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

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:53.200 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.020 head over to peteratiamd.com forward slash subscribe. My guest this week is Dr. Hanado

00:01:06.460 Tomioka, a leading expert in reproductive medicine and gynecologic surgery. Hanado's

00:01:12.180 clinical work sits at the intersection of three closely related fields, reproductive medicine,

00:01:18.280 minimally invasive gynecologic surgery, and gynecologic endocrinology, a combination that

00:01:24.080 makes him uniquely equipped to diagnose and treat some of the most consequential and under-recognized

00:01:29.820 conditions women face today. Endometriosis affects roughly 10% of reproductive-aged women,

00:01:36.960 about 200 million women globally, and contributes to infertility in 30 to 50% of cases.

00:01:44.240 Adenomyosis, its often overlooked counterpart, may be even more prevalent.

00:01:49.600 Yet the average woman waits 5 to 12 years for a diagnosis, often because her pain has been dismissed as normal.

00:01:56.980 In my conversation with Hanato, we cover what endometriosis and adenomyosis actually are,

00:02:03.460 and why they're so often missed, and how diagnosis has shifted from surgical laparoscopy towards MRI and specialized ultrasound.

00:02:11.320 how Hanato decides between hormonal therapy and surgery, and how those decisions change when

00:02:18.480 fertility is part of the goal, where IVF fits into the pathway for women with endometriosis,

00:02:24.920 adenomyosis, or age-related fertility decline, how female age shapes egg quality and quantity, 0.99

00:02:32.940 including the steep non-linear rise in chromosomal abnormalities after age 35,

00:02:38.720 and the most common mistakes in surgical and fertility decisions, and what may be on the

00:02:45.080 horizon for both endometriosis treatment and fertility preservation. So without further delay,

00:02:50.480 I hope you enjoy my conversation with Dr. Hanato Tomiope. Hanato, wonderful to see you. Thank you

00:03:02.560 for coming to Austin. Today, we're going to talk about two things that are related, but I want to

00:03:08.320 talk about them in sort of this order. The first thing I want to do is talk about the diseases of

00:03:13.240 the uterus. And I think most notably, we'll talk about endometriosis, but also others.

00:03:17.880 And then I want to talk about infertility and obviously talk about some of the treatments

00:03:22.320 for infertility. And of course, there's an overlap between those two. So let's start with the former.

00:03:28.980 Orient us to what exactly this term is. I'm sure everybody's heard of endometriosis,

00:03:33.980 but it's likely that not everybody understands exactly what it is.

00:03:37.660 So I believe the first point is to remember the layers of the uterus, right?

00:03:43.400 So we have mainly three layers, the outside layer, it's called serosa,

00:03:48.720 the middle part, which is the muscular layer called myometrium,

00:03:52.920 and the inner part where the embryo implants and develop the placenta,

00:03:57.420 which is called endometrium.

00:03:58.720 And this layer is very important because endometriosis is a disease, a chronic disease, where an endometrial-like tissue, very similar to the endometrial, is outside the uterus.

00:04:12.620 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.

00:04:22.940 So that's endometriosis, very important disease.

00:04:26.500 Around 10% of reproductive women globally have endometriosis,

00:04:31.060 which means around 200 million women.

00:04:33.860 And if you look into the data of infertile women,

00:04:38.740 it's about 30% to 50% of women, they can have endometriosis.

00:04:44.540 So just to make sure I understand that,

00:04:46.640 30% to 50% of women who are struggling with fertility have endometriosis.

00:04:51.360 And the other way around.

00:04:52.880 If you have endometriosis, you have a chance of around 40% of being infertile.

00:04:58.600 So it's causal.

00:04:59.900 Yes.

00:05:01.040 Okay.

00:05:01.640 So let's dig into this a little bit more. 0.90

00:05:05.240 So first of all, you mentioned we have three layers in the uterus.

00:05:08.860 The endometrial layer is the inner layer.

00:05:10.920 That's the part that sheds every month during a woman's reproductive... 0.96

00:05:13.360 Very dynamic.

00:05:14.240 Very dynamic, depending on the duration of the cycle, of course, where you are in the cycle.

00:05:20.820 Okay.

00:05:21.360 You have a muscular layer, and that's presumably functional. 1.00

00:05:25.940 So during childbirth, the uterus needs to contract.

00:05:28.520 So when a woman is experiencing contractions, that's what's contracting?

00:05:31.680 Precisely.

00:05:32.460 Okay.

00:05:32.760 And then the outer layer, tell me about that again, functionally.

00:05:35.480 It's just a peritoneum, like the visceral peritoneum.

00:05:39.660 It doesn't add up much, you know?

00:05:42.640 We just have, but we can have endometriosis on that layer.

00:05:46.480 and then sometimes it just infiltrates and transform to what we can say we can talk about

00:05:54.460 internal and adenomyosis like external adenomyosis I mean got it and I did want to ask you about

00:06:00.920 adenomyosis because I know that they can often be confused before I do I want to ask another

00:06:07.180 question about endometriosis which is do we have a sense of the features or characteristics that

00:06:14.700 predicted? For example, how genetic is it, and are there any environmental triggers for it?

00:06:20.580 Great question. So we have about 50% of heritability. If you have a first degree relative

00:06:28.800 with endo, you have about seven times higher chance of having endometriosis. So that's the

00:06:37.880 the main meaning mother or sister yeah okay and we know from twin studies also that of course

00:06:44.720 they share some genes but of course they are not that penetrant we have some triggers maybe

00:06:51.000 pollution and one thing that's very important bigger is what we call the repetitive ovulatory

00:06:58.340 menstruation so what what that means every time a woman is menstruating part of the the menstrual

00:07:07.300 flow goes back through the fallopian tubes and into the pelvis. So we know that by surgeries... 0.96

00:07:14.140 And I'm sorry, it goes into the pelvis by going retrograde towards the ovary, but of course the

00:07:19.460 fallopian tube doesn't enter the ovary, it enters back into the pelvis. Correctly. So remember the

00:07:24.500 fibra, like the distal part of the tubes, they are not directly connected to the ovary. They are

00:07:31.780 moving around and they can pick up the oocytes.

00:07:35.280 This always amazed me, by the way.

00:07:36.940 I don't understand why that works or how it works.

00:07:40.060 And it's actually, most of the time,

00:07:42.900 the oocyte is just on the surface of the ovary.

00:07:47.420 Sometimes it's inside the pelvis in the cul-de-sac.

00:07:51.120 But the fimbred can pick it up 0.69

00:07:53.100 and then permits the fertilization

00:07:56.000 inside the isthmus, right?

00:07:57.740 Inside the middle part of the tube, essentially. 0.99

00:08:01.780 But we know by old studies that around 90% of women,

00:08:07.100 they have this retrograde menstruation, which is amazing.

00:08:10.820 So you would think, why is that then just 10% have endometriosis, right?

00:08:16.860 Because sometimes it's not sufficient to have endometriosis,

00:08:22.760 but it's probably necessary in most cases.

00:08:27.960 There are some nuances here.

00:08:29.120 but those patients with endometriosis they might have immune dysregulation so the macrophages can

00:08:36.520 cope with that overload of menstrual flow and endometrial tissue they have also like if you

00:08:45.280 have many many many years of retrograde menstruation that can be bad there's an interesting story here

00:08:54.480 Peter, if you look like 200 years ago, a woman back then would have around 100 ovulatory cycles

00:09:04.920 in their lifetime. Menarche was about at the age of 16. Now it's 12. First pregnancy around 20, 0.98

00:09:16.600 now 30 or more. Breastfeeding for two years per child. Now almost...

00:09:22.820 So during that period, you're not ovulating.

00:09:24.760 Yes.

00:09:25.860 And they used to have like five, seven children.

00:09:29.460 Now you used to have-

00:09:30.040 So many times of not ovulating. 1.00

00:09:31.520 If you compare that women to a modern woman, it's about a fourfold increase in this retrograde 1.00

00:09:38.160 ovulatory menstruations.

00:09:40.020 And this may be the main cause that we are seeing much more endometriosis, not only diagnosing,

00:09:48.040 but probably the prevalence is getting higher and higher, right? 0.99

00:09:51.180 So, the Darwinian evolution didn't anticipate that this modern woman's reproductive pattern 0.98

00:09:59.020 that we have nowadays. 0.99

00:10:00.440 And that's probably the best proxy for us to use and to think about using oral contraceptives 1.00

00:10:09.760 or any hormonal treatment to block, to mimic that woman back then. 0.96

00:10:15.260 So, let me make sure I understand all of that.

00:10:17.480 So 200 years ago, a woman would have had 100 ovulatory cycles in her lifetime, and that would have been driven by many changes.

00:10:24.760 She got her period four years later.

00:10:26.920 She was pregnant more often, so the entirety of her pregnancy, she's not cycling.

00:10:32.320 Once she has a baby, she's breastfeeding for very, very long.

00:10:35.560 Again, not cycling.

00:10:37.200 And so you can sort of do the math.

00:10:39.240 And we didn't talk about menopause, but presumably they might not have even lived long enough to get to full menopause.

00:10:45.760 so a woman today might have 400 cycles if uninterrupted or if if if not intervened with 0.99

00:10:53.280 and every cycle produces the risk of retrograde flow that's and and and then going back to what

00:11:00.080 you talked about when you get retrograde flow of blood into the fallopian tube the macrophages that

00:11:07.860 need to come and sort of take care of it can't always do the job so presumably you're creating

00:11:12.860 anitis for infection or something that the immune system is upset about.

00:11:19.120 And if you look into the mechanism here, we have this estrogen dependence.

00:11:25.380 The endometriolic lesions, they produce by themselves estrogen, so they overexpress aromatase.

00:11:32.840 There's an upregulation in aromatase.

00:11:36.000 So sometimes just blocking the ovaries is not sufficient to block the disease.

00:11:40.760 we have also this progesterone resistance so the progesterone receptor is down regulated

00:11:48.400 so we don't have this the action of progesterone that is very important to counteract the action

00:11:54.500 of the estrogen yeah i now of course i only know this in the context of hormone replacement therapy

00:11:59.980 where to your point when you give women estrogen unopposed the endometrial lining gets thicker and

00:12:06.640 thicker and thicker, you can get hyperplasia, which could ultimately become cancer. But tell

00:12:11.260 me more about what's happening in the cycle through that. Is it basically the same thing?

00:12:17.220 You give estrogen, as she's ovulating, estrogen is increasing the thickness,

00:12:22.460 the progesterone surge causes the shedding? That's it. So remember the follicular,

00:12:27.000 like the late follicular phase, people who works with IVF know that a lot, right? Because we are

00:12:35.220 aiming to look at the endometrium at the final phase of the follicular part.

00:12:39.700 So, endometrium is about to like 8, 10 millimeters at that point.

00:12:46.100 But when you have the progesterone, it opens the implantation window.

00:12:50.940 So, we have this so-called desidualization.

00:12:54.600 Lipids and secretory phase comes in.

00:12:58.200 And then at the ultrasound, endometrium is like white, not anymore black.

00:13:03.780 and this is very important for the pregnancy.

00:13:07.600 But if there is no embryo inside the uterus,

00:13:10.880 the corpus luchum has like 12 to 14 days of life

00:13:15.680 and then it just sheds

00:13:17.860 because you have a decrease in estrogen and progesterone levels,

00:13:22.000 so it sheds.

00:13:24.100 So that is very important for endometriosis too

00:13:27.420 because remember, it's like endometrial outside the uterus.

00:13:31.560 So one of the treatment pillars is giving progesterone or progestins to these patients.

00:13:39.660 But endometriosis lesions, they have this progesterone resistance.

00:13:44.680 What does that literally mean?

00:13:46.980 You're saying that the actual endometrial cells, which I assume are like another endothelium?

00:13:54.520 Yeah.

00:13:55.080 Because it's outside the body.

00:13:56.100 Yeah, it's like stroma and glands that resembles the endometrial lining.

00:14:01.560 Okay. And they have progesterone receptors. And when you say they're resistant to progesterone,

00:14:07.820 do you mean, is it not like it's the same, but insulin resistance where progesterone hits the

00:14:12.580 receptor, but- Kind of. Kind of. Yeah. You need much more insulin or progesterone to produce the

00:14:18.360 effect. So why does that happen? It's complicated. I don't think we know for sure, but it's very

00:14:26.200 interesting because those lesions they also produce they also have somatic mutations think

00:14:33.140 about that in oncogenic genes like KRAS or PIK3 PIK kinase right so they resemble they they act

00:14:43.440 like cancer especially in deep infiltrated endometriosis and adenomyosis up to 37 percent

00:14:50.340 of those lesions, they express these oncogenes.

00:14:54.180 So they grow independently.

00:14:57.880 But do they have metastatic potential?

00:14:59.680 No, no.

00:15:01.360 Why is that?

00:15:02.080 So in a sense, they're benign tumors.

00:15:03.580 They are benign tumors.

00:15:05.080 They have the machinery to go, like to grow really fast,

00:15:10.800 but probably due to the adhesions and the fibrosis

00:15:14.400 outside the lesions, they cannot metastasize.

00:15:17.440 That's incredible.

00:15:18.140 Yeah.

00:15:18.400 It's like putting a 1,000-horsepower F1 engine into a golf cart.

00:15:24.080 You just have the machinery, but you can't go further.

00:15:27.440 This might be a good time to explain adenomyosis, which can clinically be confused with endometriosis, but has some distinct pathology.

00:15:35.060 So maybe tell us what that is.

00:15:36.840 So adenomyosis, I think, is the missed disease because everybody talks about or should talk about endometriosis, very prevalent.

