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

1. 0:00 – 0:11

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia. [upbeat music]

2. 0:11 – 9:03

   Endometriosis: definition, prevalence, infertility risk, and theories of disease development

   1. PAPeter Attia0:11

      Renato, wonderful to see you. Uh, thank you for coming to Austin. [lips smack] Um, today, we're gonna talk about two things that are related, but I wanna talk about them in sort of this order. Uh, the first thing I wanna do is talk about the diseases of the uterus. Um, and, and I think most notably, we'll talk about endometriosis, but also others. Um, and then I wanna talk about infertility, and obviously talk about some of the treatments for infertility, and of course, there's an overlap between those two. [lips smack] So let's, let's start with the former. Um, [chuckles] 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.

   2. RTDr. Renato Tomioka0:53

      So I believe the, the first point is to remember the layers of the uterus, right? So we have mainly three layers. The outside layer, the, it's called 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 endometrium, is outside the uterus, right? So instead of being inside that layer, it goes into the fallopian tubes, on the ovaries, on the bowel, the bladder, sometimes the appendix, and even the diaphragm.

   3. PAPeter Attia1:40

      Mm.

   4. RTDr. Renato Tomioka1:41

      So that's endometriosis, very important disease. Around 10% of reproductive women, uh, globally have endometriosis, which means around 200 million, 200 million women. And if you look into the data of infertile women, it's about 30% to 50% of women, they can have endometriosis, so.

   5. PAPeter Attia2:04

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

   6. RTDr. Renato Tomioka2:10

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

   7. PAPeter Attia2:17

      So it's causal?

   8. RTDr. Renato Tomioka2:19

      Yes.

   9. PAPeter Attia2:20

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

   10. RTDr. Renato Tomioka2:31

       Very dynamic. Very dynamic, depending on the, the, the dura- duration of the cycle, and of course, where you are in the cycle.

   11. PAPeter Attia2:39

       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?

   12. RTDr. Renato Tomioka2:49

       Precisely.

   13. PAPeter Attia2:50

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

   14. RTDr. Renato Tomioka2:53

       It's just a, a peritoneum.

   15. PAPeter Attia2:55

       Okay.

   16. RTDr. Renato Tomioka2:55

       Like the visceral peritoneum. No, no, like, no, no, uh, it doesn't have, it doesn't add up much, you know?

   17. PAPeter Attia3:03

       Okay.

   18. RTDr. Renato Tomioka3:03

       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 adeno- in- internal and adenomyosis, like, external adenomyosis.

   19. PAPeter Attia3:20

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

   20. RTDr. Renato Tomioka3:43

       Great question. So we have about 50% of heritability. Uh, if you have a first-degree relative with endo, you have about seven times higher chance of having endometriosis. So that's the, the, the main-

   21. PAPeter Attia4:01

       So meaning mother or sister?

   22. RTDr. Renato Tomioka4:03

       Yeah.

   23. PAPeter Attia4:03

       Okay.

   24. RTDr. Renato Tomioka4:04

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

   25. PAPeter Attia4:39

       And I'm sorry, it goes into the pelvis by going retrograde-

   26. RTDr. Renato Tomioka4:43

       Retro

   27. PAPeter Attia4:43

       ... towards the ovary, but of course, the fallopian tube doesn't enter the ovary. It enters back into-

   28. RTDr. Renato Tomioka4:48

       Correct

   29. PAPeter Attia4:48

       ... the pelvis. Okay.

   30. RTDr. Renato Tomioka4:48

       Correctly. So remember, the fimbria, like the, the distal part of the tubes, they are not directly connected to the ovary. They are like, um, they are moving around, and they can pick up the oocytes.
3. 9:03 – 13:25

   The biology of endometriosis: estrogen dependence, progesterone resistance, and tumor-like growth mechanisms

   1. RTDr. Renato Tomioka9:03

      you look into the mechanism, Peter, yeah, we have this estrogen dependence. The endom- endometria- endometriotic lesions, they produce by themselves estrogen, so they overexpress aromatase. There's an upregulation in aromatase. So sometimes just blocking the ovaries is not sufficient to block the, the disease. Uh, we have also this progesterone resistance, so the, the progesterone receptor is downregulated, so we don't have this, uh, you know, the, um, the, the action of progesterone that is very important to counteract the action of the estrogen.

   2. PAPeter Attia9:42

      Yeah, I-- Now, of course, I only know this in the context of hormone replacement therapy-

   3. RTDr. Renato Tomioka9:47

      Mm-hmm

   4. PAPeter Attia9:47

      ... 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 estro- as she's, as she's ovulating, estrogen is increasing the thickness. The progesterone surge causes the shedding?

   5. RTDr. Renato Tomioka10:12

      That's it. So remember, the fo- uh, uh, the follicular, like the late follicular phase, endometrium, or, uh, people who works with IVF know that a lot, right? Because we are, uh, aiming to look at the endometrium at the f- the final phase of the follicular part, right? So endometrium is about to, like eight, uh, 10 millimeters at that point. But when you have the progesterone, it opens the implantation window. So we, we have this so-called decidualization. Lipids and secretory phase comes in, and then, uh, at the ultrasound, it, uh, endometrium is, like, white, not anymore black, and this is very important for the pregnancy. But if there is no embryo inside the uterus, the corpus luteum, um, like, it has, like, 12 to, uh, 14 days of, of life, and then it just sheds because you have, um, um, a decrease in estrogen and progesterone levels, so it sheds.

   6. PAPeter Attia11:16

      Mm-hmm.

   7. RTDr. Renato Tomioka11:17

      So that is very important for endometriosis, too, because remember, it's like endometrium outside the uterus. So one of the, the treatment, uh, pillars is giving progesterone or progestins to these patients. But endometriosis lesions, they have this progesterone resistance.

   8. PAPeter Attia11:38

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

   9. RTDr. Renato Tomioka11:48

      Yeah.

   10. PAPeter Attia11:48

       'Cause it's outside the body.

   11. RTDr. Renato Tomioka11:49

       Yeah, it's like stroma and glands.

   12. PAPeter Attia11:52

       Yep.

   13. RTDr. Renato Tomioka11:52

       It's like that resembles the endometrial lining.

   14. PAPeter Attia11:55

       Okay, and they have progesterone receptors.

   15. RTDr. Renato Tomioka11:57

       Yeah.

   16. PAPeter Attia11:58

       And when you say they're resistant to progesterone, do you mean-- Is it, you know, not like it's the same, but insulin resistance, where progesterone hits the receptor, but it-

   17. RTDr. Renato Tomioka12:07

       Kind of.

   18. PAPeter Attia12:07

       Yeah.

   19. RTDr. Renato Tomioka12:07

       Kind of, yeah. You need much more insulin-

   20. PAPeter Attia12:10

       Yep

   21. RTDr. Renato Tomioka12:10

       ... or progesterone to produce the effect.

   22. PAPeter Attia12:12

       Yep.

   23. RTDr. Renato Tomioka12:13

       Like to activate

   24. PAPeter Attia12:13

       So why does that happen?

