's this this concept that was published in Nature Reviews

• 53:14Speaker 01

  seven years ago by Charles Chapron, a French group, that calls the endometriosis life. What that means that we should not only treat the like the main symptom, but we should think about the life of this patient that has this disease that is chronic, like type 2 diabetes, type 1 diabetes, and so on. But we're mainly doing just one appointment, one surgery or one medication and go. We're not thinking about the life, like what's gonna be like in five, 10 years. Right? So we should change the mindset on that.

• 53:53Dr. Peter Attia?

  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?

• 54:18Speaker 01

  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 a progestin. In Brazil, we have this Diana Jazz, which is a very good progestin for endometriosis. In the US, we have the Nataza. Nataza is like estrogen, estradiol plus Diana Jazz. But you need to use only the active with Diana Jazz. There are 22 pills inside a box. And if she responds well, that's it. We are controlling the disease, right?

• 54:58Dr. Peter Attia?

  And if not, you go to surgery?

• 55:00Speaker 01

  Or we can use a Merino.

• 55:01Dr. Peter Attia?

  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.

• 55:13Speaker 01

  So probably the objective is have a baby, right?

• 55:17Dr. Peter Attia?

  Yes, she wants a baby.

• 55:18Speaker 01

  Just controlling pain.

• 55:19Dr. Peter Attia?

  That's right.

• 55:20Speaker 01

  But sometimes they present with both.

• 55:21Dr. Peter Attia?

  Yeah.

• 55:22Speaker 01

  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 sperm analysis, and you need to investigate other factors that not only endometriosis can impair infertility, right? So you need to ask, request a karyotype and some other exams like a history of a pingogram.

• 56:03Dr. Peter Attia?

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

• 56:37Speaker 01

  Yes.

• 56:37Dr. Peter Attia?

  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?

• 56:47Speaker 01

  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.

• 56:58Dr. Peter Attia?

  Okay.

• 56:59Speaker 01

  So the tubes are compromised. So they can't pick up the oocytes or they can't permit the fertilization inside the tube and transport the embryo back into the uterus.

• 57:11Dr. Peter Attia?

  Right.

• 57:13Speaker 01

  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.

• 57:46Dr. Peter Attia?

  And just to make sure I understand, Hana, the surgery you're proposing is, is a laparoscopy, 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?

• 58:03Speaker 01

  You can restore the anatomy and the functionality of the pelvis.

• 58:06Dr. Peter Attia?

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

• 58:13Speaker 01

  Yeah, primarily, yes. But of course, we have plenty of data showing that.

• 58:19Speaker 01

  We have molecular differences between endometriosis and non-endometriosis pelvis. For instance, we have C-reactive protein, IL6, TNF-alpha. But clinically, it's mainly an anatomical problem, right?

• 58:34Dr. Peter Attia?

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

• 58:41Speaker 01

  Yeah, but there are some authors that may argue that implantation, so the utop 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 all sites, 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.

• 59:23Speaker 01

  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 adenomas, they are not that common. But we cannot treat the uterus.

• 59:59Dr. Peter Attia?

  Unless you do a hysterectomy.

• 1:00:01Speaker 01

  Yes.

• 1:00:02Dr. Peter Attia?

  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 self?

• 1:00:14Speaker 01

  Depends on, depends on her age and over and reserve, but we always do the self-inject.

• 1:00:19Dr. Peter Attia?

  You always take the tubes out when you take the uterus now?

• 1:00:22Speaker 01

  Yeah.

• 1:00:23Dr. Peter Attia?

  Right, yeah. Is that standard of care?

• 1:00:25Speaker 01

  Oh, yeah.

• 1:00:25Dr. Peter Attia?

  There's no gynecologist that would ever leave tubes?

• 1:00:28Speaker 01

  Yeah.

• 1:00:28Dr. Peter Attia?

  Okay, you know that that's.

• 1:00:29Speaker 01

  They shouldn't, yeah, they shouldn't, yeah.

• 1:00:31Dr. Peter Attia?

  Okay. So, I didn't understand something you said a minute ago. You said that when you took. A donor egg, a healthy, young, perfect donor egg, chromosomally normal, morphologically perfect embryo, and you transferred it, it had the same rate of failure as the woman with endometriosis's own egg, correct?

• 1:00:56Speaker 01

  No. If you're 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.

• 1:01:15Dr. Peter Attia?

  Yep.

• 1:01:16Speaker 01

  And they're mixed, 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 the uterus of a patient with or without endometriosis, we have pretty much same results.

• 1:01:44Dr. Peter Attia?

  Ah, okay.

• 1:01:45Speaker 01

  You understand that?

• 1:01:46Dr. Peter Attia?

  Yep.

• 1:01:46Speaker 01

  So, 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 oocytes in patients with endometriosis, they are not normal. But clinically, if you look into the data,

• 1:02:28Speaker 01

  just ask IVF patients with endometriosis or without endometriosis, is there any difference in quality? Probably not.

• 1:02:40Dr. Peter Attia?

  Okay.

• 1:02:40Speaker 01

  Even aneuploidy rates, they are similar.

• 1:02:43Dr. Peter Attia?

  Because you're matching for age.

• 1:02:44Speaker 01

  That's it.

• 1:02:45Dr. Peter Attia?

  Yep.

• 1:02:46Speaker 01

  Age is the proxy for chromosome abnormality, yeah.

• 1:02:51Dr. Peter Attia?

  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?

• 1:03:07Speaker 01

  So probably we're gonna offer both options, but IVF is the way to go here. Because up to 34, the difference in between a blastocyst with 31 or 34 years old, like in a patient that is 31 or 34, is not that different. It's about 35% of aneuploidy, about that. If you are 34.

• 1:03:38Dr. Peter Attia?

  Is it that high?

• 1:03:39Speaker 01

  Yeah.

• 1:03:40Dr. Peter Attia?

