Adenomyosis: The Most Common Condition You've Never Heard Of

Hello and welcome to the Ark Woman podcast. This is an exploration of woman kind. Here we discuss what it is to be a woman in the modern world while utilizing ancient and modern modalities in tandem to create a bounty of health for the body, mind and spirit. G'day ladies and welcome back to the Ark Woman podcast. Before we get into it, I'd like to pay my respects to the elders past, present and future residing on the lands of Literuida Tasmania, where I'm recording this podcast today. Always has, always will be baby. I want you to think about a condition that affects roughly one in five women globally. A condition that takes on average 11 years to diagnose that GPs have no formal training in diagnosing or treating. A condition that until 20 years ago could only be diagnosed with a full hysterectomy. That condition is a denomiosis, and today we're going to be talking all about it. So how common is a denomiosis really? A 2025 global meta-analysis published in reproductive biology and endocrinology. One of the most comprehensive ever, they looked at 199 million women, they almost got to 200 million. Almost, that would have been really cool. Across 127 studies found a denomiosis present in approximately 20% of women in the general population. And that figure jumps drastically to 41% to 49% in women already experiencing gynecological symptoms and 42% in uterus disease examined after hysterectomy. For context endometriosis affects an estimated 10% of reproductive aged women with a denomiosis may be twice as common and it gets a fraction of the research and a fraction of the interest. And previously we had this huge myth that women who had already given birth were more likely to develop a denomiosis. But we know that's not true now. It affects women of all ages because in a 2024 systematic review and meta-analysis in FNS reviews they found a denomiosis in 21% of symptomatic adolescence. This is not a disease of older women. That is a myth that's definitely dead. So if you're listening to this and you think you have a denomiosis and you've been to a doctor to talk about it and they say you're not 40, you don't have it. They haven't read the research in like 10 years. Okay, we've known this for a while now. So because we don't have that much research on this there is a bit of a diagnostic delay and that is a slight understatement. The average diagnostic delay is around 11 years from the first symptom to confirmed diagnosis. A Dutch study found a median of nine years with only 25% patients being diagnosed within two years of symptom onset. And for most of medical history the only way to confirm a denomiosis was to remove the uterus and that played into that whole myth that we had that women only had a denomiosis if they're a little bit older. But that's because women who opted for the treatment option and diagnostic option of a hysterectomy had already had babies. Can you imagine if you wanted to have children, you wanted to have a family biologically speaking and your doctor said, hey, you might have a denomiosis. The only way we can find out is a hysterectomy. What are the chances of you saying, yeah, let's go for it. Literally none. So that really fed into a lot of the myths that we had around a denomiosis only affecting women in an older age cohort. Now we know it's in younger women as well. But how fucking crazy is that is that the only way we could diagnose and treat a denomiosis 20 years ago was with a hysterectomy, which should be named you direct me. I talk about this a lot, but I'm not going to go on a tangent now. This is a pretty catastrophic selection bias where the condition is studied almost exclusively in women who have had hysterectomies, which skews everything we thought we knew about who, when and who gets it. And so this plays into the next topic, which is research neglect. If you thought that endometriosis had been neglected in the research, wait till you find out the stats on adenomyosis. As of 2024, if you search on PubMed for the word adenomyosis, you will get about 4,000 results back. And this is in stark comparison with 35,000 for endometriosis. Endometriosis receives nearly 9 times the research attention, despite adenomyosis being potentially twice as prevalent. And currently there is no drug in the world, not from the FDA, the TGA, that is made for the treatment of adenomyosis. All the treatment options we have from the pharmaceutical industry at the moment are being used off-label for other conditions. So birth control being a really good one here. For women listening to this with adenomyosis, I just want to say I hear you and I just want to give you some stats on the mental health burden that having this condition can impact women with this condition. So in 2022, a study published in the Journal of Clinical Medicine by Lee and colleagues, they found that women with adenomyosis were nearly 5 times more likely to experience depression and 3.6 times more likely to have anxiety compared to women who don't have the condition. Up to 57% of women with adenomyosis have a documented history with depression. Not as a cause of their pain, but as consequence of years of unmanaged, dismissed, and debilitating symptoms. And because of the pathophysiology of adenomyosis, which we will be getting into later in this podcast, it has a huge burden on