   25. RTDr. Renato Tomioka12:15

       It's complicated. Um, I don't, I don't think we know for sure, but it, it's very interesting because those lesions, they also produce, they also have somatic mutations. Think about that. Like, in oncogenic genes like KRAS-

   26. PAPeter Attia12:32

       Hmm

   27. RTDr. Renato Tomioka12:32

       ... PIK3, uh, PIK kinase, right? Uh, so they resembles, they, 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. But-

   28. PAPeter Attia12:54

       But do they have metastatic potential?

   29. RTDr. Renato Tomioka12:57

       No. No. Why is that?

   30. PAPeter Attia12:58

       So in a sense, they're benign tumors.
4. 13:25 – 18:51

   Adenomyosis explained: how it differs from endometriosis, why it develops, and its impact on reproductive health

   1. PAPeter Attia13:25

      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.

   2. RTDr. Renato Tomioka13:34

      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.

   3. PAPeter Attia13:47

      Hmm.

   4. RTDr. Renato Tomioka13:48

      Up to 20 or 30% of women have adenomyosis.

   5. PAPeter Attia13:51

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

   6. RTDr. Renato Tomioka13:55

      Yes.

   7. PAPeter Attia13:56

      Okay.

   8. RTDr. Renato Tomioka13:56

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

   9. PAPeter Attia14:10

      Understood.

   10. RTDr. Renato Tomioka14:11

       But now we are c- we are calling this disease differently because they, they have, they share some mechanisms, but they are different. Um, if you look into the, the studies of single-cell transcriptomics, uh, Linda Giudice last year published one beautiful paper about this. They are, they don't have the same molecular pathway, so they are different diseases. And the, the, the mechanisms in-

   11. PAPeter Attia14:35

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

   12. RTDr. Renato Tomioka14:37

       So they have the same oncogenic, uh, mut- uh, somatic mutations. Adenomyosis also have, um, also has this, uh, progesterone resistance and estrogen dominance. So they also produce or overexpress aromatase. So it's pretty much the same, but, uh, they are different diseases. And of course, you have cure in adenomyosis. If you do a hysterectomy, you c- take out the disease. It's just a disease in the uterus. Endometriosis, it's outside the uterus.

   13. PAPeter Attia15:10

       And what is the, um, overlap in women who have one, the other, and both?

   14. RTDr. Renato Tomioka15:17

       Good question.

   15. PAPeter Attia15:17

       So obviously 20% have one, 10% have the other. How many have both?

   16. RTDr. Renato Tomioka15:21

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

   17. PAPeter Attia15:27

       Up to 70% of endometriosis patients?

   18. RTDr. Renato Tomioka15:29

       Endometriosis patients, they ha- might have some type or some, uh, degree of adenomyosis, and that's very important for the infertile couple, right? So the mechanism, uh, in adenomyosis is the so-called TIAR. So it's tissue injury and repair. So essentially, the, the endometrium is going inside the uterus, like breaking that junctional zone, which is a thin layer between the endometrium and the myometrium, and it's going inside and disrupting and, like, breaking the lines and producing those islands of cysts and echogenic buds that, uh, like, increase the volume of the uterus and make it, makes it very soft to the touch. Like, during surgery can palpate the uterus.

   19. PAPeter Attia16:22

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

   20. RTDr. Renato Tomioka16:28

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

   21. PAPeter Attia16:37

       But they can't get through the myometrium.

   22. RTDr. Renato Tomioka16:40

       They can get through the myometrium, and we have some, like, risk factors. For example, uh, when you do a, when you have a miscarriage, when you have C-section, so you break the line mechanically.

   23. PAPeter Attia16:52

       Hmm.

   24. RTDr. Renato Tomioka16:52

       When you do curettage, right? You, you break that, or even hyster- uh, hysteroscopy for le- myomas or polyps, you can break that acutely and, uh, eh, the endometrium can invade the myometrium.

   25. PAPeter Attia17:07

       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.

   26. RTDr. Renato Tomioka17:23

       We have, uh, another type of adenomyosis. There's not, like, a, um, 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. But there are some authors that, uh, think they are, this, it's r- uh, not correctly, uh, to say that it's adenomyosis. So mainly adenomyosis, that what we are talking about.

   27. PAPeter Attia18:02

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

   28. RTDr. Renato Tomioka18:17

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

   29. PAPeter Attia18:38

       A- and again, this must be very confusing because it would be easy to confuse this for endometriosis, I assume. We haven't even talked about the presentation, so we can do that in a minute. But, um... Well, let's actually do that.

5. 18:51 – 22:09

   Recognizing endometriosis and adenomyosis: the “6 Ds” of endometriosis and key differences in clinical presentation

   1. PAPeter Attia18:51

      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?

   2. RTDr. Renato Tomioka19:06

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

   3. PAPeter Attia19:17

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

   4. RTDr. Renato Tomioka19:29

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

   5. PAPeter Attia19:44

      And this is not cramping; this is-

   6. RTDr. Renato Tomioka19:45

      No

   7. PAPeter Attia19:45

      ... actual pain.

   8. RTDr. Renato Tomioka19:46

      Pain.

   9. PAPeter Attia19:47

      Okay.

   10. RTDr. Renato Tomioka19:47

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

   11. PAPeter Attia20:00

       Intravenous medication

   12. RTDr. Renato Tomioka20:01

       ... intravenous medications. And they have-- The second D is deep dyspareunia, which means, uh, pain during intercourse, especially in the profound, um, posterior s- uh, wall of the vagina. Third D would be dyschezia, or pain during bowel movements.

   13. PAPeter Attia20:22

       Mm-hmm.

   14. RTDr. Renato Tomioka20:23

       Right? Especially during the period-

   15. PAPeter Attia20:25

       And the uterus is how close to the rectum? It's cl- it's close.

   16. RTDr. Renato Tomioka20:27

       Yeah. It's-

   17. PAPeter Attia20:28

       It's adjacent immediately.

   18. RTDr. Renato Tomioka20:28

       Yeah, adjacent. Yeah, yeah.

   19. PAPeter Attia20:30

       Yeah.

   20. RTDr. Renato Tomioka20:30

       And sometimes we can have lesions right there-

   21. PAPeter Attia20:32

       Yep

   22. RTDr. Renato Tomioka20:32

       ... in the septum, right? Fourth D would be dysuria, like pain during, uh, urination, especially cyclic pain, usually, uh, during the menstrual period. We can al- have also, like, bleeding, but that's not very common. Fifth D would be difficulty in getting pregnancy, in getting pregnant, right? So difficulty in conceiving, infertility. And, uh, the last one would be, I w- I will put the D, like, just for a hook, for a memory hook, but it's dysfunctional chronic pelvic pain. So, uh, those women can present with pain for more than six months without, uh, any relation with the cycle.

   23. PAPeter Attia21:14

       Hmm.

   24. RTDr. Renato Tomioka21:14

       Yeah. So it-- you have a lot of, uh, this myriad of pain, you know?

   25. PAPeter Attia21:20

       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?

   26. RTDr. Renato Tomioka21:32

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

   27. PAPeter Attia21:44

       So their only symptom would be for infertility potentially.

   28. RTDr. Renato Tomioka21:47

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

   29. PAPeter Attia22:08

       Um,

6. 22:09 – 24:08

   Uterine fibroids: classification, symptoms, and the importance of fibroid location for bleeding and fertility

   1. PAPeter Attia22:09

      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.