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

• 1:03:45Speaker 01

  30 to 35. Almost one-third of blastocysts, they are aneuploidy.

• 1:03:50Dr. Peter Attia?

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

• 1:03:53Speaker 01

  Yeah, I know.

• 1:03:55Dr. Peter Attia?

  I think, I almost think of that as prime reproductive age.

• 1:03:59Speaker 01

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

• 1:04:04Dr. Peter Attia?

  So it falls off very quickly at 30?

• 1:04:06Speaker 01

  Especially after 35.

• 1:04:09Dr. Peter Attia?

  And 35 aneuploidy is?

• 1:04:10Speaker 01

  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.

• 1:04:30Dr. Peter Attia?

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

• 1:04:57Speaker 01

  Yeah.

• 1:04:57Dr. Peter Attia?

  Yeah.

• 1:04:57Speaker 01

  So the definition is like aneuploidy is an abnormality in the number of chromosomes.

• 1:05:04Speaker 01

  So we have forty six XX, a female, or XY, a male. But, so, the normal way would be like thirty three chromosomes from the egg, X, and thirty three from the sperm, X or Y, right? So if you do the math, it would be forty six. But-

• 1:05:27Dr. Peter Attia?

  Twenty, twenty-three and twenty-three.

• 1:05:28Speaker 01

  Yeah, twenty-three, sorry, yeah, twenty-three and twenty-three, yeah. So forty-six, again. But if you have, like, problems in the egg, because essentially, any employee, they come from the old side.

• 1:05:43Dr. Peter Attia?

  The maternal side, yep.

• 1:05:43Speaker 01

  Maternal, like ninety-three and ninety-five percent, they're, they're coming from the old side. Due to errors and meiosis. So they don't split the chromosomes. And now you can get monosomy, one less, or trisomy. As you said, they're the most, quote-unquote, dangerous, because those babies can live, they can have the disease. Monosomy is not, we don't have compatibility with life. Just the monosomy of X, which is-.

• 1:06:14Dr. Peter Attia?

  Turners, yeah.

• 1:06:15Speaker 01

  So mainly, we're having an implantation failure problem, so infertility. And that's invisible to the exams, right? So a thirty-year-old woman with normal exams can get pregnant. Why is that? Because she's thirty-eight. Most embryos, they are not normal at that time. And we can have also miscarriage risk here.

• 1:06:39Dr. Peter Attia?

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

• 1:06:48Speaker 01

  Yeah, just coming back to the case. So we could do, potentially, two, like, two ways, two routes here. First one would be to go directly to IVF, then freeze the, or the old sites, or embryos, mainly embryos here. Then we can transfer the embryo later on.

• 1:07:08Speaker 01

  Between freezing the embryos and transferring, you can perform surgery. When? If the patient has large Endometriosis, like larger than five to six centimeters, because they can-

• 1:07:22Dr. Peter Attia?

  It can get that big?

• 1:07:23Speaker 01

  Yeah.

• 1:07:24Dr. Peter Attia?

  That seems massive.

• 1:07:25Speaker 01

  Yeah. I have a patient now, she has 12 centimeters in one side and eight centimeters in the other side.

• 1:07:32Dr. Peter Attia?

  Is the size proportional to the symptoms?

• 1:07:34Speaker 01

  No.

• 1:07:36Dr. Peter Attia?

  No. So it's not, because you tell me that, I would assume this woman can't leave her house. Like that would seem debilitating, but no.

• 1:07:42Speaker 01

  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 one to four, like mild, minimal, moderate, and severe disease. But it's just like a map, like a surgical description. It doesn't match with pain, neither fertility. So that's a problem. So ASRM four would be like very severe disease, but she can be asymptomatic.

• 1:08:22Speaker 01

  While a stage one patient could be like at their homes, just having pain and so on, right? So that's a 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 know, you give like zero to four, depending on the quality of the tubes and the fembron, the ovaries after surgery. So you can predict the rates, the pregnancy rates after surgery. So if the score is high, like nine or 10, they have almost 65% of chances of getting pregnant naturally after surgery. So that's useful.

• 1:09:06Speaker 01

  Which means that if the tubes are not okay, they are dilated, or you didn't have to proceed, you need to do a self-injectomy. Probably the chances are not that high after surgery, so you can walk them through IVF directly.

• 1:09:25Speaker 01

  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 Endometriosis, pain. The quality of life is not good, you can operate on them. And small bowel lesions that can obstruct. And sometimes ureteral involvement, which can lead to kidney function loss.

• 1:09:54Dr. Peter Attia?

  Hmm.

• 1:09:55Speaker 01

  Actually, I had a patient with, she had a nephrectomy, left nephrectomy due to endometriosis in the ureter, like silent disease, mostly.

• 1:10:06Dr. Peter Attia?

  And she developed hydronephrosis?

• 1:10:07Speaker 01

  Hydronephrosis and the urologist performed a nephrectomy.

• 1:10:12Dr. Peter Attia?

  Oh.

• 1:10:12Speaker 01

  Yeah. So those are the red flags. Those are the red flags to perform surgery even without symptoms.

• 1:10:21Dr. Peter Attia?

  Yeah.

• 1:10:21Speaker 01

  Like appendix is important too, because sometimes it just mimics neuroendocrine tumors.

• 1:10:26Dr. Peter Attia?

  Yep.

• 1:10:27Speaker 01

  It's essentially the same phenotype.

• 1:10:30Dr. Peter Attia?

  Wow.

• 1:10:30Speaker 01

  And small bowel and ureter, you need to operate on them.

• 1:10:35Dr. Peter Attia?

  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?

• 1:10:58Speaker 01

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

• 1:11:05Dr. Peter Attia?

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

• 1:11:18Speaker 01

  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.

• 1:11:57Dr. Peter Attia?

  Why does that work?

• 1:11:58Speaker 01

  You are treating the uterus, right? So estrogen can triggers adenomyosis lesions can.

• 1:12:05Dr. Peter Attia?