fertility. Among women presenting with infertility, nearly 1 in 3, so 31% had adenomyosis. This is from a study weighing at L 2025 from reproductive biology and endocrinology. So really recent study. Another recent study from 2021, it was a smag review. They found that clinical pregnancy rates are 31% lower in women with adenomyosis within more than doubled risk of miscarriage. One in four women with recurrent miscarriage or repeated IVF implantation implantation failure has adenomyosis. And so miscarriage, there are so many different risks associated with miscarriage, not to mention the mental health risks that are associated an emotional burden associated with that. But the risk of infection, the risk of other negative health consequences associated with repeated miscarriages are quite dire, which means that adenomyosis is a fairly dangerous and serious condition, which is really concerning because it means that we know that there has been a serious negative association with health outcomes for women with adenomyosis, but it's barely being researched. Adenomyosis is an extremely painful condition, and this has a negative outcome on women's ability to work and study. And we have a couple of studies here that talk about that. So a 2021 study published in the Journal of Women's Health found adenomyosis patients lose 38% of their overall work productivity. And absenteeism sits at 12% versus 1% in control. So the activity impairment, therefore, is 56%. I just want you to imagine a guy. Okay, just any guy could be your partner, could be your brother, could be your dad, could be just a random guy in the street. Could you imagine if he said to his work, I can only work two days out of the week because I have a painful condition in my penis. How quickly would pharmaceutical industries pick that up and find a solution? I would say there would be maybe an 18-month turnaround. Okay, and that's being generous. They would be able to figure it out faster, but because where women and pain is normal and expected in our physiology, then we're just told to put up with it. Insane, absolutely insane. A European study I found the estimated additional indirect economic cost is over 5,000 euros per patient per year. And that is what untreated adenomyosis cost women personally in lost income, lost capacity and lost time. So you have this really painful condition that has pretty much very little research on it, only 4,000 papers on pub med. That's little to no research. I would say you could imagine that you'd be pretty desperate for answers and treatment. But the fact of the matter is that most GPs have absolutely no training in the diagnosis or treatment of adenomyosis. I mean, it's already bad for endometriosis. Could you imagine how awful it's going to be for adenomyosis or for? So you go to a GP, they have no training, but they do know that there's only one diagnostic and one treatment for adenomyosis and guess what it is. Let's just take it out. Let's just have a full hysterectomy. Let's just remove all of your endocrine organs. Really invasive surgery. Really negative health outcome comes after it. It puts you in a immediate state of menopause if you go forward with that treatment. So there is a huge pipeline between if you do find out you have adenomyosis. The treatment option that very often is pushed onto young women who want to have children, even if they don't, and they want to keep their reproductive organs is a hysterectomy. And there's a lot of pressure on women. And I talk about this in my previous podcast about the medical system. There are stats from the NHS and safety governing organization in Australia that says that most hysterectomies at least in Australia and the UK aren't actually needed. Then there are other treatments. So if you're listening to this and you've just been diagnosed whether you think you have adenomyosis, I just want you to know that there are other treatment options. And if you are being pressured to have a hysterectomy, unfortunately that is normal because unfortunately that has been the gold standard treatment that we have for adenomyosis. And it might still be unfortunately. In a major US population based study conducted by Kaiser Permanente covering 2006 to 2015, 82% of women diagnosed with adenomyosis ultimately ended up having a hysterectomy. 82% of women with a full hysterectomy that is a full removal of the uterus, the floping tubes and your ovaries. And this is what the current treatment landscape looks like. It's diagnosed too late. You try a handful of off-label treatments that don't always work because we don't have much research on those treatments and eventually we remove the uterus. We can do better and that's what this episode is all about. So I know we're starting off really really dark. I just thought I'd get it over and done with. Everyone take a. Big breath. Let's do a couple. Okay, let's move forward. Adenomyosis is often called endometriosis' evil twin sister. And I just want you to understand the pathophysiology of adenomyosis. In your uterus, you have your endometrial lining. So this is the lining that is thickened by estradial and progestin over the course of your cycle. And then you slough it out at the end of your cycle. I want you to imagine that you're on a beach and the endometrium is the ocean. Then under your feet is the sand, very solid structure. It's always