   2. RTDr. Renato Tomioka22:18

      So fibroids, they are very common. Up to 70 or 80% of, uh, women will have one fibroid, mostly asymptomatic. They are, uh, benign, uh, nodules inside the uterus, can be just right at the endometrium, so-called submucosa, uh, inside the myometrium, intramuscular, or on the serosa, like subserous, right? And they can be, they can get very, very large, right? Nodules. Sometimes it disrupts the-- it can disrupt the anatomy of the uterus, especially the endometrial cavity, and provokes miscarriage. And they can bleed too, especially the submucosas.

   3. PAPeter Attia23:03

      Yeah.

   4. RTDr. Renato Tomioka23:03

      Yeah. We, we classify them by the f- uh, International Federation of Gynecologists and Obstetricians by zero up to seven, depending on the classification, up to eight. And the zero, one or, and two, they are s- submucosas, so they are the, the problematic for fertility and for bleeding.

   5. PAPeter Attia23:23

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

   6. RTDr. Renato Tomioka23:31

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

   7. PAPeter Attia23:35

      Ah, okay, okay

   8. RTDr. Renato Tomioka23:36

      ... yeah. So zero would be, like, just, uh-

   9. PAPeter Attia23:38

      In the endometrium?

   10. RTDr. Renato Tomioka23:39

       ... inside, inside the cavity.

   11. PAPeter Attia23:40

       Okay. Yep. Okay.

   12. RTDr. Renato Tomioka23:41

       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, the uterus. And the number three would be, like, just touching the endometrium.

   13. PAPeter Attia23:56

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

   14. RTDr. Renato Tomioka24:00

       Yeah

   15. PAPeter Attia24:00

       ... number, but lower and lower severity?

   16. RTDr. Renato Tomioka24:03

       Yeah.

   17. PAPeter Attia24:03

       Okay.

   18. RTDr. Renato Tomioka24:04

       Probably not severity, but yeah, clinical implications, right.

7. 24:08 – 28:26

   Understanding endometriosis pain: lesion-driven pain, nerve involvement, central sensitization, and the importance of early treatment

   1. PAPeter Attia24:08

      Okay, so the woman with, uh, you said 10% of women with endometriosis could be asymptomatic, or their only presentation could be infertility. So that would suggest that when we start talking about infertility, one thing that should be in the differential diagnosis is un- un- untreated endometriosis. Um, but otherwise, most women are going to experience some pain with something, pain with intercourse, pain with her cycle, urination, e- everything. Okay. Um, then on adenomyosis, what percentage of those are asymptomatic?

   2. RTDr. Renato Tomioka24:41

      Uh, I don't have the number in my head, but I would say that probably one-third. One-third. Because depends on the phenotype and the intensity of the disease, right? So we have... If you just have one little cyst, myometrial cyst-

   3. PAPeter Attia24:56

      Mm

   4. RTDr. Renato Tomioka24:57

      ... which is a presentation of adenomyosis, probably these patients, uh, 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, yeah, they bleed a lot. They, it, it's, it's very painful. The, the, especially the period is very painful.

   5. PAPeter Attia25:22

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

   6. RTDr. Renato Tomioka25:28

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

   7. PAPeter Attia25:49

      Yep.

   8. RTDr. Renato Tomioka25:50

      Pain, uh, from the lesion directly, so it's just hurts. And here, surgery and treatment, hormonal treatment can help. Second layer is the so-called nociplastic pain, where the nerves are infiltrated by the, the lesions, and they can have burning sensations, you know, uh, sometimes, uh, on their, their legs and the back.

   9. PAPeter Attia26:13

      Mm.

   10. RTDr. Renato Tomioka26:14

       And here, uh, medications can help. Sometimes gabapentin and SRNR, SNRIs, right? Surgery can remove s- uh, can remove, uh, some of those lesions. We do this technique called, uh, ser, uh, nerve sparing. Very difficult, sometimes impossible to do, but we can try. And the third layer, and most difficult to, to treat, is the s- nociplastic pain, when we have central sensitization. So you can have a beautiful surgery, your pelvis is clean, but you can still have pain. It's like, im- imagine this analogy. Imagine like endometriosis lesion is a burglar, right? So surgery can remove the burglar. Hormones can lock the door. But once you have this alarm system ringing and ringing years after years, the wiring changed, and now even a wind can, you know, triggers the alarm. And even removing, without the burglar, without, you know, the, the doors are locked, but you need to, you need a different specialist here. We need a physiotherapist, a pelvic floor physiotherapist, and also a pain specialist to treat those patients. And that's why the, 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, uh, empirically, uh, nowadays. Um, the ACOG just published this March, uh, twenty, twenty-fi- twenty-six, a new guidance on endometriosis diagnosis, and it allows us to not only diagnose clinically, but treat it. Because if you have a, 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,

8. 28:26 – 33:11

   Endometriosis in young women: rising prevalence, delayed diagnosis, and barriers to care

   1. RTDr. Renato Tomioka28:26

      years later.

   2. PAPeter Attia28:27

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

   3. RTDr. Renato Tomioka28:31

      Uh, we are s-- Uh, I, I don't think we have a typical presentation anymore. We are seeing endometriosis in teenagers. Look at this data. Up to 50% and 75% of teenagers with pelvic pain, they have endometriosis. Three-quarters, they have endometriosis.

   4. PAPeter Attia28:51

      And what percentage of teenagers have pelvic pain?

   5. RTDr. Renato Tomioka28:54

      Oh, I'm not sure. I'm not sure.

   6. PAPeter Attia28:56

      Presumably, it's like 5% or less.

   7. RTDr. Renato Tomioka28:58

      Yeah. I think a little bit more.

   8. PAPeter Attia28:59

      Wow.

   9. RTDr. Renato Tomioka28:59

      A little bit more. Yeah. So we are seeing teenagers presenting with endometriosis, and if just normal-

   10. PAPeter Attia29:08

       Which again, how, 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.

   11. RTDr. Renato Tomioka29:26

       Mm-hmm.

   12. PAPeter Attia29:26

       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-

   13. RTDr. Renato Tomioka29:33

       Mm-hmm

   14. PAPeter Attia29:33

       ... presumably linked to more insulin resistance and lifestyle factors that drive that. What, is there anything else that you think could be, uh, increasing the prevalence of this in young-

   15. RTDr. Renato Tomioka29:42

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

   16. PAPeter Attia29:51

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

   17. RTDr. Renato Tomioka29:53

       Yeah. Diet, probably the, the, you know, this SAD diet that you talk. Uh, poor sleep, because remember, poor sleep can-

   18. PAPeter Attia30:04

       Immune system

   19. RTDr. Renato Tomioka30:04

       ... immune sy- yeah.

   20. PAPeter Attia30:04

       Yep

   21. RTDr. Renato Tomioka30:04

       ... immune dysregulation. The macrophages, they just jump f- from one to the other type, and this may, um, increase the, the risk of endometriosis. So we are not sure about this, uh, question, but-

   22. PAPeter Attia30:19

       It's probably many things-

   23. RTDr. Renato Tomioka30:20

       Yes

   24. PAPeter Attia30:20

       ... which is what makes it so complicated.

   25. RTDr. Renato Tomioka30:21

       Yes.