  Just like endometriosis.

• 1:12:06Speaker 01

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

• 1:12:12Dr. Peter Attia?

  What are the preferred ones?

• 1:12:14Speaker 01

  We prefer, like, we have much more data with analogs, the agonists. Lupron, it's called the goseroline, they are injectable.

• 1:12:24Dr. Peter Attia?

  Yep.

• 1:12:25Speaker 01

  Subtenuously, monthly, right? So two to four months with this and then we transfer the embryo using just tiny levels.

• 1:12:34Dr. Peter Attia?

  The smallest amount of estrogen?

• 1:12:35Speaker 01

  Yes. And high amounts of progesterone.

• 1:12:40Dr. Peter Attia?

  Okay.

• 1:12:40Speaker 01

  So that's the strategy. Nowadays, nowadays we have the antagonists, the oral antagonists in the US. They are very expensive. They are called alegolix and regolix, but they are oral medications. We had just one paper published last year that compared use of antagonists versus agonists and they are pretty much the same. Here we have less side effects. They are 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

• 1:13:22Speaker 01

  if she didn't have endometriosis, adenomyosis, sorry.

• 1:13:26Dr. Peter Attia?

  Okay, so you're gonna go four months. By the way, it's not clear to me why an agonist and an antagonist both work. Do they both produce a lower level of estrogen?

• 1:13:35Speaker 01

  So mainly is the, the, the initial mechanism, the molecular mechanism in which the agonist can do a call, we call this flare up effect. So it occupies the receptors.

• 1:13:50Speaker 01

  And it triggers a flare up of FSH and LH and then can lead to ovulation. But after two to four weeks of medication, then you down regulate the receptor and then you you have this this suppression, hormonal suppression. So you produce the menopause essentially chemically.

• 1:14:08Dr. Peter Attia?

  Uh huh.

• 1:14:09Speaker 01

  But the antagonist, the action is right in the first medication. So you don't have this flare up effect. But essentially, the like, the the the objective is the same.

• 1:14:20Dr. Peter Attia?

  So so you said about four months of that. And if you were to take an ultrasound of that woman every month, what would you be seeing in her myometrium? How would it be changing?

• 1:14:31Speaker 01

  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 they are there.

• 1:14:43Dr. Peter Attia?

  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?

• 1:15:01Speaker 01

  Actually, it's a problem in pregnancy maintenance.

• 1:15:05Dr. Peter Attia?

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

• 1:15:11Speaker 01

  Six to eight weeks.

• 1:15:12Dr. Peter Attia?

  Oh, wow.

• 1:15:13Speaker 01

  Yeah, sometimes even even further.

• 1:15:16Dr. Peter Attia?

  Okay. And why?

• 1:15:18Speaker 01

  Because there there are contractions in that junctional zone.

• 1:15:22Dr. Peter Attia?

  Yep.

• 1:15:22Speaker 01

  And the uterus is just trying to kind of expel the uterus.

• 1:15:27Dr. Peter Attia?

  And okay, so then you you you give her four months of treatment, but you said you don't really shrink the the the adenomyosis.

• 1:15:35Speaker 01

  Morphologically, not that much.

• 1:15:37Dr. Peter Attia?

  But chemically, you change.

• 1:15:38Speaker 01

  Chemically, yes. Yeah.

• 1:15:40Dr. Peter Attia?

  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 how does it play out through the nine months of pregnancy?

• 1:16:06Speaker 01

  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 pre-eclampsia and small for gestational age, c-section rates.

• 1:16:33Dr. Peter Attia?

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

• 1:16:59Speaker 01

  Around 30% less with adenomyosis.

• 1:17:02Dr. Peter Attia?

  Wow.

• 1:17:02Speaker 01

  But it depends on the phenotype. If you have the involvement of the junctional zone, you have a three times higher risk of miscarriage.

• 1:17:11Dr. Peter Attia?

  Because it's more likely to contract?

• 1:17:13Speaker 01

  Yes, it's just right on top of this, like the surface where the embryo is going to implant.

• 1:17:19Dr. Peter Attia?

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

• 1:17:27Speaker 01

  Yeah, the desutilization, the progesterone resistance, the contractions in the junctional zone, and the uterus sometimes it just, you can see even, yeah, yeah, the hypertrophy, you can see the contraction sometimes in the ultrasound.

• 1:17:43Dr. Peter Attia?

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

• 1:17:49Speaker 01

  No, not gonna say no.

• 1:17:51Dr. Peter Attia?

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

• 1:17:54Speaker 01

  Yeah.

• 1:17:55Dr. Peter Attia?

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

• 1:18:24Speaker 01

  Yeah.

• 1:18:25Dr. Peter Attia?

  Seems that that would be one opportunity.

• 1:18:26Speaker 01

  Yeah, yeah, probably, but we are now just giving them much more progesterone.

• 1:18:33Dr. Peter Attia?

  If that woman who was 32 had been diagnosed immediately?

• 1:18:39Dr. Peter Attia?

  Could she have been treated with high dose progesterones and other hormonal therapies to have not arrived where she is?

• 1:18:48Speaker 01

  Like during pregnancy?

• 1:18:49Dr. Peter Attia?

  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?

• 1:19:01Speaker 01

  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.

• 1:19:19Dr. Peter Attia?

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

• 1:19:22Speaker 01

  Because if you look at the economic side, NIH like invests 15 times more dollars on diabetes than endometriosis. But an endometriosis patient 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.

• 1:19:53Dr. Peter Attia?

  Why do you think that is?

• 1:19:55Speaker 01

  That's a complicated question. I think that's because we're just recognizing that endometriosis now is an important factor. We're seeing movies and documentaries about that. So I think that's just, it's coming up, you know? That's it. I think that's, it's just a question of time, probably. Like menopause, right?

• 1:20:22Dr. Peter Attia?

  Yeah.

• 1:20:23Speaker 01

  That we're seeing this revolution.