00:15:45.700 but adenomyosis actually is more prevalent probably up to 20 or 30 percent of women have

00:15:53.400 and you're saying about 10 percent of all women in reproductive age have endometriosis okay yes

00:15:58.800 so adenomyosis is essentially the presence of this endometrial like tissue inside the myometrium

00:16:05.980 so inside the muscular wall so back then they used to call this internal endometriosis understood but

00:16:12.980 And now we are calling this disease differently because they share some mechanisms, but they

00:16:20.240 are different.

00:16:21.360 If you look into the studies of single-cell transcriptomics, Linda Giudice last year published

00:16:26.920 one beautiful paper about this.

00:16:29.280 They don't have the same molecular pathway, so they are different diseases.

00:16:33.380 And the mechanisms in-

00:16:35.080 What's the overlap?

00:16:36.080 I'm sorry to interrupt you.

00:16:37.200 So they have the same oncogenic somatic mutations.

00:16:42.380 Adermyosis also has this progesterone resistance and estrogen dominance.

00:16:48.380 So they also produce their overexpressed aromatase.

00:16:51.920 So it's pretty much the same, but they are different diseases.

00:16:56.000 And of course, you have cure in adermyosis.

00:16:58.800 If you do a hysterectomy, you can take out the disease.

00:17:01.840 It's just a disease in the uterus.

00:17:04.780 Endometriosis, it's outside the uterus.

00:17:07.820 And what is the overlap in women who have one, the other, and both?

00:17:13.720 So obviously 20% have one, 10% have the other.

00:17:16.200 How many have both?

00:17:17.800 Difficult to be precise here, Peter, but we think up to 70%.

00:17:22.540 Up to 70% of endometriosis patients, they might have some type or some degree of adenomyosis. 1.00

00:17:31.000 And that's very important for the infertile couple. 0.84

00:17:34.160 So the mechanism in adenomyosis is the so-called T-I-A-R, so it's tissue injury and repair.

00:17:43.600 So essentially the endometrium is going inside the uterus, like breaking that junctional zone,

00:17:50.800 which is a thin layer between the endometrium and the myometrium, and it's going inside

00:17:56.600 and disrupting and, like, breaking the lines

00:18:00.880 and producing those islands of cysts and echogenic buds

00:18:06.120 that, like, increase the volume of the uterus

00:18:09.200 and makes it very soft to the touch. 0.57

00:18:13.360 During surgery, it can palpate the uterus.

00:18:15.240 But why? Is there a defect in the junction

00:18:18.560 between the endometrium and the myometrium?

00:18:20.700 Yes, and probably that somatic mutations,

00:18:23.640 that aggressiveness, that they go inside.

00:18:26.700 But we're not sure about why.

00:18:30.040 But they can't get through the myometrium.

00:18:32.640 They can get through the myometrium.

00:18:35.100 And we have some risk factors.

00:18:37.880 For example, when you have a miscarriage,

00:18:41.540 when you have C-section,

00:18:43.120 so you break that line mechanically.

00:18:45.140 When you do curatage, you break that,

00:18:47.900 or even hysteroscopy for leiomyomas or polyps,

00:18:52.720 You can break that acutely, and the endometrium can invade the myometrium.

00:18:58.280 Okay.

00:18:58.500 So again, just to orient everyone, myself included,

00:19:02.520 adenomyosis is a disease where endometrial tissue spreads outward

00:19:07.340 from the inner part of the uterus into the muscular layer of the uterus.

00:19:13.100 Mainly it's that sort of interoetopia.

00:19:15.480 But we have another type of adenomyosis.

00:19:18.220 there's not like a it's not consensus but some authors they call it external adenomyosis in

00:19:27.340 which the endometriosis that deep infiltrated endometriosis is going inside the myometrium

00:19:33.700 from the cirrhosis to the myometrium and now we have not only endometriosis but adenomyosis

00:19:40.120 but there are some authors that think they are this it's not correctly to say that it's adenomyosis

00:19:47.840 So mainly adenomyosis, that's what you're talking about.

00:19:51.520 From a demographic standpoint, how does it overlap?

00:19:55.480 Is it young women? 0.99

00:19:56.860 Is it a disease of the fertile years? 0.97

00:20:00.020 Do women experience this de novo after menopause, or is it all the same sort of presentation? 0.82

00:20:06.280 So traditionally, adenomyosis was called a disease of the women at 40s because she had

00:20:13.960 like pregnancies, sometimes c-sections and, you know, curatage and miscarriage. But now we are

00:20:20.260 seeing younger patients with adenomyosis, even without pregnancies. And again, this must be very

00:20:27.400 confusing because it would be easy to confuse this for endometriosis, I assume. We haven't even talked

00:20:32.540 about the presentation, so we can do that in a minute. But, well, let's actually do that. Let's

00:20:37.080 talk about presentation. So maybe we can start with the traditional presentation and then the

00:20:43.600 nuanced. So what is the, if you were taking a board exam and it was trying to show you a woman 0.60

00:20:48.840 with endometriosis, how would she present? So typically those, those women, they have 1.00

00:20:54.260 pain, like pelvic pain. Sometimes they, they just organize their, their lives around their pain. 0.99

00:21:02.820 And tell me what that means. Is pelvic pain akin to a UTI? Is it akin, like what would be the

00:21:10.540 closest thing that someone would understand who doesn't have it? I like the framework of the six

00:21:15.840 Ds of endometriosis. The first D would be dysmenorrhea, which is pain during menstrual

00:21:22.200 period. So they have this lower abdomen. And this is not cramping. This is actual pain.

00:21:28.780 Pain. Okay. That sometimes just pain medications don't resolve it completely. Sometimes those

00:21:35.220 patients, they go to the ER to receive intravenous medications. And the second D is

00:21:46.960 deep dyspareunia, which means pain during intercourse, especially in the profound 0.91

00:21:52.740 posterior wall of the vagina. Third D would be dyskizia, or pain during bowel movements,

00:22:02.560 especially during the period. And the uterus is how close to the rectum? It's close. It's

00:22:06.940 adjacent immediately, right? Yeah, adjacent. And sometimes we can have lesions right there

00:22:11.020 in the septum. Fourth deal would be dysuria, like pain during urination, especially cyclic pain,

00:22:18.840 usually during the menstrual period. We can have also like bleeding, but that's not

00:22:24.860 very common fifth D would be difficulty in getting pregnant so difficulty in conceiving

00:22:30.980 infertility and the the last one would be I will put the D like just for a hook for a memory hook 0.92

00:22:38.940 but it's dysfunctional chronic pelvic pain so those women can present with pain for more than

00:22:45.320 six months without any relation with the cycle so it you have a lot of this myriad of pain you know 0.83

00:22:54.820 Okay. And then help us understand how that differs. If as a clinician, you were trying

00:23:01.700 to make the distinction between endometriosis and adenomyosis based on symptoms. Is that possible?

00:23:07.180 Yeah. Yeah. Adenomyosis mainly, sometimes the patients are asymptomatic. By the way,

00:23:13.660 around 10% of women with endometriosis might be asymptomatic.

00:23:18.240 So their only symptom would be for infertility potentially.

00:23:21.340 Potentially, or they just normalize the pain, which is a problem. They think that it's normal

00:23:26.660 or they're told that it's normal. But adenomyosis mainly presents with bleeding,

00:23:33.180 uterine bleeding. Like sometimes those patients, they get anemic and they bleed a lot during

00:23:40.240 their periods. Let's take one quick detour to understand another condition that produces

00:23:45.440 bleeding, which is fibroids. Maybe explain what fibroids are and how it's different from

00:23:50.880 adenomyosis. So fibroids, they are very common, up to 70 or 80 percent of women will have one

00:23:57.480 fibroid, mostly asymptomatic. They are benign nodules inside the uterus, can be just right at

00:24:05.760 the endometrium, so-called submucosal. Inside the myometrium, intramuscular or on the cirrhosis,

00:24:13.540 like subsirosis and they can get very very large right nodules sometimes it disrupts the

00:24:22.420 it can disrupt the anatomy of the uterus especially the endometrial cavity and provokes miscarriage

00:24:29.200 and they can bleed too especially the submucosus yeah we we classify them by the international

00:24:37.180 Federation of Gynecologists and Obstetricians by zero up to seven, depending on the classification

00:24:44.280 up to eight. And the zero, one, and two, they are submucosal. So they are the problematic for

00:24:51.840 fertility and for bleeding. And that's counterintuitive to me. Why would the submucosal

00:24:57.140 ones cause more issue than the ones that are closer to the lining? Actually, the submucosal,

00:25:02.580 they are the closest to the lining.

00:25:04.880 Ah, okay.

00:25:05.620 So zero will be like just inside the cavity.

00:25:09.880 Okay.

00:25:10.660 Yeah.

00:25:10.840 One is mainly inside the cavity,

00:25:12.780 but a part is in the myometrium

00:25:14.860 and then two is like mostly in the myometrium

00:25:18.140 and a part is inside the uterus.

00:25:20.600 And the number three would be like

00:25:22.300 just touching the endometrium.

00:25:25.060 Okay, got it.

00:25:26.040 And then as you go all the way out to the serosa,

00:25:28.020 it gets lower and lower or higher and higher number,

00:25:30.060 but lower and lower severity?

00:25:31.980 Yeah.

00:25:32.440 Okay.

00:25:33.080 Probably not so very, but yeah, clinical implications, right?

00:25:36.680 Okay.

00:25:37.800 Okay, so the woman with, you said 10% of women with endometriosis could be asymptomatic or

00:25:43.340 their only presentation could be infertility. 0.56

00:25:45.700 So that would suggest that when we start talking about infertility, one thing that should be

00:25:50.280 in the differential diagnosis is untreated endometriosis.

00:25:54.120 But otherwise, most women are going to experience some pain with something, pain with intercourse,

00:25:59.440 pain with her cycle, urination, everything. Then on adenomyosis, what percentage of those 0.98

00:26:06.600 are asymptomatic? I don't have the number in my head, but I would say that probably one third,

00:26:13.300 because it depends on the phenotype and the intensity of the disease. So if you just have

00:26:19.720 one leocyst, myometrial cyst, which is a presentation of adenomyosis, probably these

00:26:25.820 patients, they don't have any symptoms at all. But if you have like a very diffuse adenomyosis

00:26:32.820 or even an adenomyoma, which is a nodule of adenomyosis, it's very painful. Especially the

00:26:44.020 period is very painful. And again, it might sound like a dumb question. What is causing the actual 0.97

00:26:50.780 pain great question great question actually we have three types of pain in endometriosis

00:26:57.100 peter that's i think that's the the most complicated part for us gynecologists to

00:27:04.140 understand because we're not trained we were not trained for that but there's the so-called

00:27:10.380 nociceptive pain yep pain from the lesion directly so it just hurts and here surgery and treatment

00:27:19.860 hormonal treatment can help second layer is the so-called nociplastic pain where the nerves are

00:27:27.540 infiltrated by the lesions and they can have burning sensations you know sometimes on their

00:27:34.460 their legs and the back and here medications can help sometimes gabapentin and snris right

00:27:42.780 surgery can remove some of those lesions we do this technique called

00:27:48.660 nurse pairing very difficult sometimes impossible to do but we can try and the

00:27:54.880 third layer and most difficult to treat is the nociplastic pain when we have

00:28:01.860 central sensation so you can have a beautiful surgery your pelvis is clean

00:28:09.600 but you can still have pain it's like imagine this analogy imagine like endometriosis lesion

00:28:17.140 is a burglar so surgery can remove the burglar hormones can lock the door but once you have this

00:28:26.180 alarm system ringing and ringing years after years the wiring changed and now even a wind

00:28:33.440 can you know trigger the alarm and even removing without the burglar without you know the doors

00:28:43.060 are locked but you need to you need a different specialist here we need a physiotherapist a

00:28:49.740 pelvic floor physiotherapist and also a pain specialist to treat those patients and that's

00:28:55.860 why the delay in diagnosis and treatment of endometriosis is one of the main causes of this

00:29:02.200 central sensitization and it's very important for us to treat even empirically nowadays the ACOG

00:29:09.940 just published this March 2025 26 a new guidance on endometriosis diagnosis and it allows us to

00:29:19.480 not only diagnose clinically but treat it because if you have just based on clinical symptoms right

00:29:26.140 If you have a patient that has pelvic pain, dysmenorrhea, dyspareunia, and so on,

00:29:32.920 you can give her a medication to avoid this disease burden years later.

00:29:42.260 What's the typical age of presentation today for endometriosis?

00:29:45.840 I don't think we have a typical presentation anymore.

00:29:49.080 We are seeing endometriosis in teenagers.

00:29:52.120 Look at this data.

00:29:52.820 up to 50% and 75% of teenagers with pelvic pain,

00:29:58.560 they have endometriosis.

00:30:00.360 Three quarters, they have endometriosis.

00:30:03.400 And what percentage of teenagers have pelvic pain?

00:30:06.000 I'm not sure.

00:30:07.380 I'm not sure.

00:30:07.880 Presumably, it's like 5% or a lot of them.

00:30:10.140 Yeah, I think a little bit more.

00:30:11.680 A little bit more, yeah.

00:30:12.940 So, we are seeing teenagers presenting with endometriosis.

00:30:17.780 And if just normal-

00:30:20.320 Well, again, going back to the etiology of this, anytime you see an increase in the

00:30:25.180 prevalence of something, you have to assume there's some environmental trigger and it

00:30:30.180 would be hard to explain just the number of periods because if she's a teenager, she's

00:30:35.140 still well below a hundred.

00:30:37.380 So what else do you think?

00:30:38.880 Do you think there are some health factors?