   26. PAPeter Attia30:22

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

   27. RTDr. Renato Tomioka31:08

       Oh, yeah, unfortunately not. Because if, if you look, like, the diagnosis delay, Peter, is five to 12 years, depending on the country. I believe in the US is around six years.

   28. PAPeter Attia31:20

       Mm-hmm.

   29. RTDr. Renato Tomioka31:20

       So Brazil, around seven years. So from the first symptom up to the diagnosis, can you imagine, like, five up to 10 years?

   30. PAPeter Attia31:32

       So 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?
9. 33:11 – 45:52

   Modern diagnosis of endometriosis: specialized ultrasound, MRI, and the decline of diagnostic laparoscopy

   1. PAPeter Attia33:11

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

   2. RTDr. Renato Tomioka34:11

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

   3. PAPeter Attia34:14

      Okay.

   4. RTDr. Renato Tomioka34:15

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

   5. PAPeter Attia34:45

      Just like a colonoscopy or a sigmoidoscopy?

   6. RTDr. Renato Tomioka34:47

      Not just-- Yeah, like m- much more, like, simple.

   7. PAPeter Attia34:50

      Okay.

   8. RTDr. Renato Tomioka34:51

      Um, you have this, uh, enema in, um-

   9. PAPeter Attia34:54

      Yep

   10. RTDr. Renato Tomioka34:54

       ... like one hour before the, the exam, and no residue, uh, diet. But that simple protocol with a gel inside the vagina, so you can look into, uh, small lesions in the bowel, bladder, uh, 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, uh, one doctor doing that, Scott Young, but not for everybody. I think in the US mainly is, uh, MRI. [lip smack] MRI and ultrasonography, they are, they have very high sensitivity, about 95, 98%. Yeah, very high, and very high specificity too. But for superficial lesions, just let, let me go, step back. We have three types of, three phenotypes, right? The superficial lesions, the deep infiltrative endometriosis, and the endometriomas, the cysts of endometriosis. So for those superficial, uh, lesions, uh, ultrasound, sometimes it misses.

   11. PAPeter Attia36:12

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

   12. RTDr. Renato Tomioka36:19

       Ac- actually, uh, peritoneum, but, like, the definition will be-

   13. PAPeter Attia36:22

       Not, not deep within the peritoneum.

   14. RTDr. Renato Tomioka36:24

       Yeah.

   15. PAPeter Attia36:24

       Just sitting right on top.

   16. RTDr. Renato Tomioka36:25

       On top of the peritoneum.

   17. PAPeter Attia36:26

       Okay.

   18. RTDr. Renato Tomioka36:26

       Yeah, but less than five millimeters.

   19. PAPeter Attia36:29

       Okay. And so just to orient everybody, 'cause the anatomy here is actually [chuckles] a little confusing, this means imagine you could go inside a woman's abdomen Right? 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, um, you have bowel surrounded by peritoneum. You have the kidneys behind, the v- the blood vessels, et cetera. It's basically just a potential space. And what would be-- And, and by the way, included on top of that peritoneum, you would see the uterus. You would see the ovaries

   20. RTDr. Renato Tomioka37:07

       The fallopian tubes

   21. PAPeter Attia37:08

       ... the fallopian tubes between them

   22. RTDr. Renato Tomioka37:09

       The ligaments

   23. PAPeter Attia37:10

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

   24. RTDr. Renato Tomioka37:20

       Actually, uh, right behind it.

   25. PAPeter Attia37:22

       Ah.

   26. RTDr. Renato Tomioka37:22

       Yeah, right, uh, behind the uterus, uh, the lig- the ligaments-

   27. PAPeter Attia37:26

       Okay

   28. RTDr. Renato Tomioka37:27

       ... the so-called uterosacral ligaments. Because just, uh, the anatomy and gravity, you know?

   29. PAPeter Attia37:35

       Yeah

   30. RTDr. Renato Tomioka37:35

       S- Most lesions, they just, uh, stay there. But sometimes they can travel.
10. 45:52 – 54:11

    Clinical case example #1: Managing endometriosis in a young woman seeking pain relief while preserving future fertility

    1. PAPeter Attia45:52

       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?

    2. RTDr. Renato Tomioka46:03

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

    3. PAPeter Attia46:08

       Yes

    4. RTDr. Renato Tomioka46:08

       ... is-- we have another section. If she's trying just to get a better life without pain and not wanting to conceive now, we have much more options.

    5. PAPeter Attia46:19

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

    6. RTDr. Renato Tomioka46:36

       So we have a list of questions. First one is, uh, do you wanna get pregnant in the future? How many children do you, do you want? It's hard to, to answer that if you are 20.

    7. PAPeter Attia46:49

       Yeah.

    8. RTDr. Renato Tomioka46:50

       Um, how is your ovarian reserve, AMH, antral follicle count? Very important. Disease phenotype. What I mean here, do you have endometrioma, the cyst? Because this a, a very special phenotype, which can lead to lower ovarian reserve, and also the surgery can impair, um, can impair the, the antral follicle count and even the MR-- uh, AMH. And how's the pain, right? Like, if she has-- she's presenting with pain, we mainly start with a pill, like a birth control pill, because those patient, uh, they usually are not trying to conceive, so they want contraception, right? And if the patient doesn't have endometrioma, we can use an IUD, like a Mirena or a Kyleena, to s-

    9. PAPeter Attia47:43

       In addition to an oral contraceptive?

    10. RTDr. Renato Tomioka47:44

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

    11. PAPeter Attia47:47

        Okay.

    12. RTDr. Renato Tomioka47:48

        Right? So Mirena is not good for cysts because it, it doesn't suppress, uh, the ovulation, right? So but if the patient has, like, no endometrioma, you can use either a Mirena. Benefit is, like, um, five years of treatment.

    13. PAPeter Attia48:04

        And w-- I mean, a Mirena is progesterone-coated. Why would you use a Mirena over any IUD?

    14. RTDr. Renato Tomioka48:11

        Because you need the progesterone action to-

    15. PAPeter Attia48:14

        You're trying to suppress-

    16. RTDr. Renato Tomioka48:15

        Yeah. To-

    17. PAPeter Attia48:15

        ... endometrial hyperplasia.

    18. RTDr. Renato Tomioka48:16

        Yeah. That's it.

    19. PAPeter Attia48:17

        Okay.

    20. RTDr. Renato Tomioka48:17

        And to fin-- And, and to, to, like, to avoid menstruation.

    21. PAPeter Attia48:21

        Okay.

    22. RTDr. Renato Tomioka48:21

        Menstrual periods.

    23. PAPeter Attia48:22

        I-- Yeah. So, so in other words, a regular IUD doesn't necessarily suppress-

    24. RTDr. Renato Tomioka48:26

        No

    25. PAPeter Attia48:26

        ... whereas a Mirena will.

    26. RTDr. Renato Tomioka48:28

        It's just an inflammatory, um-

    27. PAPeter Attia48:29

        Yeah

    28. RTDr. Renato Tomioka48:29

        ... event for contraception.

    29. PAPeter Attia48:31

        Just it, it prevents conception, yeah.