• 1:20:24Dr. Peter Attia?

  Are there any other good case examples you can think of that? Well, actually, let me give you one more. So let's, let's take another one where a woman is 30 years old. She would like to conceive.

• 1:20:43Dr. Peter Attia?

  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?

• 1:21:05Speaker 01

  In that patient, no, because she's gonna try to conceive. So we have data showing that if you do that, you control the symptoms, but you don't have a cumulative effect after stopping the medication. So you are treating the disease while you are using the 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.

• 1:21:45Dr. Peter Attia?

  What is the biggest mistake that happens with respect to surgical intervention?

• 1:21:52Dr. Peter Attia?

  Like what's the biggest, like patient selection mistake?

• 1:21:55Speaker 01

  I would say that if you have a patient that has central sensitization, and you think that this surgery is gonna resolve that, that's the biggest mistake. Because surgery doesn't attack that layer of pain, the nocice plastic 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 physiotherapy. So that would be the optimal approach. The second mistake is to take out all the cysts that you know, as you see, like the Endometriosis.

• 1:22:41Speaker 01

  Because that can impair fertility by reducing the, not fertility per se, but IVF outcomes, because you reduced AMH.

• 1:22:52Speaker 01

  And

• 1:22:52Dr. Peter Attia?

  Because each of those cysts, explain why that's the case.

• 1:22:55Speaker 01

  Because they are not actually very defined cysts.

• 1:22:58Dr. Peter Attia?

  Okay.

• 1:22:58Speaker 01

  They're like pseudo cysts. So when you strip them out, you end up by taking some follicles and all sides that are healthy adjacent to the cyst. So we have data showing that.

• 1:23:13Dr. Peter Attia?

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

• 1:23:18Speaker 01

  No, they are like very attached to the cortical part of the ovary.

• 1:23:23Dr. Peter Attia?

  Uh huh.

• 1:23:23Speaker 01

  Where the primordial follicles are. So when you take out the cyst, you do a cystectomy, you can reduce AMH by forty percent, sometimes fifty percent.

• 1:23:35Dr. Peter Attia?

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

• 1:23:39Speaker 01

  Yeah, but that's a double edged sword. Why? Because the presence of the cyst decrease the

• 1:23:48Dr. Peter Attia?

  AMH because it's draining, yeah.

• 1:23:50Speaker 01

  Can decrease AMH.

• 1:23:52Dr. Peter Attia?

  So shouldn't you harvest the eggs first?

• 1:23:54Speaker 01

  That's it.

• 1:23:55Dr. Peter Attia?

  Okay.

• 1:23:55Speaker 01

  Yeah, that's it. And the mechanism is beautiful, explained by this phantom reaction, the same one that we know. And it produce hydroxyl, you know, molecules that are very toxic to the DNA. So they ended up having this so-called follicular burnout. So patients with endometrioma, they might have before surgery a lower ovarian reserve. And if you operate on them, you are just decreasing this now that this lower ovarian reserve. So it's, I think that's one, one big mistake. I think maybe the third mistake would be like to leave a damaged tube,

• 1:24:40Speaker 01

  a hydroxalpines, just to preserve the tubes. But we know that this can reduce the IVF chances by half. So if you have a dilated

• 1:24:50Dr. Peter Attia?

  Why?

• 1:24:50Speaker 01

  Tube, because the, the mechanism is like washing the embryos. Like they, they are connected to the uterus. So this

• 1:24:59Dr. Peter Attia?

  You're saying even if you implant?

• 1:25:01Speaker 01

  Yeah.

• 1:25:02Dr. Peter Attia?

  In the, in the uterus, just having the damaged fallopian tube can decrease the success of that?

• 1:25:08Speaker 01

  By half. I have.

• 1:25:10Dr. Peter Attia?

  So there's Is that widely known?

• 1:25:12Speaker 01

  Yeah, yeah, we have concurrent review on that.

• 1:25:14Dr. Peter Attia?

  Okay.

• 1:25:14Speaker 01

  So we have this mechanical effect and also the it's embryo toxic.

• 1:25:19Dr. Peter Attia?

  Yeah.

• 1:25:19Speaker 01

  Cytokines.

• 1:25:20Dr. Peter Attia?

  Being secreted down.

• 1:25:21Speaker 01

  Yeah, we need to take out that too. You need to do a sub injectomy.

• 1:25:27Dr. Peter Attia?

  In your practice, how much time are you spending on endometriosis? Inclusive of discussions around fertility, like how often are you operating for this?

• 1:25:35Speaker 01

  Operating?

• 1:25:36Dr. Peter Attia?

  Yes.

• 1:25:37Speaker 01

  Like you mean surgery, right?

• 1:25:38Dr. Peter Attia?

  Yes.

• 1:25:39Speaker 01

  Probably 20% of cases.

• 1:25:42Dr. Peter Attia?

  20% of your cases are removing endometriosis.

• 1:25:45Speaker 01

  But but you know, 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.

• 1:25:56Dr. Peter Attia?

  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?

• 1:26:36Speaker 01

  I want just to emphasize that age is the most important factor. And even doctors don't just, they just don't realize it. Because sometimes you just see the patient with the doctor trying like they operate on them and they try to conceive naturally. At 42 years old, so that's a big mistake because you're just feeding this desire of natural pregnancy that it's not that common at that age. And the risks are very high. So age is probably nobody knows that a lot. So what I do in my clinic during the appointment.

• 1:27:21Speaker 01

  I show a table, we can put in the show notes.

• 1:27:25Speaker 01

  Of the aneuply rates by year after year. And it's very interesting to know that it's not a

• 1:27:33Dr. Peter Attia?

  It's not linear.

• 1:27:34Speaker 01

  It's not linear.

• 1:27:34Dr. Peter Attia?

  No, it's exponential.

• 1:27:36Speaker 01

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

• 1:27:40Dr. Peter Attia?

  It's a J curve.