00:30:40.720 Do you think it's like, so for example, we see more PCOS today, presumably linked to

00:30:45.120 more insulin resistance and lifestyle factors that drive that.

00:30:48.540 Is there anything else that you think could be increasing the prevalence of this?

00:30:52.560 We don't have definitive data here, but probably even microplastics, we have some studies about

00:30:59.820 that.

00:31:00.800 Pollution.

00:31:01.700 Oh, you mentioned pollution, yep.

00:31:03.400 Yeah.

00:31:03.780 Diet, probably the, you know, this sad diet that you talk.

00:31:09.560 Poor sleep, because remember, poor sleep-

00:31:12.220 The immune system.

00:31:13.180 Immune, yeah, immune system regulation.

00:31:14.960 the macrophages, they just jump from one to the other type, and this may increase the risk of

00:31:22.720 endometriosis. So, we are not sure about this question, but... It's probably many things,

00:31:28.260 which is what makes it so complicated. Yes.

00:31:30.400 So, the implication, of course, of what you just said with the burglar analogy is you need to treat

00:31:36.880 as soon as possible because the longer you wait, the more you rewire in a negative fashion.

00:31:41.380 so let's talk about treatment options for well let's actually talk more about the diagnosis

00:31:49.340 let's go down the formal so so a woman presents to you or to a gynecologist and with a story

00:31:56.080 and actually how uniform is the understanding of this amongst primary care doctors and

00:32:02.860 gynecologists or is everybody attuned to making the diagnosis based on a presentation or do

00:32:09.160 women slip through the cracks oh yeah unfortunately not because if you look like the diagnosis the

00:32:15.720 lapier is five to twelve years depending on the country i believe in the u.s is around six years

00:32:22.720 and in brazil brazil around seven years so from the first symptom up to the diagnosis

00:32:30.620 can you imagine like five up to ten years no i can't understand that so that means that for

00:32:38.020 a period of five years a woman is saying to somebody i'm having symptom x y and z

00:32:43.580 and they're not able to make the diagnosis mainly because of i think three factors here the first

00:32:50.760 one is this cultural normalization of pain right female pain especially so they are told that oh

00:32:58.040 that's normal just have a medication have an anti-inflammatory and go but some teenagers they

00:33:04.200 just can't go to school they miss school sometimes they miss work they cannot like properly work

00:33:13.520 so we have the the estimate cost is around 80 to 120 billion per year and two-thirds of that

00:33:21.840 is productivity loss not only medications and hospitalizations and surgeries so that means that

00:33:29.800 we have this big culture, unfortunately, of normalization, right? And misleading. The second

00:33:36.200 one is that we don't have a biomarker, like a simple biomarker, like a blood biomarker, right?

00:33:41.900 We need a very good imaging system that's actually very simple, not that complex, like a transvaginal

00:33:49.840 ultrasound, but with a specialist or even an MRI. And yeah, I think that's, and the third one would

00:33:56.780 be that traditionally the diagnosis has been made with diagnostic laparoscopy, right?

00:34:03.140 Which is a big step to take.

00:34:04.780 Yeah, we shouldn't do that anymore.

00:34:06.880 Okay. So let's talk a little bit about that. So for folks unfamiliar with the term diagnostic

00:34:12.080 laparoscopy, laparoscopy, of course, is when you put actual cameras and air, insufflate the abdomen,

00:34:19.940 put cameras inside, and this is a surgical procedure. It requires general anesthesia.

00:34:24.280 and i guess the rationale for doing that was we are looking for endometrial tissue inside the

00:34:33.480 abdomen so that's as good a place to look as any and it's easier to look with your eyes which is

00:34:38.820 what you're able to do with a camera in an insufflated abdomen than it is to look with

00:34:43.680 a ct scan but now you mentioned mri and then obviously ultrasound so when did the shift of

00:34:52.180 diagnostic acumen or success start to move towards non-invasive or non-surgical treatment?

00:35:00.360 That's a good point.

00:35:01.100 Around 25 years ago.

00:35:03.900 Okay.

00:35:04.760 So for us in Brazil, the specialized ultrasonography is a very good exam.

00:35:11.760 We have Dr. Luciano Achamia, who's now in Boston, the Mass General.

00:35:18.140 Manuel Orlando, they are like one of the best radiologists in the world for endometriosis.

00:35:23.780 And they developed this protocol in which you have bowel prep.

00:35:30.440 Just like a colonoscopy or a sigmoidoscopy?

00:35:33.080 Yeah, much more like simple.

00:35:35.500 Okay.

00:35:36.100 You have this enema in like one hour before the exam and no residue diet. 1.00

00:35:43.220 but that simple protocol with a gel inside a vagina so you can look into small lesions 0.99

00:35:53.100 in the bowel bladder and you can even see the layers of the bowel so it's it's a beautiful

00:35:59.940 exam but that started around 25 years ago and that's not widespread yet i know that i was just

00:36:08.840 talking to Luciana this day and she told me that in I think in Mayo Clinic Arizona there's a one

00:36:15.380 doctor doing that Scott Young but not for everybody I think in the U.S. mainly is MRI

00:36:22.000 but MRI and ultrasonography they are they have very high sensitivity about 95 98 percent and

00:36:31.040 very high specificity too but for superficial lesions just let let me go step back we have

00:36:38.340 three phenotypes, the superficial lesions, the deep infiltrative endometriosis, and the endometriomas,

00:36:46.140 the cysts of endometriosis. So for those superficial lesions, ultrasound, sometimes it

00:36:53.280 You say superficial, you mean superficial away from the endometrium closer to the peritoneum?

00:37:00.120 Actually, peritoneum, but the definition will be-

00:37:03.620 Not deep within the peritoneum, just sitting right on top.

00:37:05.840 On top of the peritoneum, yeah, but less than five millimeters.

00:37:10.140 Okay, and so just to orient everybody,

00:37:12.200 because the anatomy here is actually a little confusing,

00:37:15.200 this means imagine you could go inside a woman's abdomen,

00:37:19.420 and what do you see?

00:37:20.920 Well, you see nothing, because it's all collapsed.

00:37:22.700 So let's assume you can put air into there

00:37:25.100 and blow it up and separate everything.

00:37:27.220 You have bowel surrounded by peritoneum.

00:37:29.580 You have the kidneys behind, the blood vessels, et cetera.

00:37:32.920 It's basically just a potential space.

00:37:34.600 and what would be and by the way included on top of that peritoneum you would see the uterus you

00:37:41.960 would see the ovaries fallopian tubes the fallopian tubes between them the ligaments

00:37:46.700 and is the most common place you're going to see these endometrial deposits situated on top of

00:37:54.880 uterus fallopian tubes actually right behind it ah yeah right behind the uterus uh the ligaments

00:38:03.080 the so-called utero-sacral ligaments, because just of the anatomy and gravity. Most lesions,

00:38:13.060 they just stay there, but sometimes they can travel. Yeah, you said it could get up to the

00:38:18.620 diaphragm, so that's a big transit. Yeah, 80% on the right side because of the anatomy of the

00:38:24.980 sigmoid, so it blocks the left side mainly. But yeah, the bladder, around 10 to 12%

00:38:32.920 of endometriosis patients,

00:38:34.500 they might have urinary tract lesions,

00:38:37.660 but mostly it's on the pertineone.

00:38:39.620 And then what about between the rectum and the uterus?

00:38:43.060 That's rare.

00:38:43.900 Because the space is too tight. 1.00

00:38:45.460 So it needs to go inside from the uterus sacral ligaments, 0.93

00:38:50.200 from behind the uterus, 0.57

00:38:52.420 and go to the septum.

00:38:54.240 So that's rare, but that's very hard to treat

00:38:57.900 because sometimes it goes deep into the muscle,

00:39:02.120 the muscle floor, you know, of the pelvis and invades the nerves. And those patients

00:39:09.640 present with lots of fibrosis. Okay. So if you're doing an ultrasound,

00:39:15.640 how is this different from any normal transvaginal ultrasound? Is the difference that you're doing

00:39:21.260 the enema and the bowel prep so you can get a better look posterior? Very important question,

00:39:26.860 Peter, if you do a normal ultrasound and you don't have endometriosis in the report, doesn't

00:39:35.260 mean that you don't have endometriosis. That's one of the most important things, I think, in this

00:39:40.580 episode. So if you complain about pain, you have dysmenorrhea, dyspareunia, and so on, and you do

00:39:49.380 a normal ultrasound, that's one of the problems. That's very, very low sensitivity. Very low

00:39:54.900 yeah we see that a lot but we haven't we have three layers of ultrasound this is the normal

00:40:02.640 one the regular the augmented ultrasound with this lighting sign so you can use the probe to 0.92

00:40:09.960 push the posterior wall of the vagina and see if there is any adhesion there so and sometimes we

00:40:19.100 Even without Bauer PrEP, it's better than the normal ultrasound, but the best will be

00:40:24.760 the detailed protocol with an expert with this Bauer PrEP to look into the pelvis.

00:40:32.680 And who does this, a radiologist or the gynecologist?

00:40:34.920 A radiologist.

00:40:35.860 Sometimes it's a gynecologist specialized in radiology.

00:40:40.020 And again, just because I've never done any of these procedures, so it's not clear to

00:40:43.880 me what the difference is.

00:40:44.900 So, a regular transvaginal ultrasound, I assume, is a relatively small device, like the size of a pen?

00:40:51.360 No, a little larger.

00:40:53.080 How big in diameter?

00:40:54.900 Would be something close to this arm here.

00:40:57.880 Okay, so basically an inch in diameter, two centimeters in diameter.

00:41:01.740 Okay.

00:41:02.760 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.

00:41:11.700 Now, are you doing that because you're trying to get the probe to look further or are you

00:41:16.380 trying to elicit pain? 0.69

00:41:17.900 Yeah, to move the uterus. 1.00

00:41:19.220 Okay.

00:41:19.660 So you can see this sliding sign, right?

00:41:22.620 Okay.

00:41:23.360 And MRI cannot do that, right?

00:41:25.600 Right, it's static.

00:41:26.420 It's static, yeah.

00:41:27.680 And the probe can see 180 degrees plus in front?

00:41:32.980 Yeah.

00:41:33.580 Okay.

00:41:34.420 So then when you're, and again, I'm still a bit unclear as to why the bowel prep is needed.

00:41:39.340 So you can check for endometriosis in the bowel, especially in the rectum.

00:41:46.040 I see.

00:41:46.600 And if you have stool in the rectum, you can't get...

00:41:49.660 Yeah, it has some pitfalls.

00:41:50.120 You need air on the other side.

00:41:51.380 Yeah.

00:41:51.880 Okay.

00:41:52.640 Or liquid.

00:41:53.460 Yeah, we need liquid.

00:41:54.420 Okay.

00:41:55.360 Air is not good for ultrasound.

00:41:56.760 Yeah, yeah.

00:41:58.140 Okay, so is this a different device?

00:42:01.360 Is the ultrasound a different type of device?

00:42:03.060 Good question.

00:42:03.880 No.

00:42:04.820 Actually, the difference is just the experience.

00:42:08.940 and the protocol. But it takes time. And what is the official name of the protocol?

00:42:13.640 It's called a detailed protocol for endometriosis with bowel prep. It depends on the country.

00:42:19.460 Okay. So if someone's listening to this now and they want to do this, it sounds like you've

00:42:24.180 already mentioned Mass General Mayo in Arizona. Is it possible that there's someone who lives in

00:42:30.660 a city where there's nobody that does this? In the US? Definitely. I was talking to my friend

00:42:35.880 and she told me that in the U.S.

00:42:38.840 This is the woman at MGH.

00:42:40.240 Yeah, one of the best.

00:42:43.540 And in the U.S. it's mainly MRI,

00:42:46.840 but they do the augmented ultrasonography.

00:42:49.860 So you can do that, the second layer,

00:42:52.440 but just a few clinics in the U.S.,

00:42:55.320 probably Mayo Clinic, Cleveland Clinic,

00:42:58.260 they are doing the protocol for endometriosis.

00:43:00.800 And why is that?

00:43:01.700 Because it takes lots of time, like one hour exam.

00:43:04.680 so you need to allocate the person and also you need of course the machine is not available like

00:43:13.040 all the time right so we because we in this country obviously have so many mri machines it's

00:43:18.340 it's easier to do that it sounds to me like the mri is very good high sensitivity high specificity

00:43:24.540 the drawback is you don't get the dynamic phase but you don't yeah but it's not that good for

00:43:29.840 bowel endometriosis. And is it a safe assumption that a woman who's having pain with stool is more 1.00

00:43:39.440 likely to have bowel endometriosis? Definitely. So then if you have a woman who is suspected

00:43:44.300 of having endometriosis, but has none of the rectal symptoms, are you more confident that

00:43:49.740 the MRI is going to make the diagnosis? Yeah. Probably sufficient. Okay. But if you are

00:43:55.080 planning a surgery, the ultrasound is, for me, is essential.

00:44:00.280 You would never operate without the ultrasound.

00:44:01.800 Yeah, we have the privilege in Sao Paulo to have access to probably five or six very

00:44:08.440 good radiologists that do this type of protocol.

00:44:11.380 You have five or six people in one city that can do this.

00:44:13.500 Yeah, Sao Paulo is one of the best city to do, probably the best city.

00:44:17.240 Italy is also a good country for that, but it depends on people, right?

00:44:21.800 So Manuel Orlando, Luciana Chamier, Ana Luisa Nicola, there are a few radiologists that are very experienced, not only in diagnosing, but also the follow-up of those patients.

00:44:34.820 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.

00:44:44.660 To correlate what she, I mean, that's brilliant.

00:44:47.360 Brilliant.

00:44:47.840 Yeah, that's the brilliance.