    30. RTDr. Renato Tomioka48:32

        Yeah.
11. 54:11 – 1:01:24

    Clinical case example #2: Comparing treatment strategies for symptom control versus fertility

    1. PAPeter Attia54:11

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

    2. RTDr. Renato Tomioka54:49

       So first line, medical therapy. We would y- because remember, if she doesn't want to conceive, she needs contraception So we could, we could use a, a combined, uh, pill or progestin. In Brazil, we have this Dianogest, which is, is a very good progestin for endometriosis. In the US, we, we have the Natiza. Natiza is like, uh, estrogen, estradiol plus Dianogest, but you need to use only the active, uh, with Dianogest. There are 22 pills inside a, a box. And if she responds well, that's, that's it. We are controlling the disease, right?

    3. PAPeter Attia55:32

       And if not, you go to surgery.

    4. RTDr. Renato Tomioka55:34

       Or we can use a Mirena.

    5. PAPeter Attia55:35

       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.

    6. RTDr. Renato Tomioka55:47

       So probably the, the objective is have a baby, right?

    7. PAPeter Attia55:51

       Yes, she wants a baby.

    8. RTDr. Renato Tomioka55:52

       It's not just controlling pain.

    9. PAPeter Attia55:53

       That's right.

    10. RTDr. Renato Tomioka55:54

        But sometimes they present with both.

    11. PAPeter Attia55:56

        Yeah.

    12. RTDr. Renato Tomioka55:56

        Pain plus, uh, infertility. So this patient, we, we, we have a, a series of questions that, remember, infertility is a couple's disease. Probably the only disease that I know in medicine that involves two people, right? It's defined by the incapacity to, to achieve pregnancy after one year of trying to do that. So you need to investigate the male factor, like a sperm analysis, and you need to investigate the other factors that not only endometriosis can impair infertility, right? So you need to, to ask, request a karyotype and some other exams like hysterosalpingogram.

    13. PAPeter Attia56:38

        So let's say you do the fertility workup, and you do not see any evidence in the male for-

    14. RTDr. Renato Tomioka56:50

        Mm-hmm

    15. PAPeter Attia56:50

        ... uh, with motility count or anything like that. Um, and I'm making this up because I don't know if this is how it would present. They don't seem to have difficulty with a chemical pregnancy, but it never, she's always miscarrying at four weeks, six weeks, eight weeks. Like, she's never getting past. Is that a, does that, is that consistent more with maternal age?

    16. RTDr. Renato Tomioka57:14

        Yes.

    17. PAPeter Attia57:15

        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.

    18. RTDr. Renato Tomioka57:24

        Very good question. Actually, we, now we mainly think of, uh, the mechanism about a mechanical mechanism.

    19. PAPeter Attia57:32

        Mm-hmm.

    20. RTDr. Renato Tomioka57:32

        We think that it's mainly mechanical, not biological.

    21. PAPeter Attia57:35

        Okay.

    22. RTDr. Renato Tomioka57:36

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

    23. PAPeter Attia57:48

        Got it.

    24. RTDr. Renato Tomioka57:48

        Right? And surgery can fix that sometimes if the tubes are not too damaged, but we have some adhesions, not too much, but, you know, you can, can do that by laparoscopy or robotic surgery. But it depends a lot on the couple, right? If the, if male factor is okay, if age is okay, and the, the couple just want, like, one child, probably this 36-year-old woman, she has time to do that. And if she doesn't get pregnant after one year of surgery, you can go-

    25. PAPeter Attia58:24

        And just to make sure I understand, Renato, the surgery you're proposing is an, uh, uh, g- is a laparoscope-

    26. RTDr. Renato Tomioka58:32

        Laparoscopic

    27. PAPeter Attia58:32

        ... 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.

    28. RTDr. Renato Tomioka58:41

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

    29. PAPeter Attia58:45

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

    30. RTDr. Renato Tomioka58:52

        Yeah. Primarily, yes. But of course, we have plenty of data showing that we have molecular, um, um, differences between endometriosis and non-endometriosis pelvis. For instance, we have, uh, C-reactive protein, IL-6, TNF alpha, but clinically, it's mainly, uh, an, an anatomical problem, right?
12. 1:01:24 – 1:11:50

    Endometriosis and fertility: the roles of age, embryo quality, IVF, and surgery

    1. PAPeter Attia1:01:24

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

    2. RTDr. Renato Tomioka1:01:47

       No.

    3. PAPeter Attia1:01:48

       Oh.

    4. RTDr. Renato Tomioka1:01:48

       If you, if you are looking just for recipients of-

    5. PAPeter Attia1:01:52

       Yep

    6. RTDr. Renato Tomioka1:01:52

       ... uh, donor eggs-

    7. PAPeter Attia1:01:53

       Yep

    8. RTDr. Renato Tomioka1:01:53

       ... one group has endometriosis.

    9. PAPeter Attia1:01:56

       Yes.

    10. RTDr. Renato Tomioka1:01:56

        The other one is no endometriosis.

    11. PAPeter Attia1:01:58

        Yep.

    12. RTDr. Renato Tomioka1:01:58

        Confirmed by laparoscopy-

    13. PAPeter Attia1:02:00

        Yep

    14. RTDr. Renato Tomioka1:02:00

        ... which is very important because-

    15. PAPeter Attia1:02:01

        Yep

    16. RTDr. Renato Tomioka1:02:01

        ... mainly those, those studies, they are very heterogeneous.

    17. PAPeter Attia1:02:06

        Yep.

    18. RTDr. Renato Tomioka1:02:07

        And they mixed, and they, they just don't know if the patient has adenomyosis too.

    19. PAPeter Attia1:02:14

        Got it. Okay.

    20. RTDr. Renato Tomioka1:02:14

        So my opinion is that the missing factor is adenomyosis. It, this can confound implantation rate and miscarriage rate. So what I'm, uh, saying is that if you transfer a good embryo in a uterus of a patient with or without endometriosis, we have pretty much same results, but-

    21. PAPeter Attia1:02:36

        Ah.

    22. RTDr. Renato Tomioka1:02:37

        You understand that?

    23. PAPeter Attia1:02:37

        Yep.

    24. RTDr. Renato Tomioka1:02:38

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

    25. PAPeter Attia1:03:30

        Hmm. Okay.

    26. RTDr. Renato Tomioka1:03:32

        Even aneuploidy rates, they are similar.

    27. PAPeter Attia1:03:37

        Because you're matching for age.

    28. RTDr. Renato Tomioka1:03:38

        That's it.

    29. PAPeter Attia1:03:38

        Yep.

    30. RTDr. Renato Tomioka1:03:39

        Age is a-
13. 1:11:50 – 1:20:51

    Clinical case example #3: Managing adenomyosis after failed IVF transfers to improve implantation and pregnancy outcomes

    1. PAPeter Attia1:11:50

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

    2. RTDr. Renato Tomioka1:12:13

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

    3. PAPeter Attia1:12:22

       Yes. Let's assume she still has, uh, so, so she has three embryos still frozen.

    4. RTDr. Renato Tomioka1:12:28

       Okay.

    5. PAPeter Attia1:12:28

       Two of them, you know, she got a lot. She had a decent reserve, but two have failed, and now they, they don't want to waste any more without knowing what's going on.