• 1:27:41Speaker 01

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

• 1:27:45Dr. Peter Attia?

  Oh, I didn't know that.

• 1:27:46Speaker 01

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

• 1:27:57Dr. Peter Attia?

  Yep.

• 1:27:57Speaker 01

  But the sweet spot would be around twenty five. And even at that age.

• 1:28:02Dr. Peter Attia?

  You're saying at twenty, you have a worse chance than you do at twenty five? Because the egg is more likely to be missing a chromosome.

• 1:28:11Speaker 01

  Yeah, I would say that the risk of aneuply is probably higher at twenty than twenty five. But of course.

• 1:28:19Dr. Peter Attia?

  That's incredible.

• 1:28:20Speaker 01

  Yeah, it's incredible.

• 1:28:21Dr. Peter Attia?

  And do you think, I mean, this is a silly theoretical question. Do you think that's because evolution is trying to optimize for twenty five year olds having babies?

• 1:28:30Speaker 01

  Yeah, that's why.

• 1:28:31Dr. Peter Attia?

  More than twenty year olds or eighteen year olds and obviously thirty year olds. It's really saying, I want this, a twenty five year old woman is the perfect fitness to carry, deliver and raise a child?

• 1:28:43Speaker 01

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

• 1:28:50Dr. Peter Attia?

  Do we think that that's drifted? Like, do you think two hundred years ago, if we could go back in time, do you think it would have been lower?

• 1:28:57Speaker 01

  No, I don't think so. Because the mechanisms, they they should be the same, right?

• 1:29:01Dr. Peter Attia?

  That's that's unbelievable.

• 1:29:03Speaker 01

  Yeah, so that means that if you're, if you are twenty five and going to IVF, not all the embryos, they're gonna be euploid. About twenty percent or twenty five percent will be aneuploid.

• 1:29:17Dr. Peter Attia?

  Even at twenty five?

• 1:29:19Speaker 01

  Yeah.

• 1:29:19Dr. Peter Attia?

  Twenty to twenty five percent

• 1:29:21Speaker 01

  Yeah.

• 1:29:21Dr. Peter Attia?

  of your eggs are already aneuploid. So you never are walking around fully euploid.

• 1:29:26Speaker 01

  So what I say to my patients bigger is that reproduction in humans.

• 1:29:32Speaker 01

  It's very inefficient. So if you think about it, you need one egg. You have just, you lose a thousand eggs every month.

• 1:29:42Dr. Peter Attia?

  You make one, you lose a thousand.

• 1:29:44Speaker 01

  Yeah, you lose a thousand, apoptosis. But you just have a cohort of like 10, 15. And of them, just one ovule. And you have millions and thousands of sperm. Just for one to go inside and produce the embryo. And you need one year to say that it's not working, right? Because infertility is like, it's not just, oh, try this month. 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 polyurine is very low.

• 1:30:29Speaker 01

  They are very efficient at producing good embryos.

• 1:30:34Speaker 01

  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.

• 1:30:54Dr. Peter Attia?

  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?

• 1:31:29Speaker 01

  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 embryo is not that beautiful. You know, sometimes morphologically, they are different. The morphokinetics, they are not similar. But clinically, it's not that big difference.

• 1:32:02Dr. Peter Attia?

  Interesting.

• 1:32:03Speaker 01

  Yeah.

• 1:32:05Dr. Peter Attia?

  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. Uh, maybe she hasn't even met her partner yet. Um, but she deep down thinks she wants to have a child.

• 1:32:37Dr. Peter Attia?

  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. She cut, and you're her regular GYN. Just you're, 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?

• 1:32:53Speaker 01

  Not for all the patients. But I would say that it's reasonable to do an AMH. Like check your reserve, right?

• 1:33:02Dr. Peter Attia?

  But let's say she's normal. She's not, she's not, she's not ahead of time. She's not behind time. She's just a normal 25 year old. But thinking about the J curve, right? Which is the difference between being 25, 30 and 35 is significant. And she's not, just from an optionality perspective, she's, she can't tell you, I, Hinato, I'm definitely going to do it by 30. In which case, maybe you could say, okay, it doesn't change much.

• 1:33:29Speaker 01

  Yeah, if she, if she's not, if she's sure that she, she want, she wants child, children in the future. I would 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 oposites? Like globally?

• 1:33:50Dr. Peter Attia?

  All the women who freeze eggs?

• 1:33:52Speaker 01

  Yes.

• 1:33:53Dr. Peter Attia?

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

• 1:33:56Speaker 01

  Yes, of 100 women that froze their eggs, like, how many come back, are coming back to?

• 1:34:03Dr. Peter Attia?

  To do something with them?

• 1:34:04Speaker 01

  Yeah.

• 1:34:05Dr. Peter Attia?

  Seventy-five?

• 1:34:06Speaker 01

  Actually, around 10%.

• 1:34:09Dr. Peter Attia?

  What?

• 1:34:09Speaker 01

  Yes.

• 1:34:10Dr. Peter Attia?

  Ninety percent of women who freeze eggs never touch them?

• 1:34:14Speaker 01

  Yeah, or because they had time.

• 1:34:17Dr. Peter Attia?

  Because they get pregnant, maybe?

• 1:34:18Speaker 01

  They got pregnant and sometimes they just don't wanna use that. But the sweet spot would be around thirty-something, thirty-two, thirty-five. Because the cost effectiveness of doing that is better than at twenty-five. So biologically, of course, does it make sense to freeze earlier?

• 1:34:42Dr. Peter Attia?

  Yep.

• 1:34:43Speaker 01

  But the chances of the time you spend on it, the cost you spend?

• 1:34:46Dr. Peter Attia?

  Let's, help me understand the costs. And I know it's different in Brazil from in the US. But I assume in Brazil, this is all paid by out of pocket. This is, so I think in the same, in the US, I don't even understand.

• 1:34:57Speaker 01

  US, I think there, there are some differences.

• 1:35:01Dr. Peter Attia?