00:44:48.520 Yeah, but that's very rare, unfortunately.

00:44:50.560 So you made a very interesting point, which is you can make the diagnosis with MRI with one blind spot, which is rectal.

00:45:00.820 Now let's talk about treatment.

00:45:04.060 Sorry to interrupt, Peter, just to be clear.

00:45:08.260 MRIs is better for extra pelvic lesions, such as diaphragm, and for the lateral part of the pelvis.

00:45:19.040 Where the ultrasound loses its echogenicity.

00:45:21.900 Yes.

00:45:22.480 So for instance, to see the ureter and to look for the deep pelvis, the nerve infiltration,

00:45:30.900 it's better than the ultrasound.

00:45:33.240 So do you do both?

00:45:34.920 Sometimes.

00:45:35.800 Mostly both.

00:45:36.780 Yeah.

00:45:37.140 And what's the sequence of MRI, by the way?

00:45:39.420 Is it special?

00:45:40.220 Does it require gadolinium?

00:45:41.700 No.

00:45:42.320 So non-contrast?

00:45:43.800 T1, T2? 1.00

00:45:44.860 They just usually put some gel inside a vagina. 1.00

00:45:48.480 Yeah. 2-1, 2-2, that's it. 1.00

00:45:50.580 Okay. So relatively easy MRI.

00:45:52.840 Yeah.

00:45:53.500 Probably a 20-minute scan.

00:45:55.600 Yeah. But there are some pitfalls like movements, you know, bowel movements.

00:45:59.640 Yep.

00:45:59.900 The patient cannot stand too much, you know. Sometimes you just get some artifacts.

00:46:06.100 Yep. Okay. So now let's assume you have the diagnosis. What are the treatment options?

00:46:13.440 How do you think about non-surgical and surgical treatment options?

00:46:18.340 So it depends a lot on the object, right?

00:46:21.240 If the patient is trying to conceive, we have another section.

00:46:25.280 If she's trying just to get a better life without pain and not wanting to conceive now, we have much more options.

00:46:34.600 Okay, so let's start with that.

00:46:36.180 Let's start with 20-year-old woman not trying to conceive but having pain and just wants symptom resolution,

00:46:44.280 but wants to preserve the option of conception in five years.

00:46:49.020 So we have a list of questions.

00:46:50.980 First one is, do you want to get pregnant in the future?

00:46:54.740 How many children do you want?

00:46:57.020 It's hard to answer that if you are 20.

00:47:00.740 How is your ovarian reserve, AMH, enterofolical count?

00:47:05.060 Very important.

00:47:07.200 Disease phenotype.

00:47:08.740 What I mean here, do you have endometrioma, the cyst?

00:47:12.020 because this is a very special phenotype

00:47:15.400 which can lead to lower ovarian reserve

00:47:18.880 and also the surgery can impair the enterofallical count

00:47:21.960 and even the AMH.

00:47:24.800 And how's the pain?

00:47:26.540 If she's presenting with pain,

00:47:29.620 we mainly start with a pill,

00:47:32.060 like a birth control pill

00:47:33.420 because those patients,

00:47:35.380 they usually are not trying to conceive

00:47:37.600 so they want contraception, right?

00:47:39.360 And if the patient doesn't have endometrioma, we can use an IUD, like a Mirena or a Chilina.

00:47:49.200 In addition to an oral contraceptive?

00:47:50.760 No, just, we tend to use just one.

00:47:53.920 Okay.

00:47:54.380 So Mirena is not good for cysts because it doesn't suppress the ovulation, right?

00:48:01.000 So, but if the patient has like no endometrioma, you can use either a Mirena.

00:48:06.800 Benefit is like five years of treatment.

00:48:09.480 And a Mirena is progesterone-coded.

00:48:11.780 Why would you use a Mirena over any IUD?

00:48:14.340 Because you need the progesterone action.

00:48:16.960 You're trying to suppress endometrial hyperplasia.

00:48:20.020 That's it. 0.75

00:48:20.580 And to avoid menstruation.

00:48:24.360 Okay. 0.65

00:48:25.120 Yeah, so in other words,

00:48:26.780 a regular IUD doesn't necessarily suppress,

00:48:29.760 whereas a Mirena will.

00:48:31.000 It's just an inflammatory event for contraception. 0.50

00:48:34.580 It prevents conception, yeah.

00:48:35.080 Yeah. 1.00

00:48:35.200 okay and do you all things equal in this example i gave you so 20 year old woman who wants to 1.00

00:48:42.700 preserve her right to fertility but at the moment is just trying to deal with pain

00:48:47.620 she has pelvic symptoms how are you deciding between the Mirena and the oral contraceptive

00:48:53.940 that's a good question if she doesn't have myofascial pain which is like a contractions

00:48:59.740 and the muscle part of the pelvis. 0.96

00:49:02.800 And Mirena is a good option.

00:49:04.860 So no endometrioma, no myofascial pain,

00:49:07.060 Mirena is a good option.

00:49:08.200 But sometimes they just don't want to insert Mirena, right?

00:49:13.280 So you can start with a pill,

00:49:15.540 a progestin-only pill,

00:49:17.180 like norethindrone or Dianagest or Dizogesrel,

00:49:21.960 or you can use a combined contraceptive pill,

00:49:26.160 like the traditional ones, right?

00:49:27.560 Estrogen, progesterone.

00:49:28.940 Yeah, ethinyl estradiol or just estradiol plus progestin.

00:49:33.180 And you don't use a low dose.

00:49:35.140 You don't use a low, low estin or you do...

00:49:36.980 Yes, we prefer using the lowest effective dose.

00:49:40.700 Yeah, because remember, estrogen can activate the lesions.

00:49:46.340 So it's better to use the low dose.

00:49:48.740 But the data points to like, they are pretty much similar.

00:49:52.680 So if we do that three months or six months later, the patient is not better.

00:49:57.780 we can change the method or we can plan surgery but mainly we try to use medications

00:50:05.760 and why is that because if you do surgery right from the beginning it's very probable that this

00:50:13.960 patient is going to recur endometriosis like in five years or even 10 years and she'll need

00:50:21.060 more surgeries afterwards. And the surgery here is a laparoscopic procedure. It's a blunt force

00:50:28.280 tool. You're going in and you're literally laparoscopically cutting out. And are they

00:50:35.480 that visible to the eye? Yeah. Most of lesions, they are visible, but there are some tiny lesions

00:50:42.040 that we cannot see. And that's why probably the recurrence rate, it's not actually recurrence.

00:50:47.900 Think about how different this is from cancer, right?

00:50:50.920 Like endometriosis presents like metastatic peritoneal cancer

00:50:55.860 and no one in, there's no treatment

00:50:58.980 that would ever involve surgery for that.

00:51:01.020 You treat this systemically.

00:51:02.300 Once the cancer is at that level,

00:51:05.020 it's only systemic treatment.

00:51:07.220 And the reason of course, in part,

00:51:09.400 is because you can never get it all.

00:51:11.740 Even if you only took what you can see,

00:51:13.820 you know you're missing things

00:51:15.800 that are below the threshold of your vision.

00:51:18.500 And so is that not the case here, or is it the case that you're, you're missing things?

00:51:22.880 And that when you say the problem with surgery is she's going to recur in five years, is it

00:51:27.780 that she recurred in five years or it's, she's just going to present with what you didn't see?

00:51:32.520 Yeah, that's, that's the point.

00:51:34.260 Yeah.

00:51:34.460 Sometimes you, even with a good surgery, excising all the lesions, if you don't use

00:51:41.300 a medication after surgery, recurrence rate is around 10% per year.

00:51:46.700 especially in endometriomas.

00:51:49.640 So it might be that surgery doesn't cause recurrence,

00:51:52.660 it's just that surgery is a sign of recalcitrant disease.

00:52:00.160 It's a disease that doesn't respond to medication,

00:52:03.260 and that's why those patients need repeated surgery.

00:52:05.960 And that's where the progesterone resistance come in.

00:52:10.320 And do you have an assay to measure this,

00:52:12.320 or it's a clinical diagnosis?

00:52:14.860 We don't have it.

00:52:15.800 Yeah, we don't have it.

00:52:17.300 And remember, they produce aromatase,

00:52:19.380 they produce their own estrogen,

00:52:21.460 like their own fuel to keep growing.

00:52:25.180 So we don't have like a chemo for endometriosis.

00:52:28.460 We just have this ovulator blockage, you know.

00:52:32.620 We just suppress ovulation.

00:52:35.260 And by doing that, we, of course,

00:52:37.820 we decrease the risk of recurrence.

00:52:40.420 There's a study published that show

00:52:42.360 that if you insert a Mirena after a surgery,

00:52:45.920 recurrence rate is 88% lower to a placebo.

00:52:52.020 So it's better to use something after surgery.

00:52:54.680 So coming back to that patient with the patient 20 years old, 0.62

00:52:58.520 probably she's going to respond to medication.

00:53:01.240 If not, we can change the medication or we can plan surgery.

00:53:04.900 But always, we should think about this as a chronic disease.

00:53:09.280 And there's this concept that was published in Nature Reviews seven years ago by Charles Chaperon, a French group, that calls the endometriosis life.

00:53:21.140 What that means is that we should not only treat the main symptom, but we should think about the life of this patient that has this disease that is chronic, like type 2 diabetes, type 1 diabetes, and so on.

00:53:36.440 But we are mainly doing just one appointment, one surgery or one medication and go.

00:53:44.440 We're not thinking about the life, like what's going to be like in five, 10 years, right?

00:53:50.780 So we should change the mindset on that.

00:53:53.500 Okay. 1.00

00:53:54.600 Let's now consider a woman who's in her late thirties. 1.00

00:53:59.020 She's had two kids.

00:54:01.740 AMH is declining.

00:54:02.940 so she's technically still fertile but is not trying to conceive again and is mostly just

00:54:10.520 trying to deal with her symptoms and she has significant lesions in her pelvis. How do you

00:54:18.000 approach her? So first line medical therapy because remember if she doesn't want to conceive 1.00

00:54:24.320 she needs contraception so we could use a combined pill or progestin. In Brazil we have this

00:54:31.940 dianogest, which is a very good protesting for endometriosis. In the U.S., we have the

00:54:38.680 Natiza. Natiza is like estrogen, estradiol plus dianogest, but you need to use only the active

00:54:47.000 with dianogest. There are 22 pills inside a box. And if she responds well, that's it. We are

00:54:56.260 controlling the disease, right? And if not, you go to surgery?

00:55:00.020 Or we can use a Mirena.

00:55:01.580 Okay.

00:55:02.220 So now let's go same question, 36-year-old. 0.97

00:55:06.600 Everything I said is the same, except now she wants to conceive,

00:55:09.600 but her AMH is, as I said, declining, and therefore the clock is running out.

00:55:13.460 So probably the objective is have a baby, right?

00:55:17.240 Yes, she wants a baby. 0.79

00:55:18.300 Not just controlling pain.

00:55:19.300 That's right.

00:55:19.600 But sometimes they present with both, pain plus infertility.

00:55:24.740 So this patient, we have a series of questions that, remember, infertility is a couple's disease.

00:55:31.480 Probably the only disease that I know in medicine that involves two people.

00:55:36.920 It's defined by the incapacity to achieve pregnancy after one year of trying to do that.

00:55:43.960 So you need to investigate the male factor, like a sperm analysis,

00:55:49.460 and you need to investigate other factors

00:55:51.820 that not only endometriosis can impair infertility, right?

00:55:56.080 So you need to ask, request a karyotype

00:55:59.800 and some other exams like a hysterosopingogram.

00:56:03.600 So let's say you do the fertility workup

00:56:06.180 and you do not see any evidence in the mail

00:56:12.840 with motility count or anything like that.

00:56:18.680 And I'm making this up because I don't know if this is how it would present.

00:56:22.480 They don't seem to have difficulty with a chemical pregnancy, but it never, she's always

00:56:28.400 miscarrying at four weeks, six weeks, eight weeks.

00:56:32.080 She's never getting past.

00:56:33.700 Is that consistent more with maternal age? 0.86

00:56:37.580 Yes.

00:56:38.020 Okay.

00:56:38.480 So how does the infertility of endometriosis present structurally?

00:56:45.520 They can't implant.

00:56:47.480 Very good.

00:56:48.060 question actually we now we mainly think of the mechanism about a mechanical mechanism we think

00:56:56.220 that it's mainly mechanical not biological okay so the tubes are compromised so they can't pick

00:57:03.240 up the oocytes or they can't permit the fertilization inside the tube and transport

00:57:09.380 the embryo back into the universe right and surgery can fix that sometimes if the tubes are

00:57:17.080 not too damaged but we have some adhesions not too much but you know you can can do that by

00:57:22.820 laparoscopy or robotic surgery but it depends a lot on the couple if male factor is okay if age

00:57:31.180 is okay and the the couple just want like one child probably this 36 year old woman she has 0.82

00:57:39.220 time to do that and if she doesn't get pregnant after one year of surgery you just make sure

00:57:47.060 I understand, Renato.

00:57:48.420 The surgery you're proposing is a laparoscopic procedure

00:57:54.360 where you attempt to remove any at all adhesions.

00:57:58.220 And just doing that, the hope is that the fallopian tubes

00:58:01.560 become less dysfunctional.

00:58:02.860 You can restore the anatomy and the functionality of the pelvis.

00:58:06.340 And is that because it is such a mechanical issue

00:58:08.740 where the adhesions can literally kink the fallopian tubes

00:58:12.080 or create obstructions?

00:58:13.580 Yeah, primarily, yes.

00:58:14.980 But, of course, we have plenty of data showing that we have molecular differences between endometriosis and non-endometriosis pelvis.