    6. RTDr. Renato Tomioka1:12:35

       So she-

    7. PAPeter Attia1:12:35

       So that's why they came to you

    8. RTDr. Renato Tomioka1:12:36

       ... so she has, uh, embryo, uh, embryos that are frozen, and you can perform, if she didn't do that yet, um, a GnRH analog or, uh, agonist use before, uh, the, 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, uh, symptoms.

    9. PAPeter Attia1:13:05

       Mm-hmm.

    10. RTDr. Renato Tomioka1:13:06

        That's the side effects. But we have data showing that this can increase implantation rate, but decrease miscarriage rate and increase live birth rate. So you are treating-

    11. PAPeter Attia1:13:18

        So why does that work?

    12. RTDr. Renato Tomioka1:13:18

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

    13. PAPeter Attia1:13:25

        Just like endometriosis

    14. RTDr. Renato Tomioka1:13:27

        ... just like endometriosis. And if you use GnRH antagonists, we have now in the US-

    15. PAPeter Attia1:13:32

        What are the preferred ones?

    16. RTDr. Renato Tomioka1:13:34

        [lip smack] We prefer, like, we have much more data with analogs, the agonists. Leuprone, um, it's called, uh, goserelin. They, they are injectable.

    17. PAPeter Attia1:13:45

        Yep.

    18. RTDr. Renato Tomioka1:13:45

        Subcutaneously. Monthly, right? So two to four months with this, and then we transfer the, the embryo using just tiny levels of-

    19. PAPeter Attia1:13:54

        The smallest amount of estrogen

    20. RTDr. Renato Tomioka1:13:55

        ... yes, and high amounts of progesterone.

    21. PAPeter Attia1:14:00

        Okay.

    22. RTDr. Renato Tomioka1:14:00

        So that's the strategy. Nowadays, uh, nowadays we have, uh, the antagonists. The oral antagonists in the US, it, they are very expensive. They are called Elagolix, Relugolix, but they are oral medications. We j- had just one paper published last year that compared the use of, uh, antagonists versus agonists, and they are pretty much the same. [lip smack] Here we have less side effects. They're very expensive. I think around $1,000, uh, s- per month.

    23. PAPeter Attia1:14:32

        Okay.

    24. RTDr. Renato Tomioka1:14:32

        Yeah. So in Brazil we don't have these medications. We mainly use, uh, the agonists. And by doing that, we can achieve, uh, similar rates of pregnancy and miscarriage as, uh, patients if she didn't have endometriosis. Uh, adenomyosis, sorry.

    25. PAPeter Attia1:14:48

        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.

    26. RTDr. Renato Tomioka1:14:56

        Oh, sorry. Yeah, yeah.

    27. PAPeter Attia1:14:56

        Do they both produce a lower level of estrogen?

    28. RTDr. Renato Tomioka1:14:58

        So mainly it's the, the, the, the initial mechanism, the molecular mechanism in which the agonist can do a call, f- we call this flare-up effect. So it occupies the receptors, and it triggers a flare-up of FSH and LH, and then can leads to ovulation. But after two to four weeks of medication, you, then you down-regulate the receptor, and then you, you have this, this suppression, hormonal suppression. So you produce the menopause essentially, chemically.

    29. PAPeter Attia1:15:31

        Mm-hmm.

    30. RTDr. Renato Tomioka1:15:32

        But the antagonist, the action is r- 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.
14. 1:20:51 – 1:22:01

    The funding gap in endometriosis research: disease burden, economic impact, and growing awareness

    1. RTDr. Renato Tomioka1:20:51

       yes, but we don't have much data on that.

    2. PAPeter Attia1:20:53

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

    3. RTDr. Renato Tomioka1:20:57

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

    4. PAPeter Attia1:21:30

       Why do you think that is?

    5. RTDr. Renato Tomioka1:21:31

       [chuckles] It's comp- that, that's a complicated question. I think that's because we're just recognizing that endometriosis now is an important factor. We're seeing movies and documentaries about that, so I think that's just, uh, it's coming up, you know? That's it. I, I think that's, it's just, uh, a, a question of time probably.

    6. PAPeter Attia1:21:57

       Mm-hmm.

    7. RTDr. Renato Tomioka1:21:57

       Like menopause, right?

    8. PAPeter Attia1:21:58

       Yeah.

    9. RTDr. Renato Tomioka1:21:59

       That we are seeing this revolution.

    10. PAPeter Attia1:22:00

        [lip smack]

15. 1:22:01 – 1:27:43

    Clinical case example #4: Surgical decision-making in endometriosis—balancing pain relief, fertility preservation, and common treatment pitfalls

    1. PAPeter Attia1:22:01

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

    2. RTDr. Renato Tomioka1:22:46

       In that patient, no, because she's, she's gonna try to conceive. So we have data showing that if you do that, you control the, the symptoms, but you don't have a cumulative effect after stopping the medication. So you are treating the disease while you are using the medications, and the medications, they are mainly contraceptives by nature, right? So after you stop the medication, you just lost some time, you know?

    3. PAPeter Attia1:23:14

       Hmm.

    4. RTDr. Renato Tomioka1:23:14

       So that patient probably will benefit from surgery because you can treat the pain, and then she can try to conceive naturally.

    5. PAPeter Attia1:23:25

       What is the biggest mistake that happens with respect to surgical intervention? Like, what's the biggest-

    6. RTDr. Renato Tomioka1:23:32

       There's-

    7. PAPeter Attia1:23:32

       ... like, patient selection mistake?

    8. RTDr. Renato Tomioka1:23:34

       Uh, I would say that if you, 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, uh, attack that layer of pain, the nociplastic pain, right? So we need sometimes, uh, physiotherapy eight weeks before surgery to prepare the pelvis, and then you operate on them. And after surgery, two to four weeks, you can restart the physical therapy. So that would be the optimal approach. The second mistake is to take out all the cysts that you know, [chuckles] that you see, like the endometriomas, because that can impair fertility by reducing the... N- not fertility per se, but IVF outcomes because you reduced, uh, AMH.

    9. PAPeter Attia1:24:32

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

    10. RTDr. Renato Tomioka1:24:35

        Because they are not actually, uh, very defined cysts.

    11. PAPeter Attia1:24:39

        Okay.

    12. RTDr. Renato Tomioka1:24:39

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

    13. PAPeter Attia1:24:53

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

    14. RTDr. Renato Tomioka1:24:58

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

    15. PAPeter Attia1:25:03

        Uh-huh

    16. RTDr. Renato Tomioka1:25:03

        ... where the f- primordial follicles are. So when you take out the cyst, you pr- you do a cystectomy, you can reduce AMH by 40%, sometimes 50%.

    17. PAPeter Attia1:25:16

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

    18. RTDr. Renato Tomioka1:25:19

        Yeah, that, but that's a double-edged sword. Why? Because, uh, the presence of the cyst decrease The, the, it can decrease-

    19. PAPeter Attia1:25:29

        AMH because it's draining. Yeah

    20. RTDr. Renato Tomioka1:25:30

        ... yeah, it can decrease the AMH.

    21. PAPeter Attia1:25:32

        So shouldn't you harvest the eggs first?

    22. RTDr. Renato Tomioka1:25:34

        That's it. That's it.

    23. PAPeter Attia1:25:35

        Okay. Yep.