  Some insurance might cover.

• 1:35:02Speaker 01

  Yeah.

• 1:35:02Dr. Peter Attia?

  But let's just, let's talk about the cash price of doing it in, in Brazil. So if this 25-year-old came and said, I wanna go ahead and do this. What is the cost of harvesting, of doing one harvest cycle?

• 1:35:13Speaker 01

  In Brazil, she would spend about $5,000.

• 1:35:18Dr. Peter Attia?

  US dollars?

• 1:35:19Speaker 01

  US dollars, because our currency is like five, one to one, yeah.

• 1:35:23Dr. Peter Attia?

  Yeah, yeah. Okay, so she spends $5,000 US dollars to do one harvest cycle. And then how much does she spend per year to keep them in storage, safe storage?

• 1:35:31Speaker 01

  It's like $150.

• 1:35:34Dr. Peter Attia?

  Okay, so now that you're compared to the, okay, so the big cost is she's gonna 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?

• 1:36:01Speaker 01

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

• 1:36:13Dr. Peter Attia?

  But since this is not embryos, you're not going to be fertilizing these.

• 1:36:16Speaker 01

  Yes.

• 1:36:16Dr. Peter Attia?

  You're just getting an egg.

• 1:36:17Speaker 01

  Yes, so we have a like a

• 1:36:18Dr. Peter Attia?

  So you don't touch them?

• 1:36:19Speaker 01

  No, we just freeze the, the M2 all site, the mature all sites.

• 1:36:23Dr. Peter Attia?

  And you won't know until you fertilize.

• 1:36:25Speaker 01

  About 75%, 75% of the all sites, 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 least one baby.

• 1:36:54Dr. Peter Attia?

  Which still seems not that high, but.

• 1:36:57Speaker 01

  Yeah, but remember, a fertile

• 1:37:00Dr. Peter Attia?

  But that's all the way to baby, meaning, yeah, yeah. So how many embryos and then each implantation has a rate of fall off, et cetera.

• 1:37:07Speaker 01

  Yeah.

• 1:37:09Dr. Peter Attia?

  Okay, so.

• 1:37:10Speaker 01

  So biologically, of course, that makes sense, but.

• 1:37:13Dr. Peter Attia?

  Economically, it doesn't.

• 1:37:14Speaker 01

  Yeah, that's just economics.

• 1:37:16Dr. Peter Attia?

  Okay.

• 1:37:17Speaker 01

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

• 1:37:25Dr. Peter Attia?

  And the main driver of that cost is the medication, the procedure, is it split about equally?

• 1:37:30Speaker 01

  Yeah, one third medication, one third, yeah, one third like clinic and one third lap.

• 1:37:38Dr. Peter Attia?

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

• 1:37:49Speaker 01

  Mine is thirty-seven, thirty-eight. Yes, very high.

• 1:37:54Dr. Peter Attia?

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

• 1:37:57Speaker 01

  Because I think that's just a new treatment, kind of new treatment. And because I have bias, as we're in Sao Paulo, like, yeah.

• 1:38:05Dr. Peter Attia?

  You're treating the hardest cases.

• 1:38:07Speaker 01

  Yeah, probably.

• 1:38:08Dr. Peter Attia?

  So when a thirty-seven-year-old woman comes to you, I assume she's been trying for a while to get pregnant. Because she's thirty-seven, she's probably had many aneuploid miscarriages. So she comes to you and says, "Look, we can't leave this to chance anymore. You're gonna do a cycle." You will typically get how many os sites in her?

• 1:38:28Speaker 01

  So my infertile patient is even older, like forty. Like a social freezing is around thirty-seven. So it depends a lot on ovarian reserve. So if the reserve is like normal, forty-year-old woman.

• 1:38:46Dr. Peter Attia?

  What's a typical AMH for a forty-year-old?

• 1:38:48Speaker 01

  Will be around one milligram per ml.

• 1:38:51Dr. Peter Attia?

  And that corresponds to roughly how many eggs left?

• 1:38:54Speaker 01

  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 from a practical standpoint. Because sometimes we check the ovaries, we do the intrafollicle 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.

• 1:39:25Dr. Peter Attia?

  Okay.

• 1:39:26Speaker 01

  And eight eggs at forty is not sufficient mostly to produce an euploid embryo.

• 1:39:33Dr. Peter Attia?

  Oh my god, because eight eggs, you're gonna fertilize them, and more than half of them are gonna be aneuploid.

• 1:39:40Speaker 01

  Yeah.

• 1:39:41Dr. Peter Attia?

  So you might get two.

• 1:39:42Speaker 01

  Seven, eighty percent of them, yeah.

• 1:39:44Dr. Peter Attia?

  Okay, so you might get one to two euploid to implant.

• 1:39:50Speaker 01

  Yeah, we see that it's like a funnel. It's very important for the layperson to understand that. You have the follicles. Each follicle might have one os site. Every os site has a chance of being matured, seventy-five percent. Every mature egg can be fertilized and on day one present this pronuclein. We say that it's it's fine.

• 1:40:13Dr. Peter Attia?

  That's the M two phase.

• 1:40:14Speaker 01

  Yeah, after the M two phase.

• 1:40:16Dr. Peter Attia?

  Yep.

• 1:40:17Speaker 01

  And then from day one to day five or day six, which is a blastocyst. Around thirty up to sixty percent of the 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 aneplay rate.

• 1:40:37Dr. Peter Attia?

  Yeah, so hence the inefficiency. You're just multiplying negative numbers after you're multiplying so many small numbers together.

• 1:40:43Speaker 01

  Yeah.

• 1:40:44Dr. Peter Attia?

  That the the outcome is very difficult.

• 1:40:46Speaker 01

  So when the patient is freezing her own eggs, it's very important for her to know that the, you know, the.

• 1:40:54Dr. Peter Attia?

  The funnel is steep.