00:58:24.760 For instance, we have C-reactive protein, IL-6, TNF-alpha.

00:58:29.580 But clinically, it's mainly an anatomical problem, right?

00:58:34.600 This is, it's so hard to believe that it's that crude, if you will, that it's plumbing, basically.

00:58:40.620 Yeah, but there are some authors that may argue that implantation, so the utopic endometrium is also dysfunctional molecularly, but clinically not that much.

00:58:55.100 Why is that?

00:58:55.660 because we have beautiful data and papers published like 20 years ago

00:59:00.000 that compared women without endometriosis,

00:59:04.320 donor ozites, so good quality embryos, 0.96

00:59:07.420 and they transferred the embryos,

00:59:09.020 the implantation rate, miscarriage rate,

00:59:11.240 and live birth rate were pretty much similar.

00:59:14.840 So, which means that clinically,

00:59:18.080 endometriosis probably doesn't impair implantation.

00:59:22.240 and that's very important for IVF too

00:59:26.080 because if you have a frozen embryo

00:59:28.620 you do IVF and you freeze all the embryos

00:59:31.740 if the patient has endometriosis

00:59:34.780 does she benefit from surgery

00:59:37.260 before doing the frozen embryo transfer 0.96

00:59:40.080 probably not 0.94

00:59:41.980 but if she has adenomyosis 0.97

00:59:45.260 she will probably benefit from doing the hormonal suppression

00:59:49.640 because you cannot operate on adenomyosis,

00:59:53.680 mainly just the adenomyomas.

00:59:56.420 They are not that common. 0.91

00:59:57.860 But we cannot treat the uterus

00:59:59.740 with a laparoscopy.

01:00:02.100 So in other words, 0.98

01:00:03.020 the only women who can be relieved surgically 0.95

01:00:06.700 from adenomyosis are women 1.00

01:00:08.180 who no longer want to conceive 1.00

01:00:09.600 because you're going to do a hysterectomy.

01:00:12.000 Do you do the oophorectomy as well? 1.00

01:00:14.240 Depends on her age and ovarian reserve. 1.00

01:00:17.840 but we always do the self-injectory. 0.74

01:00:20.080 You always take the tubes out 0.76

01:00:21.140 when you take the uterus now. 0.99

01:00:22.880 Yeah. 0.58

01:00:23.180 Great, yeah.

01:00:23.860 Is that standard of care?

01:00:25.120 Oh, yeah.

01:00:25.480 There's no gynecologist 0.99

01:00:26.640 that would ever leave tubes.

01:00:28.340 Yeah, because we know...

01:00:28.820 Okay, you know that that's what it is.

01:00:30.180 Yeah, they shouldn't, yeah.

01:00:31.220 Okay.

01:00:32.020 So I didn't understand something

01:00:34.700 you said a minute ago.

01:00:36.380 You said that when you took a donor egg,

01:00:41.500 a healthy, young, perfect donor egg,

01:00:43.580 chromosomally normal,

01:00:44.760 morphologically perfect embryo and you transferred it, it had the same rate of failure

01:00:51.020 as the woman with endometriosis's own egg, correct?

01:00:56.860 No. If you are looking just for recipients of donor eggs, one group has endometriosis,

01:01:05.360 the other one has no endometriosis, confirmed by laparoscopy, which is very important, because

01:01:10.600 mainly those those studies they are very heterogeneous yeah and they mixed and they

01:01:17.680 they just don't know if the patient has adenomyosis too so my opinion is that

01:01:24.920 the missing factor is adenomyosis if this can confound implantation rate and miscarriage rate

01:01:32.300 so what i'm saying is that if you transfer a good embryo in the uterus of a patient with

01:01:39.240 or without endometriosis, we have pretty much the same results.

01:01:44.760 Ah, okay.

01:01:45.760 You understand that?

01:01:46.420 Yep.

01:01:46.920 But if a patient with endometriosis is doing IVF,

01:01:53.200 she will probably have less oocytes, less mature oocytes,

01:02:01.160 and less embryos to transfer, 0.99

01:02:03.480 which means that she needs much more cycles to do 0.91

01:02:07.460 than the patient without endometriosis.

01:02:09.820 But that doesn't mean that the quality is impaired.

01:02:14.500 It's very subtle.

01:02:16.340 We have also molecular data showing that all sites in patients with endometriosis,

01:02:22.440 they are not normal.

01:02:24.680 But clinically, if you look into the data, just ask,

01:02:30.480 I have patients with endometriosis or without endometriosis,

01:02:34.320 is there any difference in quality?

01:02:36.980 Probably not.

01:02:39.940 Okay.

01:02:40.600 Even any play rates, they are similar.

01:02:43.400 Because you're matching for age.

01:02:44.940 That's it.

01:02:45.480 Yeah.

01:02:45.980 Age is the proxy for chromosome abnormalities.

01:02:50.900 Okay.

01:02:51.800 So in the case of this woman, who's in her late 30s, 0.74

01:02:55.520 are you going to treat her surgically and give her a year?

01:03:00.160 Are you going to harvest eggs to give her a year? 0.93

01:03:05.020 like what is your algorithm so probably we're gonna offer both options but ivf is the the way

01:03:13.460 to go here because up to 34 the difference in between a blastocyst with 31 or 34 years old

01:03:26.560 like in a patient that is 31 or 34 is not that different it's about 35 percent of aneuploidy

01:03:35.480 about that if you are 30 is it that high yeah a 31 year old woman has a 35 percent chance of

01:03:44.040 aneuploidy 30 to 35 almost one third of blastocysts they are aneuploidy i mean i just don't think of

01:03:52.300 31 is old.

01:03:53.680 Yeah, I know.

01:03:55.760 I think, I almost think of that as prime reproductive age.

01:03:59.400 Yeah, prime time would be like 25 up to 30, because it's very interesting.

01:04:04.360 So it falls off very quickly at 30.

01:04:06.960 Yeah, especially after 35.

01:04:09.180 And 35 aneuploidy is?

01:04:10.760 It's around 40%, around 40, and 38, around 60%, 40, around 70%, 42, around 80, 85%.

01:04:24.840 So it ramps up.

01:04:28.460 And so that's very important.

01:04:30.120 So if you draw-

01:04:30.900 I want to make sure you and I are talking about this very casually, but I want to make

01:04:33.860 sure the listener understands what we mean.

01:04:35.340 aneuploidy is when the egg is split and you don't get an equal number of chromosomes so you get

01:04:41.980 either two or zero instead of the one chromosome you want and that's almost uniformly fatal those

01:04:49.860 almost always result in miscarriages there are a few notable exceptions like trisomy you know

01:04:54.620 down syndrome which is what trisomy 21 yeah yeah so the definition is like aneuploidy is an

01:05:00.220 abnormality in the number of chromosomes so we have 46 xx a female or xy a male but so the normal

01:05:12.940 way would be like 33 chromosomes from the egg x and 33 from the sperm x or y right so if you do the

01:05:23.580 the math will be uh 46 but 20 23 and 23 yeah 23 sorry yeah 23 and 23 yeah so 36 in the end but

01:05:33.660 if you have like problems in the egg because essentially any employee they come from

01:05:42.460 the maternal side yeah let's turn like 93 and 95 percent there they come from their outside

01:05:47.980 with due to errors in meiosis so they don't split the chromosomes and now you can get monosomy

01:05:57.500 one less or trisomy as you said they are the most uh quote-unquote dangerous because those babies

01:06:04.860 can live they can have the disease monosomy is not uh we don't have a compatibility with life

01:06:11.420 Just the monosomy of X, which is Turner's.

01:06:14.920 Yeah.

01:06:15.440 So mainly we're having an implantation failure problem,

01:06:18.940 so infertility, and that's invisible to the exams, right?

01:06:22.900 So a 30-year-old woman with normal exams can get pregnant. 0.94

01:06:28.140 Why is that? 1.00

01:06:28.780 Because she's 38.

01:06:31.360 Most embryos, they are not normal at that time.

01:06:35.140 And we can have also miscarriage risk here.

01:06:39.500 Okay.

01:06:39.640 Okay, so you're going to pursue both paths in parallel with her,

01:06:44.560 but given her age, you're going to harvest some eggs and have them handy.

01:06:48.640 Yeah, just coming back to the case.

01:06:50.280 So we could do potentially two ways, two routes here.

01:06:56.420 First one would be to go directly to IVF,

01:06:59.060 then freeze the or the oocytes or embryos, mainly embryos here.

01:07:03.660 Then we can transfer the embryo later on.

01:07:07.260 between freezing the embryos and transferring you can perform surgery when if the patient has

01:07:15.780 large endometriomas like larger than five to six centimeters because they can they can get that big

01:07:23.740 yeah that seems massive yeah i have a patient now she has 12 centimeters in one side and eight

01:07:30.760 centimeters in the other side is the size proportional to the symptoms no no so it's

01:07:36.960 not because you tell me that i would assume this woman can't leave her house like that would seem 0.98

01:07:41.820 debilitating but no yeah that's the problem of the classification system that we have we we tend

01:07:46.900 to use the asrm that's the american society for reproductive medicine classification but

01:07:53.220 it doesn't capture it all because it doesn't match the severity of the disease it's classified

01:08:00.140 one to four like mild minimal moderate and severe disease but it's just a like a map like a surgical

01:08:08.980 description it doesn't match with pain neither fertility so that's a problem so an asrm4 would

01:08:17.080 be like very severe disease but she can can be asymptomatic while a stage one patient could be

01:08:25.040 like at their homes just having pain and so on right so that's a problem we have but we have

01:08:32.380 like talking about classification and scoring we have this endometriosis fertility index

01:08:38.180 which is a score based in some you know you give like zero to four depending on the quality of the

01:08:45.680 tubes and the fimbria and the ovaries after surgery so you can predict the rates the pregnancy rates

01:08:52.840 after surgery. So if the score is high, like 9 or 10, they have almost 65% of chances of getting

01:09:01.440 pregnant naturally after surgery. So that's useful, which means that if the tubes are not

01:09:08.860 okay, they are dilated, or you need to do a self-injectomy, probably the chances are not

01:09:19.680 that high after surgery so you can walk them through IVF directly so just coming back to that

01:09:28.060 patient so if if you freeze the the embryos then you can operate on the endometriosis if there is

01:09:34.280 indication mainly indications are large endometriomas pain if the quality of life is not good you can

01:09:42.360 operate on them and small bowel lesions that can obstruct and sometimes ureteral involvement

01:09:50.440 which can lead to kidney function loss actually i have i had a patient with she had a nephrectomy

01:09:58.460 left nephrectomy due to endometriosis in the ureter like silent disease mostly she developed

01:10:06.740 hydronephrosis? Hydronephrosis and the urologist performed a nephrectomy. 0.99

01:10:12.140 Oh. Yeah. So those are the red flags. Those are the red flags to perform surgery even without

01:10:19.940 symptoms. Yeah. Like appendix is important too, because sometimes it just mimics neuroendocrine

01:10:26.120 tumors. Yep. It's essentially the same phenotype. Wow. And small bowel and ureterum,

01:10:33.540 you need to operate on them.

01:10:35.920 Okay. 1.00

01:10:37.280 Let's talk about a 32-year-old woman 1.00

01:10:39.600 comes to you. 1.00

01:10:41.860 She has had difficulty conceiving,

01:10:45.180 two failed IVF transfers.

01:10:49.560 You're seeing her for the first time.

01:10:51.680 You do a workup.

01:10:52.900 You find she has adenomyosis.

01:10:56.300 What can you do to help this woman?

01:10:58.200 That's very common.

01:10:59.200 A very good example, Peter. 1.00

01:11:00.340 so if she still have embryos frozen yes let's assume she still has uh so so she has three 0.63

01:11:09.280 embryos still frozen two of them you know she got a lot she had a decent reserve but two have failed

01:11:14.860 and now but they don't want to waste anymore without knowing what's going on so that's why

01:11:18.480 they came so she has embryos that are frozen and you can perform if she didn't do that yet

01:11:24.740 a GnRH analog or agonist use before the transfer.

01:11:31.540 What that means?

01:11:32.820 That you can treat adenomyosis with medication,

01:11:37.040 suppressing the ovulation and suppressing the estradiol levels.

01:11:42.420 So it can produce like a menopause symptoms.

01:11:46.160 That's the side effect.

01:11:47.240 But we have data showing that this can increase implantation rate,

01:11:51.900 but decrease miscarriage rate and increase live birth rate.

01:11:57.400 So why does that work? 0.52

01:11:58.720 You are treating the uterus, right? 0.52

01:12:01.200 So estrogen can triggers adenomyosis lesions, can-

01:12:05.560 Just like endometriosis.

01:12:06.760 Just like endometriosis.

01:12:08.400 And if you use, generate antagonists,

01:12:11.520 we have now in the US-

01:12:12.560 What are the preferred ones?

01:12:14.580 We prefer, like we have much more data

01:12:16.920 with analogs, the agonists.

01:12:19.220 lupron it's called the goceroline they are injectable subcutaneously monthly right so

01:12:27.400 two to four months with this and then we transfer the embryo using just tiny levels

01:12:34.300 smallest amount of estrogen yes and high amounts of progesterone okay so that's the strategy

01:12:41.720 nowadays nowadays we have the antagonist the oral antagonist in the u.s they are very expensive

01:12:48.580 they are called allegolix and relegolix but they are oral medications we had just one paper

01:12:55.840 published last year that compared the use of antagonists versus agonists and they are pretty

01:13:03.020 much the same here we have less side effects they're very expensive i think around one thousand

01:13:09.380 dollar per month so in brazil we don't have these medications we mainly use the agonists

01:13:15.400 And by doing that, we can achieve similar rates of pregnancy and miscarriage as patients if she didn't have endometriosis, endometriosis, sorry.