    24. RTDr. Renato Tomioka1:25:36

        That's it. And the mechanism is, is b- is beautiful, ex- uh, explained by this phantom reaction, the same one that we know, and it produce hydroxyl, um, uh, 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, um-

    25. PAPeter Attia1:26:10

        Mm-hmm

    26. RTDr. Renato Tomioka1:26:10

        ... now that this lower ovarian reserve. So it's, I, I think that's one, one big mistake. And, uh, s- I think maybe the third mistake would be, like, to leave a damaged tube, a hydrosalpinx, just to preserve the tubes, but we know that this can reduce the IVF chances by half. So if you have a dilated tube-

    27. PAPeter Attia1:26:34

        Why?

    28. RTDr. Renato Tomioka1:26:34

        Because the, the mechanism is like washing the embryos. Like, the, they con- they are connected to the uterus, so, uh, this-

    29. PAPeter Attia1:26:43

        You're saying even if you implant-

    30. RTDr. Renato Tomioka1:26:45

        Yeah
16. 1:27:43 – 1:34:23

    Common misconceptions about fertility: maternal age, embryo aneuploidy, the inefficiency of human reproduction, and the limits of IVF

    1. PAPeter Attia1:27:43

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

    2. RTDr. Renato Tomioka1:28:31

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

    3. PAPeter Attia1:29:31

       It's not linear

    4. RTDr. Renato Tomioka1:29:32

       ... it's not linear.

    5. PAPeter Attia1:29:32

       No, it's exponential.

    6. RTDr. Renato Tomioka1:29:34

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

    7. PAPeter Attia1:29:38

       It's a J curve.

    8. RTDr. Renato Tomioka1:29:39

       It's a J curve.

    9. PAPeter Attia1:29:39

       Oh.

    10. RTDr. Renato Tomioka1:29:40

        Very young patients, they can have monosomy.

    11. PAPeter Attia1:29:43

        Oh, I didn't know that.

    12. RTDr. Renato Tomioka1:29:43

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

    13. PAPeter Attia1:29:57

        Yep.

    14. RTDr. Renato Tomioka1:29:58

        But the sweet spot would be around 25, and even at that age-

    15. PAPeter Attia1:30:02

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

    16. RTDr. Renato Tomioka1:30:12

        Yeah, I would say that the risk of aneuploidy is h- probably higher at 20 than 25, but of course-

    17. PAPeter Attia1:30:20

        That's incredible.

    18. RTDr. Renato Tomioka1:30:21

        Yeah, it's incredible. Yeah.

    19. PAPeter Attia1:30:22

        And do you think, I mean, this is a silly theoretical question, do you think that's because evolution is trying to optimize for 25-year-olds having babies?

    20. RTDr. Renato Tomioka1:30:31

        Probably, yeah. That's what I think.

    21. PAPeter Attia1:30:32

        More than 20-year-olds or 18-year-olds, and obviously 30-year-olds. It's really saying, "I want..." This, a 25-year-old woman is the perfect fitness to carry, deliver, and raise a child?

    22. RTDr. Renato Tomioka1:30:44

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

    23. PAPeter Attia1:30:52

        Do we think that that's drifted? Like, do you think-

    24. RTDr. Renato Tomioka1:30:55

        Mm

    25. PAPeter Attia1:30:55

        ... 200 years ago, if we could go back in time-

    26. RTDr. Renato Tomioka1:30:57

        No

    27. PAPeter Attia1:30:57

        ... do you think it, it would've been lower?

    28. RTDr. Renato Tomioka1:30:58

        No. No.

    29. PAPeter Attia1:30:58

        Or do you think it's current?

    30. RTDr. Renato Tomioka1:30:59

        I don't think so. Because the mechanisms, they, they should be the same, right?
17. 1:34:23 – 1:45:49

    Elective egg freezing: timing, success rates, the fertility funnel, and the tradeoffs of fertility preservation

    1. PAPeter Attia1:34:23

       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, um, who still has five, six, seven years ahead of her in really, really working hard and does not want to have a child in that period of time. Uh, maybe she hasn't even met her partner yet. Um, but she deep down thinks she wants to have a child. Um, but it's possible she's not gonna be thinking about it for another 10 years till she's 35. So she's 25. She co- And you're her regular GYN, just, you're, you're doing your regular sort of exam. Y- she tells you all of this. Are-- Would you advise her to freeze eggs right now at 25?

    2. RTDr. Renato Tomioka1:35:11

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

    3. PAPeter Attia1:35:20

       But let's say she's normal. She's not defic- she's not, she's not ahead of time, she's not behind time. She's just a normal 25-year-old. But thinking about the J curve, right, which is the difference between being 25, 30, and 35 is significant, and she's not... Just from an optionality perspective, she's, she can't tell you, "I, Renato, I'm definitely gonna do it by 30," in which case maybe you could say, "Okay, it doesn't change much."

    4. RTDr. Renato Tomioka1:35:47

       Yeah, if she, if she's not, if she's sure that, uh, she, she want, uh, she wants child- children in the future, I would talk, uh, to her, but the, the chances... You know, look at this statistic, Peter. What do you think is the, the rate of patients that come back to use their own oocytes, like, globally?

    5. PAPeter Attia1:36:11

       All the women who freeze eggs-

    6. RTDr. Renato Tomioka1:36:13

       Yes

    7. PAPeter Attia1:36:13

       ... you're saying how many of them never come back and touch them?

    8. RTDr. Renato Tomioka1:36:17

       Yes, of 100 women that-

    9. PAPeter Attia1:36:19

       Yeah

    10. RTDr. Renato Tomioka1:36:19

        ... froze their, their eggs, like, how many come back, are coming back to, to use them?

    11. PAPeter Attia1:36:24

        To do something with them.

    12. RTDr. Renato Tomioka1:36:25

        Yeah.

    13. PAPeter Attia1:36:27

        75.

    14. RTDr. Renato Tomioka1:36:30

        Actually, around 10%.

    15. PAPeter Attia1:36:33

        What?

    16. RTDr. Renato Tomioka1:36:34

        Yes.

    17. PAPeter Attia1:36:34

        90% of women who freeze eggs never touch them.

    18. RTDr. Renato Tomioka1:36:38

        Yeah. Or j- because they had child-

    19. PAPeter Attia1:36:40

        Because they get pregnant maybe.

    20. RTDr. Renato Tomioka1:36:42

        Yeah, they, they got pregnant.

    21. PAPeter Attia1:36:43

        Okay.

    22. RTDr. Renato Tomioka1:36:43

        And sometimes they just don't wanna u- use that. And, but the sweet spot would be around 30-something, 32, 35, because the cost effectiveness of doing that is better than at 25, right? So biologically, of course, does, it makes sense to freeze earlier.

    23. PAPeter Attia1:37:08

        Yep.

    24. RTDr. Renato Tomioka1:37:08

        But the chances of, uh, like the time you spend on it, the cost you spend-

    25. PAPeter Attia1:37:13

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

    26. RTDr. Renato Tomioka1:37:23

        Yeah, US, I think there, there are some differences. Uh, um, it depends on-

    27. PAPeter Attia1:37:27

        Some insurance might cover it.