• 1:40:55Speaker 01

  Very important because sometimes it's very sad to to see a patient that is coming back. Like she froze her eggs at thirty four and she's coming back at forty and she had just eight eggs. And now you thaw them and then you produce just one blastocyst and does an implant. So that's it. And now she's forty.

• 1:41:18Dr. Peter Attia?

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

• 1:41:55Speaker 01

  Yeah, Ja- Japan is facing this right now.

• 1:41:58Dr. Peter Attia?

  Yeah.

• 1:41:58Speaker 01

  So Israel, in in Israel, you can do how many cycles you want you need.

• 1:42:05Dr. Peter Attia?

  Yeah.

• 1:42:05Speaker 01

  To produce your family.

• 1:42:07Dr. Peter Attia?

  Yeah.

• 1:42:07Speaker 01

  So I think from a longevity perspective, you you're right. You can avoid this disease called infertility, but you can prevent that by freezing all sites earlier. But I think that's a problem of access right now.

• 1:42:26Dr. Peter Attia?

  Yeah.

• 1:42:26Speaker 01

  We have the technology.

• 1:42:27Dr. Peter Attia?

  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 forty, she's come back only to realize that nothing, nothing worked. So, but she still wants to have a baby. So right now, her only option is to use an egg donor, correct?

• 1:42:48Speaker 01

  Uh huh.

• 1:42:49Dr. Peter Attia?

  Okay. In which case, she will use the egg of a young woman. She'll use the egg of a twenty-five-year-old woman, likely with her partner's sperm. And that's fine. That's a great treatment, right? That works, that, that works very, very well. But I have now heard about an emerging technology where that woman who is forty can use her genetic material with 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,

• 1:43:34Dr. Peter Attia?

  and she could even use a surrogate. So, so help me understand that technology.

• 1:43:38Speaker 01

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

• 1:43:49Dr. Peter Attia?

  Yep.

• 1:43:50Speaker 01

  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. And, but twenty-two patients with mitochondrial disease. Because remember, we have like twenty thousand, up to twenty-five thousand genes, and thirty-seven genes in the mitochondria, the so-called mitochondrial DNA.

• 1:44:20Speaker 01

  And for those very specific cases, they basically took out the the pronuclei from the the parent embryo, fertilized after fertilization. So they have in day one, the pronuclei they take out and they insert in a enucleated osid, new osid, 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.

• 1:44:51Dr. Peter Attia?

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

• 1:44:55Speaker 01

  No.

• 1:44:56Dr. Peter Attia?

  Got it.

• 1:44:56Speaker 01

  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 like it's like a battery swap for the for the egg, but you're not changing the engine, right?

• 1:45:25Dr. Peter Attia?

  Yep.

• 1:45:25Speaker 01

  The engine is the main problem.

• 1:45:28Dr. Peter Attia?

  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?

• 1:45:46Speaker 01

  They're, I think, yeah, not for that situation, but they are, 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.

• 1:46:02Dr. Peter Attia?

  Yep.

• 1:46:03Speaker 01

  Very interesting idea, but we don't have publications on that. Actually, we have a huge line, like a huge waitlist of patients trying to to do that.

• 1:46:14Speaker 01

  Makes sense, but we don't have data.

• 1:46:17Dr. Peter Attia?

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

• 1:46:27Speaker 01

  Autologous.

• 1:46:28Dr. Peter Attia?

  Yes, autologous. Is this her own ovarian tissue that was set aside earlier in life?

• 1:46:35Speaker 01

  Like at thirties.

• 1:46:37Dr. Peter Attia?

  At thirties. So they do a partial oophorectomy.

• 1:46:40Speaker 01

  Yeah, and you can then transplant like forty five. When you are forty five and then you can postpone. There is actually like a math behind that. You can postpone menopause like ten, fifteen years, sometimes even more.

• 1:46:54Dr. Peter Attia?

  Where do they re-implant?

• 1:46:55Speaker 01

  The same.

• 1:46:56Dr. Peter Attia?

  In the peritoneum?

• 1:46:57Speaker 01

  Yeah, peritoneum.

• 1:46:57Dr. Peter Attia?

  Okay.

• 1:46:59Speaker 01

  Or you could put in the subcutaneous too.

• 1:47:03Dr. Peter Attia?

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

• 1:47:10Speaker 01

  Yeah.

• 1:47:11Dr. Peter Attia?

  Or are you?

• 1:47:13Speaker 01

  That's mainly for menopause, like to produce her own.

• 1:47:16Dr. Peter Attia?

  That's just to produce estrogen and progesterone?

• 1:47:18Speaker 01

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

• 1:47:30Dr. Peter Attia?

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

• 1:47:41Speaker 01

  That's the question. I just gave a lecture last year about that. So I think because of the culture thing about menopause, right? About hormone replacement therapy after

• 1:47:56Speaker 01

  two thousand two, July two thousand two, double HI, 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.

• 1:48:23Dr. Peter Attia?

  Yeah.

• 1:48:23Speaker 01

  But we don't have data. But to your question, we probably in the future, we're gonna have like stem cells producing new all sites.

• 1:48:33Speaker 01

  We are not there yet.

• 1:48:34Dr. Peter Attia?

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

• 1:48:42Speaker 01

  Not that much. I think more like ten years.

• 1:48:45Dr. Peter Attia?

  Why? Why so difficult? What has to be done? Explain what it is, first of all.

• 1:48:50Speaker 01

  It's, 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.

• 1:49:13Dr. Peter Attia?

  Now, we're doing this in animals right now?

• 1:49:15Speaker 01

  Yeah.

• 1:49:16Dr. Peter Attia?

  Which animals? How?

• 1:49:17Speaker 01

  I think cattle, probably, yeah.

• 1:49:21Dr. Peter Attia?

  And so are they doing this in primates yet?

• 1:49:24Speaker 01

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

• 1:49:27Dr. Peter Attia?

  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.

• 1:49:46Speaker 01

  That has been, there's a publication about that, yeah.