01:13:26.180 Okay, so you're going to go four months.

01:13:28.260 By the way, it's not clear to me why an agonist and an antagonist both work.

01:13:33.340 Do they both produce a lower level of estrogen?

01:13:35.600 So mainly is the initial mechanism, the molecular mechanism in which the agonist can do a call, we call this flare-up effect.

01:13:46.760 So it occupies the receptors and it triggers a flare-up of FSH and LH and then can lead to ovulation.

01:13:56.100 but after two to four weeks of medication,

01:14:00.340 then you down-regulate the receptor

01:14:02.380 and then you have this suppression,

01:14:05.480 hormonal suppression.

01:14:06.380 So you produce the menopause essentially, chemically.

01:14:08.840 But the antagonist, the action

01:14:11.180 is right in the first medication.

01:14:13.740 So you don't have this flare-up effect.

01:14:16.940 But essentially the objective is the same.

01:14:20.940 So you said about four months of that.

01:14:23.240 And if you were to take an ultrasound

01:14:25.400 sound of that woman every month, what would you be seeing in her myometrium? How would it be

01:14:30.600 changing? Good question. Not much, but yeah, sometimes we just see the uterus shrinking

01:14:36.600 a little bit, like reducing in volume, but sometimes the lesions, they are there. 1.00

01:14:43.480 And why did this woman have a hard time conceiving? You said this is a common presentation, 0.86

01:14:47.680 but what is it that in this woman with, and let's assume that this is IVF, so we know that 1.00

01:14:53.580 these are good eggs, right? These are chromosomally normal eggs. What prevented the implantation in 0.95

01:15:01.220 her? Actually, it's a problem in pregnancy maintenance. I see. So she implanted, but 1.00

01:15:07.100 something happened in the first week or two weeks, or where is she typically failing? Six to eight

01:15:12.580 weeks. Oh, wow. Yeah. Sometimes even further. Okay. And why? Because there are contractions

01:15:19.780 in that junctional zone.

01:15:22.040 Yep. 0.99

01:15:22.520 And the uterus is just trying to kind of expel the embryos. 1.00

01:15:27.260 And, okay, so then you give her four months of treatment,

01:15:31.920 but you said you don't really shrink the adenomyosis.

01:15:35.680 Morphologically, not that much.

01:15:37.380 But chemically, you change.

01:15:38.920 Chemically, yes.

01:15:39.520 Yeah. 0.99

01:15:40.220 And then you can give her the embryo back,

01:15:43.980 low dose of estrogen, lots of progesterone,

01:15:47.220 the embryo implants and is there a critical window in which she just needs to make it through

01:15:54.800 to then not have the adenomyosis or any form of contraction be a problem does this increase her 0.57

01:16:00.900 risk of premature labor if it starts to contract too soon like how how does it play out through

01:16:05.500 their nine months of pregnancy if you do the treatment you have higher chances of implantation

01:16:11.840 and lower chances of miscarriage.

01:16:14.160 But we don't have data on pregnancy complications.

01:16:17.920 But we know that endometriosis and adenomyosis,

01:16:21.080 they can increase the risk of preterm birth,

01:16:24.520 like preeclampsia,

01:16:26.800 and small for gestational age,

01:16:31.100 C-section rates.

01:16:33.440 So if you're speaking to this woman

01:16:35.260 before you'd go through all of this,

01:16:38.500 you would say to her,

01:16:39.940 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.

01:16:54.640 Now, because of this condition, how much less are your chances of success?

01:16:59.460 Around 30% less with adenomyosis.

01:17:02.540 Wow.

01:17:02.920 But it depends on the phenotype.

01:17:04.100 If you have the involvement of the junctional zone, you have a three times higher risk of miscarriage.

01:17:11.820 Because it's more likely to contract.

01:17:13.420 Yes.

01:17:14.180 It sits right on top of this surface where the embryo is going to implant.

01:17:19.640 And remind me again, did you tell me already why you think adenomyosis is occurring?

01:17:24.840 We think there's a disruption basically in the boundary layer?

01:17:27.620 Yeah, the desidualization, the progesterone resistance, the contractions in the junctional zone, and the ureterus sometimes, you can see the contractions sometimes in the ultrasound.

01:17:43.540 Are there drugs in the pipeline that are trying to address the progesterone resistance?

01:17:49.280 No.

01:17:50.160 I'm not going to say no.

01:17:51.220 It seems like that would be an interesting area of study.

01:17:54.880 Yeah.

01:17:55.140 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.

01:18:09.720 And we have a sense of what that is.

01:18:10.740 And there's even a drug that can target that directly.

01:18:14.260 So it's conceivable that with enough understanding of what happens when the progesterone molecule hits the progesterone receptor inside the cell, what creates the resistance.

01:18:24.580 Yeah.

01:18:24.760 It seems that that would be one opportunity.

01:18:27.160 Yeah. Yeah, probably.

01:18:28.500 But we are now just giving them much more progesterone.

01:18:32.660 If that woman who was 32 had been diagnosed immediately,

01:18:38.460 could she have been treated with high-dose progesterones

01:18:42.540 and other hormonal therapies to have not arrived where she is?

01:18:48.140 Like during pregnancy?

01:18:49.180 No, pre-pregnancy.

01:18:50.620 In other words, could she have been maintained

01:18:52.720 on some sort of birth control routine

01:18:55.780 for three years prior to trying to conceive?

01:19:00.440 And would that have increased her odds?

01:19:01.820 That's the point, Peter.

01:19:03.020 We think that if we diagnose an adolescent

01:19:06.840 or even a young woman earlier,

01:19:09.820 we can avoid 40% of the lesions or the disease burden.

01:19:16.160 So yeah, probably yes.

01:19:17.320 But we don't have much data on that.

01:19:19.640 So why don't we have much data

01:19:20.880 given the prevalence of this condition?

01:19:22.720 Because if you look at the economic side, NIH invests 15 times more dollars on diabetes than endometriosis.

01:19:38.340 But an endometriosis patient might cost around $16,000 per year, while a diabetic patient would cost $12,000 per year.

01:19:51.660 So we don't have much funding for that.

01:19:54.220 Why do you think that is?

01:19:58.160 That's a complicated question.

01:19:59.920 I think that's because we're just recognizing that

01:20:03.560 endometriosis now is an important factor.

01:20:06.860 We're seeing movies and documentaries about that.

01:20:10.960 So I think that's just, it's coming up, you know, that's it.

01:20:15.560 I think that's it's just a question of time probably like menopause right yeah that we're

01:20:23.520 seeing this revolution are there any other good case examples you can think of that well actually 1.00

01:20:33.420 let me give you one more so let's let's take another one where a woman is 30 years old she

01:20:40.100 would like to conceive, but she's not trying to at the moment. But her symptoms are horrific. So 1.00

01:20:48.380 she has the worst symptoms you've ever seen, truly debilitating. When you look at the ultrasound and

01:20:54.580 the MRI, you don't see a very high burden of disease. You see a very diffuse disease, but

01:20:59.320 nothing big. You will always try chemical therapy first. You'll always try hormone therapy first.

01:21:05.140 And that patient, no, because she's going to try to conceive. 0.93

01:21:09.020 So we have data showing that if you do that, you control the symptoms,

01:21:13.440 but you don't have a cumulative effect after stopping the medication.

01:21:19.660 So you are treating the disease while you are using the medications,

01:21:23.860 and the medications, they are mainly contraceptives by nature, right?

01:21:27.740 So after you stop the medication, you just lost some time.

01:21:32.500 you know so that patient probably will benefit from surgery because you can treat the pain and

01:21:41.460 then she can try to conceive naturally what is the biggest mistake that happens with respect

01:21:48.740 to surgical intervention what's the biggest like patient selection mistake i would say that

01:21:56.420 if you have a patient that has central sensitization and you think that this surgery

01:22:05.820 is going to resolve that, that's the biggest mistake. Because surgery doesn't attack that

01:22:12.940 layer of pain, the nociplastic pain. So we need sometimes physiotherapy eight weeks before surgery

01:22:21.040 to prepare the pelvis and then you operate on them and after surgery two to four weeks you can

01:22:27.700 restart the physical therapy so that would be the optimal approach the second mistake is to

01:22:35.720 take out all the seeds that you know that you see like the endometriomas because that can impair

01:22:42.400 fertility by reducing, not fertility per se, but IVF outcomes because you reduced AMH.

01:22:52.640 Because each of those cysts, explain why that's the case.

01:22:55.520 Because they are not actually very defined cysts.

01:22:58.660 They're like pseudo-cysts.

01:23:00.620 So when we strip them out, you end up by taking some follicles and all sites that are healthy

01:23:09.460 adjacent to the cyst.

01:23:12.140 So we have data showing that.

01:23:13.340 Wait, you're saying that endometrial cysts are dragging follicles with them?

01:23:18.080 No, they are very attached to the cortical part of the ovary

01:23:23.180 where the primordial follicles are.

01:23:25.820 So when you take out the cysts, you do a cystectomy,

01:23:30.480 you can reduce AMH by 40%, sometimes 50%.

01:23:34.820 So you don't want to take the cysts out if you're trying to preserve fertility?

01:23:38.740 Yeah, but that's a double-edged sword. Why? Because the presence of the cyst 0.67

01:23:45.780 decreases the... AMH because it's draining.

01:23:50.100 Yeah, it can decrease the AMH.

01:23:52.100 So shouldn't you harvest the eggs first?

01:23:54.740 That's it.

01:23:55.140 Okay, yeah.

01:23:56.020 That's it. And the mechanism is beautiful, explained by this phantom reaction, the same

01:24:01.940 one that we know and it produced hydroxyl you know molecules that are very toxic to the dna

01:24:09.460 so they ended up having this so-called follicular burnout so patients with endometrioma they might

01:24:17.540 have before surgery a low ovarian reserve and if you operate on them you are just decreasing this

01:24:27.220 this uh now that this lower very reserve so it's i think that's one one big mistake

01:24:34.900 i think maybe the third mistake would be like to leave a damaged tube

01:24:40.020 hydro cell pinks just to preserve the tubes but we know that this can reduce the ivf chances by half

01:24:48.740 so if you have a dilated tube because the the mechanism is like washing the embryos like the

01:24:55.780 they can, they are connected to the uterus. So then this, you're saying even if you implant

01:25:01.420 in the, in the uterus, just having the damaged fallopian tube can decrease the success of that?

01:25:08.460 Yes, by half, by half. So there's that widely known? Yeah. Yeah. We have Cochrane review on

01:25:14.180 that. Okay. So we have this mechanical effect and also the, it's embryotoxic cytokines.

01:25:20.940 Being secreted down into uterus. Yeah. We need to take out the,

01:25:23.760 you need to do a self-injectomy.

01:25:26.800 In your practice,

01:25:27.960 how much time are you spending on endometriosis,

01:25:30.900 inclusive of discussions around fertility?

01:25:33.480 Like, how often are you operating for this?

01:25:35.620 Operating?

01:25:36.340 Yes.

01:25:37.340 Like, you mean surgery, right?

01:25:38.620 Yes.

01:25:39.820 Probably 20% of cases.

01:25:42.160 20% of your cases are removing endometriosis.

01:25:44.860 Yeah, but, you know, I have a fertility clinic,

01:25:48.780 so I have this bias.

01:25:51.080 people tend to come to me to do IVF so okay so let's pivot and talk a little bit about that

01:25:58.160 you have arguably the premier fertility clinic in in Sao Paulo in Brazil and this is a huge

01:26:06.140 clinical interest of yours what do you think is the most misunderstood thing about fertility that

01:26:14.000 we haven't already discussed now you've already made a very important point which is it's a

01:26:17.480 disease of two people, not one. But as it pertains to the female side of the equation, you've also 0.96

01:26:24.380 shared numbers that are even worse than I imagined with respect to aneuploidy and age.

01:26:29.820 What else do you think is just not fully realized by a person or a couple out there that are trying

01:26:35.780 to conceive? I want just to emphasize that age is the most important factor. And even doctors

01:26:44.340 don't just they just don't realize it because sometimes you just see the patient with the

01:26:50.780 doctor trying like they operate on them and they try to conceive naturally at 42 years old so that's

01:26:59.020 a big mistake because you're just feeding this desire of natural pregnancy that it's not that

01:27:07.560 common at that age, and the risks are very high. So age is probably, nobody knows that a lot. So

01:27:17.520 what I do in my clinic during the appointment, I show a table, we can put in the show notes,

01:27:25.000 of the annual play rates by year after year. And it's very interesting to know that it's not a,

01:27:33.560 It's not linear.

01:27:34.200 It's not linear.

01:27:34.880 No, it's exponential.

01:27:36.080 And it's not only explanation, but it's like this.

01:27:39.440 We have a sweet spot.

01:27:40.260 It's a J curve.

01:27:41.100 It's a J curve.

01:27:42.640 Very young patients, they can have monosomy.

01:27:45.300 Oh, I didn't know that.

01:27:46.060 Yeah.

01:27:46.580 And we see that in other primates.

01:27:48.820 We don't know why, but that's not that risky for the couple, right?

01:27:54.300 Because monosomy, they don't live, right?

01:27:57.120 Yep.

01:27:57.600 But the sweet spot would be around 25.

01:28:01.180 And even at that age-

01:28:02.220 But you're saying at 20, you have a worse chance than you do at 25 because the egg is

01:28:08.980 more likely to be missing a chromosome.

01:28:11.400 Yeah.

01:28:11.520 I would say that the risk of annual plodding is probably higher at 20 than 25, but of course-

01:28:19.640 That's incredible.