    28. RTDr. Renato Tomioka1:37:28

        Yeah.

    29. PAPeter Attia1:37:28

        But let's just-

    30. RTDr. Renato Tomioka1:37:29

        Depending on the company also
18. 1:45:49 – 1:55:10

    Emerging fertility technologies: mitochondrial replacement, ovarian tissue preservation, stem-cell-derived eggs, and current limitations

    1. PAPeter Attia1:45:50

       I have now heard about an emerging technology where that woman, who is 40, can use her genetic material with the remainder of the egg from a donor so that she has all of the benefits of the young egg, except she gets her genetic material in there so that the sur- the, the donor is only providing the scaffolding, and she could even use a surrogate. So, so help me understand that technology.

    2. RTDr. Renato Tomioka1:46:25

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

    3. PAPeter Attia1:46:36

       Yeah.

    4. RTDr. Renato Tomioka1:46:36

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

    5. PAPeter Attia1:47:42

       Ah.

    6. RTDr. Renato Tomioka1:47:43

       Yeah.

    7. PAPeter Attia1:47:43

       I see. So it is not solving the age problem.

    8. RTDr. Renato Tomioka1:47:46

       No.

    9. PAPeter Attia1:47:47

       Got it.

    10. RTDr. Renato Tomioka1:47:48

        As far as I know, it's not, um, available, uh, for infertility, but there are some clinics, I think, in North Cyprus or Greece, and they are, like, selling this, uh, as a egg rejuvenation. That, that's misleading, in my opinion. But you are just trying to replicate, like... It's like a battery swap for the o- for the egg, but you're not changing the engine, right?

    11. PAPeter Attia1:48:16

        Yep.

    12. RTDr. Renato Tomioka1:48:17

        The engine is the main problem.

    13. PAPeter Attia1:48:19

        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?

    14. RTDr. Renato Tomioka1:48:37

        There, I think, yeah, n- not for that situation, but they are, uh, there, there's a clinic in, uh, UK, in the UK, that is, uh, trying to freeze ovaries, like cortex.

    15. PAPeter Attia1:48:50

        Mm-hmm.

    16. RTDr. Renato Tomioka1:48:51

        Like long years before menopause, like to prevent or to postpone menopause.

    17. PAPeter Attia1:48:56

        Yep.

    18. RTDr. Renato Tomioka1:48:56

        Very interesting idea, but we don't have publications on that. Actually, we have a, a huge, uh, line, like a huge wait list of patients trying to, to do that. Makes sense, but we don't have data.

    19. PAPeter Attia1:49:10

        Sorry, just make sure I understand that. That means, um, so the, the analogy would be somebody with Type 1 diabetes that gets implanted pancreatic or beta cells that secrete insulin.

    20. RTDr. Renato Tomioka1:49:22

        Autologous, yeah.

    21. PAPeter Attia1:49:23

        Yes, autologous. Um, is this her own ovarian tissue-

    22. RTDr. Renato Tomioka1:49:30

        Yeah

    23. PAPeter Attia1:49:30

        ... that was set aside earlier in life?

    24. RTDr. Renato Tomioka1:49:32

        Like, at 30s.

    25. PAPeter Attia1:49:34

        At 30s.

    26. RTDr. Renato Tomioka1:49:35

        And then you can-

    27. PAPeter Attia1:49:36

        So they do a partial oophorectomy.

    28. RTDr. Renato Tomioka1:49:37

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

    29. PAPeter Attia1:49:55

        Where do they re-implant?

    30. RTDr. Renato Tomioka1:49:57

        In the same like-
19. 1:55:10 – 1:58:30

    The future of endometriosis treatment: new guidelines, biologic therapies, and unanswered questions about IVF

    1. RTDr. Renato Tomioka1:55:10

       Probably yes.

    2. PAPeter Attia1:55:11

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

    3. RTDr. Renato Tomioka1:55:18

       Epigenetics. Yeah. Like freeze-

    4. PAPeter Attia1:55:20

       And how do you think that shows up phenotypically?

    5. RTDr. Renato Tomioka1:55:23

       Probably, uh, some malformations, some, uh, neural, um, neurological consequences, um, heart disease.

    6. PAPeter Attia1:55:36

       Do we see this in the epidemiology? I mean-

    7. RTDr. Renato Tomioka1:55:38

       Yeah

    8. PAPeter Attia1:55:38

       ... these, n- So it, again, people born of IVF are still very young. They're-

    9. RTDr. Renato Tomioka1:55:44

       Yeah

    10. PAPeter Attia1:55:44

        ... you know, they're, they're not even 50 yet.

    11. RTDr. Renato Tomioka1:55:45

        Like Louise, Louise Brown is, like, 40-something or-

    12. PAPeter Attia1:55:48

        Yeah

    13. RTDr. Renato Tomioka1:55:48

        ... 48.

    14. PAPeter Attia1:55:49

        Yeah, she's 48.

    15. RTDr. Renato Tomioka1:55:51

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

    16. PAPeter Attia1:56:00

        Yeah, that's the hard part is how do you get out? 'Cause by definition, you're talking older parents, you're talking about more, you know, affluent, access.

    17. RTDr. Renato Tomioka1:56:08

        Infertile, infertile, yeah.

    18. PAPeter Attia1:56:08

        There's so-- infertility. There's so many confounders.

    19. RTDr. Renato Tomioka1:56:11

        Yeah, yeah, but-

    20. PAPeter Attia1:56:12

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

    21. RTDr. Renato Tomioka1:56:15

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

    22. PAPeter Attia1:56:31

        Yeah. Mm-hmm.

    23. RTDr. Renato Tomioka1:56:32

        And yeah, but it's, it's a new, a, a new technology, right?

    24. PAPeter Attia1:56:37

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

    25. RTDr. Renato Tomioka1:56:42

        Actually, I was very excited about this new guidance, uh, 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-

    26. PAPeter Attia1:57:08

        Early

    27. RTDr. Renato Tomioka1:57:09

        ... earlier.

    28. PAPeter Attia1:57:10

        Yeah.

    29. RTDr. Renato Tomioka1:57:11

        And, uh, avoid infertility, and I'm very excited about this, so we should spread this word, right? And, um, there, there's one molecule called HMI115. It's, uh, um, um, uh, antibody, a monoclonal antibody that targets the receptor of prolactin.

    30. PAPeter Attia1:57:33

        Mm-hmm.
20. 1:58:30 – 2:00:25

    Why earlier diagnosis matters: reducing years of suffering from endometriosis and adenomyosis

    1. RTDr. Renato Tomioka1:58:30

       more effectively.

    2. PAPeter Attia1:58:31

       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.

    3. RTDr. Renato Tomioka1:58:54

       That's it.

    4. PAPeter Attia1:58:54

       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."

    5. RTDr. Renato Tomioka1:59:07

       That's it.

    6. PAPeter Attia1:59:08

       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.

    7. RTDr. Renato Tomioka1:59:16

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

    8. PAPeter Attia1:59:34

       That they finally have a diagnosis.

    9. RTDr. Renato Tomioka1:59:35

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

    10. PAPeter Attia2:00:08

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

    11. RTDr. Renato Tomioka2:00:13

        Great to be here. Thank you, man. [upbeat music]

Episode duration: 2:00:25