• 1:49:51Dr. Peter Attia?

  That you can make the egg out of a stem cell?

• 1:49:52Speaker 01

  Yeah, but we are not sure about the consequences and the clinical benefits of the, like the safety of that.

• 1:50:00Dr. Peter Attia?

  Has it been done in mice?

• 1:50:01Speaker 01

  Yeah.

• 1:50:02Dr. Peter Attia?

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

• 1:50:07Speaker 01

  Yeah.

• 1:50:07Dr. Peter Attia?

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

• 1:50:10Speaker 01

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

• 1:50:25Dr. Peter Attia?

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

• 1:50:34Speaker 01

  Probably. I don't know if that's safe, that's gonna be safe, like.

• 1:50:41Speaker 01

  If you ask me, you are thirty.

• 1:50:46Speaker 01

  Me and my wife, we are healthy.

• 1:50:50Speaker 01

  We don't have any fertility problems. Would you do IVF or try naturally?

• 1:50:57Dr. Peter Attia?

  Always start naturally.

• 1:50:59Speaker 01

  And why is that?

• 1:51:00Dr. Peter Attia?

  Well, I mean, that's a bit different. I mean, I think I would say for cost and just there's no reason to rush. I mean, but, but look, if, if you, if you struggled for a year, we wouldn't hesitate to do IVF, right?

• 1:51:13Speaker 01

  But for me, I think we are, like IVF is, the first baby was

• 1:51:19Dr. Peter Attia?

  Seventy-eight.

• 1:51:20Speaker 01

  Yeah, seventy-eight, yeah. So it's actually a new technology. We can't reproduce everything that we would need to reproduce inside the tubes naturally. There are some epigenetic effects which we can't control and we, we don't know what are the consequences. So if the, the couple had, if the couple has this natural chance, I would try naturally. And

• 1:51:52Dr. Peter Attia?

  The stem cell takes it to a whole new level.

• 1:51:54Speaker 01

  The, the problem is, yes, if you, oh, you can count on stem cells, okay. But wouldn't be better to use my own old size than just froze like at thirty-five?

• 1:52:06Dr. Peter Attia?

  Yeah.

• 1:52:07Speaker 01

  I don't know, probably yes.

• 1:52:10Dr. Peter Attia?

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

• 1:52:16Speaker 01

  The genetics, yeah.

• 1:52:18Dr. Peter Attia?

  And how do you think that shows up phenotypically?

• 1:52:22Speaker 01

  Probably some malformations, some neuro

• 1:52:28Speaker 01

  neurological consequences.

• 1:52:33Speaker 01

  Heart disease.

• 1:52:35Speaker 01

  Yeah, it's

• 1:52:36Dr. Peter Attia?

  Do we see this in the epidemiology? I mean, these, so again, people born of IVF are still very young. They're, you know, they're, they're not even fifty yet.

• 1:52:46Speaker 01

  Louise Brown is like forty something, forty eight.

• 1:52:49Dr. Peter Attia?

  She's forty eight.

• 1:52:51Speaker 01

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

• 1:53:00Dr. Peter Attia?

  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 so infertility, there's so many confounders.

• 1:53:11Speaker 01

  Yeah.

• 1:53:12Dr. Peter Attia?

  And we're never going to do a randomized control trial for IVF.

• 1:53:15Speaker 01

  But there's data showing that if that same couple that needed IVF and then now they are getting pregnant naturally, because sometimes it happens, right? That it's mainly a bias, a selection bias problem, not the technology itself. Yeah, but it's, it's a new, a new technology, right?

• 1:53:37Dr. Peter Attia?

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

• 1:53:42Speaker 01

  Actually, I was very excited about this new guidance from ACOG. Very simple, because probably we're gonna 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.

• 1:54:08Dr. Peter Attia?

  Early.

• 1:54:09Speaker 01

  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 a monoclonal antibody that targets the receptor of prolectin. 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 prolectin receptors. Very interesting.

• 1:54:52Speaker 01

  Maybe that's gonna be the first biologic treatment for endometriosis. That it's not using hormones.

• 1:55:00Speaker 01

  So like to your point that some, why don't we have like medications that targets?

• 1:55:06Dr. Peter Attia?

  Target the disease directly?

• 1:55:08Speaker 01

  Yeah, yeah. Probably we're getting that like soon. And yeah, I, I, and I think the diagnosis, Peter.

• 1:55:16Dr. Peter Attia?

  Yeah.

• 1:55:17Speaker 01

  Yeah, I think with this widespread, you know, ultrasonography and MRI and just the awareness of the disease, we're gonna, yeah, not only diagnose and treat more effectively.

• 1:55:31Dr. Peter Attia?

  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.

• 1:55:54Speaker 01

  That's it.

• 1:55:55Dr. Peter Attia?

  So you just have to be a bull in a china shop and demand a diagnosis and say, I'm not gonna take no for an answer. I want an MRI. And if necessary, I want an ultrasound done with this correct protocol.

• 1:56:08Speaker 01

  That's it.

• 1:56:08Dr. Peter Attia?

  That's it. And we're not gonna take no for an answer. We're gonna get these diagnoses. So we can start the treatment because the earlier you start the treatment, the better the prognosis.

• 1:56:16Speaker 01

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

• 1:56:35Dr. Peter Attia?

  That they finally have a diagnosis.

• 1:56:36Speaker 01

  When I tell them, you, you know, you are suffering, I, 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, we have technology for that. We have treatment for that. And. We should do that, right?

• 1:57:10Dr. Peter Attia?

  A perfect way to end it, Hinato. Thank you very much and I really appreciate you getting this message out.

• 1:57:15Speaker 01

  Great to be here. Thank you, man.

• 1:57:17Dr. Peter Attia?

  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 peteratiaMD. You can also leave us a 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

• 1:58:02Dr. Peter Attia?

  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 peterattiamd.com/about, where I keep an up-to-date and active list of all disclosures.