01:28:20.340 Yeah, it's incredible.

01:28:21.360 And do you think, I mean, this is a silly theoretical question.

01:28:24.100 Do you think that's because evolution is trying to optimize for 25-year-olds having babies? 0.53

01:28:30.700 Yeah, that's why I think-

01:28:32.200 20-year-olds or 18-year-olds and obviously 30-year-olds. 0.93

01:28:35.440 It's really saying, a 25-year-old woman is the perfect fitness 0.98

01:28:40.440 to carry, deliver, and raise a child? 0.97

01:28:43.340 That's exactly what I think.

01:28:44.680 But we are not sure yet about that.

01:28:48.860 But that's interesting because-

01:28:50.860 Do we think that that's drifted?

01:28:53.160 Like, do you think 200 years ago, if we could go back in time,

01:28:55.880 do you think it would have been lower?

01:28:57.380 No, I don't think so.

01:28:58.840 Because the mechanisms, they should be the same, right?

01:29:01.460 That's unbelievable.

01:29:03.260 Yeah.

01:29:03.640 So that means that if you are 25 and going to IVF,

01:29:09.100 not all the embryos, they're going to be euploid.

01:29:12.180 About 20% or 25% will be euploid.

01:29:17.120 Even at 25? 1.00

01:29:18.480 Yeah.

01:29:19.540 20% to 25% of your eggs are already euploid.

01:29:23.400 So you never are walking around fully euploid.

01:29:26.060 So what I say to my patients, Bigger, is that reproduction in humans, it's very inefficient.

01:29:34.860 So if you think about it, you need one egg, you have just, you lose a thousand eggs every

01:29:41.280 month.

01:29:42.560 You ovulate.

01:29:42.900 You make one, you lose a thousand.

01:29:44.560 Yeah, you lose a thousand apoptosis, but you just have a cohort of like 10, 15, and of

01:29:52.800 them just one ovulate and you have millions and thousands of sperm just for one to go inside and

01:30:01.480 produce the embryo and you need one year to say that it's not working right because infertility

01:30:08.260 is like it's not just oh try this month if you're not pregnant you have infertility no you need to

01:30:13.440 try much more that's because our reproduction system it's not that efficient if you look into

01:30:21.080 the data of like mouse or rabbits any palliative rate is very low they are very efficient at

01:30:30.960 producing good embryos and that means that when we do IVF we are just grouping we're just like

01:30:41.860 making more embryos, but we are not increasing their quality. So if a woman is 40, you sometimes

01:30:51.100 need to do much more cycles. But all things equal, if you take the 40-year-old versus the 25-year-old, 0.77

01:30:59.920 once you have euploid eggs, are the qualities the same or are there other non-visible changes?

01:31:09.700 So for example, we know with sperm, they're not the same, even though chromosomally they appear

01:31:15.260 the same between 25 and 50, we know that genetically they're different. And so older

01:31:20.940 fathers are more likely to produce children with more neuropsychiatric, polygenic conditions.

01:31:28.120 But what do we know on the egg side? Yeah, that's a good point. We have data on that.

01:31:31.960 There's a beautiful table showing that the clinical pregnancy with a euploid embryo at 30, 35, 40, and so on.

01:31:41.320 It's pretty similar.

01:31:43.280 But we know from the lab, if you ask an embryologist, she would say that the embryo is not that quote-unquote beautiful.

01:31:51.940 You know, sometimes morphologically they are different.

01:31:55.380 The morphokinetics, they are not similar.

01:31:59.160 But clinically, it's not that big difference.

01:32:01.960 Interesting. Yeah. Would you advise a woman who's listening to this, who's 25 years old,

01:32:10.600 who is in graduate school, business school, law school, medical school, pick your favorite, 0.99

01:32:18.100 who still has five, six, seven years ahead of her in really, really working hard and does not want

01:32:26.180 to have a child in that period of time. Maybe she hasn't even met her partner yet.

01:32:31.960 Um, but she deep down thinks she wants to have a child.

01:32:36.660 Um, but it's possible she's not going to be thinking about it for another 10 years

01:32:40.620 till she's 35.

01:32:41.760 So she's 25.

01:32:43.840 She, and you're her regular GYN, just you're, you're doing your regular sort of exam.

01:32:48.640 She tells you all of this.

01:32:50.280 Would you advise her to freeze eggs right now at 25?

01:32:53.580 Not for all the patients.

01:32:55.220 Uh, but I would say that it's reasonable to do a, an AMH.

01:33:00.140 like check your reserve right but let's say she's normal she's not defeat she's not she's not ahead

01:33:07.120 of time she's not behind time she's just a normal 25 year old but thinking about the j curve right

01:33:13.100 which is the difference between being 25 30 and 35 is significant and she's not just from an

01:33:19.940 optionality perspective she's she can't tell you i hanato i'm definitely going to do it by 30

01:33:26.160 In which case, maybe you could say, okay, it doesn't change much.

01:33:29.800 Yeah.

01:33:30.020 If she's sure that she wants child children in the future, I would talk to her.

01:33:38.660 But the chances, you know, look at this statistic, Peter.

01:33:43.180 What do you think is the rate of patients that come back to use their own oocytes, like globally? 0.98

01:33:50.940 All the women who freeze eggs. 0.99

01:33:52.500 Yes. 1.00

01:33:52.840 You're saying how many of them never come back and touch them?

01:33:56.560 Yes. 1.00

01:33:56.860 Of 100 women that froze their eggs, like how many are coming back to use them? 1.00

01:34:03.140 To do something with them. 1.00

01:34:04.680 Yeah.

01:34:05.400 75.

01:34:06.480 Actually, around 10%.

01:34:08.640 What?

01:34:09.840 Yes. 0.99

01:34:10.340 90% of women who freeze eggs never touch them. 1.00

01:34:14.160 Yeah. 1.00

01:34:14.700 Or because they- 0.93

01:34:16.800 Because they get pregnant, maybe. 0.83

01:34:17.920 Yeah, they got pregnant. 1.00

01:34:19.140 Okay. 0.97

01:34:19.280 Sometimes they just don't want to use that.

01:34:22.060 but the sweet spot would be around 30 something 32 35 because the cost effectiveness of doing that

01:34:33.320 is better than at 25 so biologically of course does it make sense to freeze earlier yeah but

01:34:43.300 the chances of the time you spend on it the cost you let's help me understand the costs and i know

01:34:49.200 what's different in Brazil from in the U.S.,

01:34:50.980 but I assume in Brazil, this is all paid by out-of-pocket.

01:34:54.320 So I think in the same, in the U.S.,

01:34:56.360 I don't even understand.

01:34:57.400 Yeah, U.S., I think there are some differences.

01:35:01.060 Some insurance might come.

01:35:02.100 Yeah, depends on the company.

01:35:03.320 But let's talk about the cash price of doing it in Brazil.

01:35:06.280 So if this 25-year-old came and said,

01:35:08.260 I want to go ahead and do this,

01:35:09.700 what is the cost of harvesting,

01:35:12.740 of doing one harvest cycle?

01:35:13.900 In Brazil, she would spend about $5,000.

01:35:18.460 U.S. dollars.

01:35:19.200 US dollars because, uh, our currency is like five, five to one.

01:35:23.360 Yeah.

01:35:23.840 Yeah.

01:35:24.400 Okay. 1.00

01:35:24.600 So she spends 5,000 US dollars to do one harvest cycle. 1.00

01:35:28.400 And then how much does she spend per year to keep them in storage? 0.95

01:35:31.880 It's like one hundred and fifty dollars.

01:35:34.920 So now compared to the, okay.

01:35:36.200 So the big cost is she's going to incur that.

01:35:38.880 And again, I'm just being devil's advocate.

01:35:41.520 My view is if you could afford $5,000, why not do it at 25 instead of 30?

01:35:48.360 just because you've capped your downside.

01:35:50.580 Your downside is you're out $5,000.

01:35:52.780 Your upside is how many would you expect?

01:35:56.600 How many euploid eggs do you expect to get

01:35:58.880 out of a 25-year-old per cycle?

01:36:01.040 We were talking about blastocysts or embryos

01:36:03.660 in day five to day seven, about 80%.

01:36:06.960 Around 75%, 80% of the embryos, they are euploid.

01:36:13.360 But since this is not embryos,

01:36:14.660 you're not going to be fertilizing these.

01:36:16.000 You're just getting an egg.

01:36:17.160 yes so we have a like you don't touch them you don't you just freeze the the m2 oocyte the

01:36:23.080 material side you won't know until you fertilize about 75 percent uh 75 percent of the oocytes

01:36:29.400 they are matured so we freeze just the mature eggs and we have some calculators to like to

01:36:37.080 estimate the pregnancy rate and not only that but the live birth rate depending on the age

01:36:43.400 and number of eggs so at that age probably if you have like 15 eggs your chances are

01:36:50.600 higher than 80 percent i have one at least one baby which still seems not that high but

01:36:57.240 yeah but remember uh a fertile but that's all the way to baby meaning yeah yeah so how many

01:37:03.720 embryos and then each implantation has a rate of fall off etc yeah okay so so biologically of course

01:37:11.960 that makes sense but economically it doesn't that yeah that's just economics okay the risk is pretty

01:37:18.360 low like the risk of ovarian torsion and bleeding and you know infections it's about one percent

01:37:25.880 and the main driver of that cost is the medication the procedure is it split about equally yeah

01:37:31.720 one-third medication one-third yeah one-third like clinic and one-third like lab yeah what is the

01:37:40.680 median age of women who are coming to you to have eggs frozen but they're not planning to fertilize

01:37:49.400 mine is 37 38 yes very high why so high why are they coming so late for eggs because i think

01:37:58.360 that's just a new treatment kind of new treatment and because i have bias because we're in sao

01:38:05.000 You're treating the hardest cases.

01:38:07.260 Yeah, probably. 0.97

01:38:08.380 So when a 37-year-old woman comes to you, 0.98

01:38:11.200 I assume she's been trying for a while to get pregnant. 0.97

01:38:14.400 Because she's 37,

01:38:16.500 she's probably had many aneuploidic miscarriages.

01:38:20.480 So she comes to you and says,

01:38:22.320 look, we can't leave this to chance anymore. 0.54

01:38:24.940 You're going to do a cycle. 1.00

01:38:26.540 You will typically get how many ocytes in her?

01:38:29.020 So my infertile patient is even older, like 40.

01:38:33.260 like a social freezing is around 37 so it depends a lot on our ovarian reserve so if the reserve is

01:38:43.720 like normal for a 40 year old woman what's a typical amh for a 40 year old would be around

01:38:49.500 one okay nanogram per ml and that corresponds to roughly how many eggs left depends along a lot on

01:38:56.440 the cohort on that cycle which can be different between the follicular phase and the luteal phase

01:39:03.080 and that's very important from a practical standpoint

01:39:07.280 because sometimes we check the ovaries,

01:39:10.460 we do the enterofollicle count,

01:39:11.860 that's not fine.

01:39:13.920 We wait and recheck another phase

01:39:17.940 because it varies a lot.

01:39:21.100 But we would expect around 8X,

01:39:24.640 something like this.

01:39:26.080 And 8X at 40 is not sufficient

01:39:29.900 mostly to produce a nucleoid embryo.

01:39:33.080 Oh my God. Because eight eggs, you're going to fertilize them and more than half of them are

01:39:38.620 going to be aneuploid. Yeah. So you might get two.

01:39:42.340 Like seven, 80% of them. Yeah.

01:39:44.060 Okay. So you might get one to two euploid to implant.

01:39:50.140 Yeah. We say that it's like a funnel. It's very important for the layperson to understand that.

01:39:54.940 You have the follicles. Each follicle might have one oocyte. Every oocyte has a chance of being

01:40:02.560 matured 75 percent every matured egg can be fertilized and on day one present this pronuclei

01:40:11.600 we say that it's it's fine that's the m2 phase yet after the m2 phase and then from day one to

01:40:19.140 day five or day six which is a blastocyst around 30 up to 60 percent of the those day one can

01:40:27.620 develop into a blastocyst. It depends a lot on the sperm quality too, and the lab of course.

01:40:34.340 And on top of that, you have the antibody rate. It's a big funnel.

01:40:37.780 So hence the inefficiency, you're just multiplying negative numbers after,

01:40:41.620 you're multiplying so many small numbers together that the outcome is very difficult.

01:40:46.180 So when the patient is freezing her own eggs, it's very important for her to know that the,

01:40:53.540 you know the funnel is very important because sometimes it's very sad to to see a patient that

01:41:00.100 is coming back like she froze her eggs at 34 and she's coming back at 40 and she had just eight eggs

01:41:09.700 and now you thaw them and then you produce just one blastocyst and doesn't implant so that's it

01:41:17.380 and now she's 40.

01:41:18.800 Yeah. 1.00

01:41:19.820 Which again, goes back to my question of why isn't every 25-year-old woman

01:41:25.560 who is unclear on her timeline, I guess, you know, it's funny,

01:41:31.320 like I wonder if in countries where population growth is not high enough.

01:41:36.640 So if you look at a country where the reproductive rate is below 2.1,

01:41:40.140 and that turns out to be a lot of countries,

01:41:43.080 and immigration alone won't solve your demographic problem,

01:41:46.440 you actually need de novo reproduction this strikes me as a reasonable cost for the government

01:41:54.440 to bear yeah japan is is facing this right now yeah so israel uh in israel you can do

01:42:02.600 how many cycles you want you need to produce your family yeah so i think from a longevity perspective

01:42:11.980 You're right.

01:42:12.820 You can avoid this disease called infertility,

01:42:17.020 but you can prevent that by freezing oocytes earlier.

01:42:22.280 But I think that's a problem of excess right now.

01:42:26.320 We have the technology.

01:42:27.660 Okay, now let's talk about something very extreme

01:42:31.140 at the other end of this spectrum. 1.00

01:42:32.960 So you now talk about that woman who's 40,

01:42:35.880 she's come back only to realize that nothing worked. 1.00

01:42:41.000 So, but she still wants to have a baby. So right now her only option is to use an egg donor. Correct. Okay. In which case she will use the egg of a young woman. She'll use the egg of a 25 year old woman likely with her partner's sperm. And that's fine. That's a great treatment, right? That works. That works very, very well. 0.92

01:43:01.720 But I have now heard about an emerging technology where that woman who is 40 can use her genetic material with the remainder of the egg from a donor so that she has all of the benefits of the young egg except she gets her genetic material in there.

01:43:29.020 so that the donor is only providing the scaffolding

01:43:34.120 and she could even use a surrogate. 0.90

01:43:36.540 So help me understand that technology. 1.00

01:43:38.740 Yeah, that technology is called mitochondrial replacement therapy.

01:43:43.420 So that doesn't solve the problem

01:43:46.480 because the problem is in the nucleus, right?

01:43:49.700 Yep.

01:43:50.240 So the problem is chromosomal.

01:43:52.620 And we had, I think, two papers published last year

01:43:56.260 in New England Journal of Medicine

01:43:58.020 by a UK group, Newcastle,

01:44:02.120 but 22 patients with mitochondrial disease.

01:44:07.120 Because remember, we have like 20,000 up to 25,000 genes

01:44:13.020 and 37 genes in the mitochondria,

01:44:17.360 the so-called mitochondrial DNA.

01:44:20.080 And for those very specific cases,

01:44:23.760 they basically took out the pronuclei

01:44:27.720 from the parents embryo fertilized after fertilization.

01:44:32.780 So they have in day one, the pronuclei,

01:44:34.900 they take out and they insert in a enucleated oocyte,

01:44:40.200 new oocyte that has this new mitochondria

01:44:43.900 that are normal.

01:44:45.360 They are supposed to be healthy.

01:44:47.180 So this solves just the problem of the cytoplasm,

01:44:50.020 the mitochondria.

01:44:51.280 Ah, I see.

01:44:52.680 So it is not solving the age problem.

01:44:55.260 No. 0.84

01:44:56.140 Got it.

01:44:56.540 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 an egg rejuvenation.

01:45:13.120 That's misleading, in my opinion.

01:45:16.180 But you are just trying to replicate, like, it's like a battery swap for the egg, but you're not changing the engine, right?

01:45:25.300 Yeah.

01:45:25.700 The engine is the main problem. 1.00

01:45:28.200 So is there currently anything on the horizon for the 40-year-old woman who wants to conceive

01:45:35.420 and would like it to be her genetic material, even though she no longer has eggs,

01:45:41.680 or if she has any eggs, they're not dividing correctly? 0.99

01:45:46.420 I think, yeah, not for that situation, but there's a clinic in the UK that is trying to freeze ovaries. 0.62

01:45:55.700 like cortex, like long years before menopause,

01:46:00.100 like to prevent or to postpone menopause.

01:46:03.320 Very interesting idea,

01:46:05.020 but we don't have publications on that.

01:46:07.040 Actually, we have a huge line,

01:46:10.200 like a huge wait list of patients trying to do that.

01:46:14.960 Makes sense, but we don't have data.

01:46:17.340 Sorry, just to make sure I understand that.

01:46:19.380 So the analogy would be somebody with type 1 diabetes

01:46:22.580 that gets implanted pancreatic or beta cells

01:46:26.440 that secrete insulin.

01:46:27.620 Autologous, yes.

01:46:28.460 Yes, autologous. 0.86

01:46:29.540 Is this her own ovarian tissue

01:46:33.200 that was set aside earlier in life? 0.99

01:46:35.460 Like at 30s.

01:46:37.140 At 30s.

01:46:38.460 So they do a partial oophorectomy.

01:46:40.280 Yeah, and you can then transplant like 45

01:46:43.560 when you are 45, and then you can postpone.

01:46:46.740 There is actually like a math behind that.

01:46:49.500 It can postpone menopause like 10, 15 years,

01:46:53.380 sometimes even more.

01:46:54.500 Where do they re-implant?

01:46:55.840 In the peritoneal. 0.90

01:46:57.040 Yeah, peritoneal.

01:46:57.940 Okay.

01:46:59.200 Or you could put in the subcutaneous too.

01:47:03.080 And so you're not only postponing menopause

01:47:06.900 from a hormone perspective,

01:47:08.400 you're postponing fertility. 0.96

01:47:10.960 Yeah.

01:47:11.680 Actually, that's mainly for menopause, 1.00

01:47:15.060 like to produce her own- 1.00

01:47:16.660 That's just to produce estrogen and progesterone.

01:47:18.680 Yeah, yeah.

01:47:19.500 But for all sites, we have data on ovarian cortex freezing.

01:47:25.460 But the better outcomes, they come from egg freezing.

01:47:30.100 And why would this autologous ovarian implantation or transfer

01:47:37.540 be superior to just standard menopausal hormone therapy?

01:47:41.100 That's the question.

01:47:42.260 I just gave a lecture last year about that.

01:47:45.520 So I think because of the cultural thing about menopause, right, about hormone replacement therapy after 2002, July 2002, WHI, right, I think there's just this big misconception about menopause hormone therapy.

01:48:05.840 it's much more it's much easier to just give estrogen progesterone and sometimes testosterone

01:48:12.140 then freezing the the ovary and then transplanting and probably getting like premenstrual syndrome

01:48:21.360 you know symptoms doing that yeah but we don't have data but to your question uh we probably

01:48:27.520 in the future we're gonna have like stem cells producing new oocytes we are not there yet i read

01:48:34.980 an article very recently suggesting that that could be five years away what's your view on that

01:48:40.940 are you optimistic not that much i think more like 10 years why why so difficult what has to be done

01:48:48.760 explain what it is first of all it's i think i'm not the right person to answer that but it's very

01:48:55.100 hard to produce an egg it's easier to produce a sperm and uh we don't know the consequences of

01:49:03.840 that. So we need data after doing fertilization and transferring to see if those babies are

01:49:11.480 healthy. They're still healthy. And we're doing this in animals right now?

01:49:15.780 Yeah. Which animals? How? I think cattle probably. Yeah.

01:49:21.920 And so are they doing this in primates yet? I'm not sure, but probably yes. Yeah.

01:49:27.960 Okay. So what has to be done is you have to demonstrate that you can take

01:49:31.860 a pluripotent stem cell

01:49:33.580 and somehow turn it into an egg.

01:49:35.640 And that hasn't been done yet.

01:49:37.280 But if you can do that,

01:49:39.840 you have to ensure

01:49:40.900 that that becomes

01:49:42.920 chromosomally and genetically

01:49:44.420 normal in the long event.

01:49:46.760 That has been,

01:49:48.300 there's a publication about that.

01:49:50.760 Yeah.

01:49:51.060 That you can make the egg

01:49:52.000 out of a stem cell.

01:49:52.740 Yeah, but we are not sure

01:49:54.660 about the consequences

01:49:55.800 and the clinical benefits

01:49:58.160 of the safety of that.

01:50:00.320 Has it been done in mice?

01:50:01.320 and in mice, because their lifespan is short enough,

01:50:05.480 does it produce a normal phenotype?

01:50:07.060 Yeah.

01:50:07.620 Okay, so that's promising but not guaranteeing.

01:50:10.420 Yeah, but that's going to be like a game changer for us.

01:50:14.240 I think when we do that,

01:50:16.100 we are going to not do any more vitrification like frozen.

01:50:21.900 We are not freezing eggs anymore, right?

01:50:25.500 So just imagine that.

01:50:26.780 So you're saying in 10 years, any couple of any age

01:50:31.900 could potentially reproduce?

01:50:34.820 Probably.

01:50:35.700 I don't know if that's safe, if that's going to be safe.

01:50:39.580 Like, if you ask me, you are 30, me and my wife, we are healthy.

01:50:49.600 We don't have any fertility problems.

01:50:52.180 would you do ivf or try naturally always start naturally and why is that well i mean that's a

01:51:01.840 bit different i mean i think i would say for cost and just there's no reason to rush i mean but but

01:51:08.020 look if if you if you struggled for a year we wouldn't hesitate to do ivf right yes but for me

01:51:14.360 I think we are, like IVF is, the first baby was born in 78.

01:51:21.480 So it's actually a new technology.

01:51:25.120 We can't reproduce everything that we would need to reproduce inside the tubes naturally.

01:51:33.480 There are some epigenetic effects which we can't control,

01:51:38.300 and we don't know what are the consequences.

01:51:41.180 so if the the couple has if the couple has this uh natural chance i will try naturally and

01:51:50.920 the stem cell takes it to a whole new level yeah the the problem is yes if you oh you can count

01:51:57.660 on stem cells okay but wouldn't be better to use my own oocytes that i just froze like at 35 yeah

01:52:06.960 i don't know probably yes is there anything about ivf that we don't know that worries you

01:52:14.020 like what are the unknown unknowns about ivf genetics yeah like and how do you think that

01:52:19.840 shows up phenotypically probably some malformations some neuro neurological consequences

01:52:30.880 um heart disease yeah it's do we see this in the epidemiology i mean yeah these

01:52:39.240 so again people born of ivf are still very young they're yeah you know they're they're not even

01:52:45.900 louise brown is like 40 something yeah 48 yeah yeah but we see definitely uh some signs

01:52:55.780 We're not sure about whether it's a bias, a selection bias.

01:53:00.680 Yeah, that's the hard part is how do you get out?

01:53:02.940 Because by definition, you're talking older parents.

01:53:05.460 You're talking about more affluent access.

01:53:08.460 Infertility. 0.97

01:53:09.080 Infertility. 0.56

01:53:09.720 There's so many confounders.

01:53:11.640 Yeah.

01:53:11.880 And we're never going to do a randomized control trial for IVF. 0.78

01:53:15.320 But there's data showing that if that same couple that needed IVF

01:53:19.840 and then now they are getting pregnant naturally,

01:53:23.240 because sometimes it happens, right?

01:53:25.260 that it's mainly a bias, a selection bias problem,

01:53:29.480 not the technology itself.

01:53:32.340 Yeah, but it's a new technology, right?

01:53:37.020 So what are you most excited about in your field today?

01:53:42.760 Actually, I was very excited about this new guidance from ACOG.

01:53:47.200 Very simple, because probably we're going to avoid complications

01:53:52.400 of endometriosis and adenomyosis.

01:53:55.260 especially in those vulnerable adolescents,

01:53:59.460 and not only treat the disease,

01:54:01.380 but as like statin in longevity.

01:54:04.840 You can modify the disease progression.

01:54:08.820 Early.

01:54:09.860 Earlier. 0.73

01:54:11.060 And avoid infertility.

01:54:13.880 And I'm very excited about this.

01:54:16.820 So we should spread this word, right?

01:54:19.900 And there's one molecule called HMI-115.

01:54:24.560 It's a monoclonal antibody that targets the receptor of prolactin.

01:54:34.240 Probably this leads to, it's in phase 3 trial now,

01:54:38.700 and this leads to less pain and less disease progression and mitrosis

01:54:45.900 because those lesions can express prolactin receptors.

01:54:51.160 Very interesting.

01:54:51.800 maybe that's going to be the first biologic treatment for endometriosis that it's not using

01:54:58.060 hormones so like to your point that no some why don't we have like medications that targets

01:55:06.880 the disease directly yeah yeah probably we're getting that like soon and yeah i and i think

01:55:15.280 the diagnosis, Peter. Yeah. Yeah. I think with this widespread, uh, you know, uh, ultrasonography

01:55:22.060 and MRI and, uh, just the awareness of the disease, we're gonna, yeah, not only diagnose

01:55:29.520 and treat more effectively. Okay. So basically the final and closing thought here should be,

01:55:35.280 if you're listening to this and you're struggling with any symptoms that may be even remotely

01:55:40.620 suggestive of endometriosis or adenomyosis, or your partner is experiencing them, the biggest

01:55:46.740 single win is getting that diagnostic window from six years in the US or seven years in Brazil down

01:55:53.660 to six months. That's it. So you just have to be a bull in a China shop and demand a diagnosis and

01:56:00.200 say, I'm not going to take no for an answer. I want an MRI. And if necessary, I want an ultrasound

01:56:05.880 done with this correct protocol. That's it. That's it. And we're not going to take no for

01:56:10.340 answer, we're going to get these diagnoses. So we can start the treatment because the earlier you

01:56:14.220 start the treatment, the better the prognosis. And you know, Peter, just to close that the cases

01:56:20.560 that stay with me are not the most complex surgeries, not the difficult IVF cycles.

01:56:28.560 There are those women that cry, not from pain, but during the appointment from relief.

01:56:35.120 They finally have a diagnosis.

01:56:36.400 when i tell them you you know you are suffering i i know that's real it has a name we have a

01:56:43.920 plan for that and if you're listening to this and you have pain and you know you're suffering

01:56:50.940 please uh don't uh don't take like this is normal this is just your regular period

01:56:58.280 please have a second opinion and we have we have technology for that we have treatment for that

01:57:05.900 and we should do that right a perfect way to end it henado thank you very much

01:57:13.160 and i really appreciate you getting this message great to be here thank you man

01:57:16.680 thank you for listening to this week's episode of the drive head over to peter atia md.com

01:57:23.940 forward slash show notes if you want to dig deeper into this episode you can also find me

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The Peter Attia Drive - June 22, 2026

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

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