there. It's always at the beach, right? Unless the tide is high, the tide is high. You have lots of endometrium. And when a tide is low, it means you've just had your period and the endometrium is sloughed. But the myometrium, the muscle structure of your uterus is always there. It's always there. When we look at a MRI or an ultrasound, we've come a long way with trans-vaginal ultrasounds for the diagnosis of adenomyosis. I'll get to that in a bit. We see that there is a very clear difference between what we see in these imaging of what is the myometrium and what is the endometrium. They're really different structures. What happens with adenomyosis is that we generally see that the endometrium starts to form little tunnels and it starts to form lesions and push itself into the myometrium. Instead of there being a very, very clear distinction between the endometrium and the myometrium, it's becoming a lot more gray. When you would look on an MRI or an ultrasound for someone who doesn't have adenomyosis, you would see two very different structures, very, very distinct. But if we look at a woman who has adenomyosis, it's very unclear. What can happen is that the endometrial lining that is pushing itself into the myometrium, it's still hormonally active and responsive, which means when you have a period, you can have endometrial growths inside of your myometrium, so deep in the muscle layer of your uterus. And when estrogen drops and progesterone drops, you can have a menstrual bleed, which means you're bleeding into the muscle of your uterus. That this increases a lot of inflammation because serum ions, so ion that isn't bound to anything, can be really, really, really inflammatory if it's gone uncontrolled. And we also see that we have a high risk of infection here as well. So it's very, very, very painful. And because there is a damage to the muscle in your uterus, so the myometrium, it means it's not actually able to contract properly. So generally, generally what we see in a contraction of the uterus is it's kind of like a top bottom. So we're kind of squeezing from the top down the bottom because remember, we're squeezing out the endometrium. That's our period, basically. But if you have damage in the muscle structure of your myometrium, it means that the muscle doesn't really have the connection it needs to its other filaments in the structure of the muscle, that it can effectively squeeze the endometrium out. So it's squeezing up, it's squeezing down, squeezing to the side and to the other side. And it's quite ineffective, which means that women with adenomyosis have really, really painful periods, generally have a lot of inflammation and bloating. And generally, we'll experience possibly longer and more heavy periods as well. And you might be thinking, okay, that sounds a lot like endometriosis. And it is. And it's the interesting thing is that we generally see endometriosis and adenomyosis appearing together. We do see these two conditions co-occurring a lot. But I don't want you to think that adenomyosis is endometriosis. There is some difference between these two conditions. And the main one is that endometriosis tissue is found throughout the body. We've found endometriosis tissue in people's noses, in knee gaps, in the spine. You can find a case study online. That surgeons are reporting they found endometrial tissue all over the body. But that is not the case with adenomyosis. And adenomyosis lesion tissue is only found localized in the uterus. That is a very specific distinction that we need to understand. So endometriosis tissue is found all over the body. Adenomyosis is only localized in the myometrium of your uterus. And another difference that we see associated with endometriosis and adenomyosis is that generally we know that endometriosis is a estrogen dominant condition, though a systemic estrogen dominant condition, which means that we have a genetic predisposition, which means we produce far more estrogen in our ovulatory state. Or our bodies receptors are really, really, really sensitive to that estrogen. Maybe we don't have lots of good clearance in our liver. So our liver gets red rid of estrogen and it metabolizes estrogen and it's phase one and phase two. Maybe we have something in the gut, which means we're taking previously digested estrogen, we're turning it back on or we're popping it back into circulation generally with women with endometriosis. It's a mix of those. It's not generally ever one. We see that with women with adenomyosis who also have endometriosis, but we don't find that with women who don't have endometriosis and they do have endodenomyosis, but we still do understand that adenomyosis is an estrogen dominant condition, but not in the way that endometriosis is. Endometriosis is systemic. Adenomyosis is localized and this is really confusing for doctors and for GPs and specialists, but they're getting better at it. I will give them that. What we do see with adenomyosis and its pathophysiology is that we have a lot of estrogen localized in the area of the pelvis and we don't see it throughout the entire body. It's not systemic, it's localized. So in that area of your pelvis, you might be releasing more excess estrogen, your cells in the area of your myometrium and your endometrium, they might be more sensitive to estrogen and we can also have upregulated aroma taste activity here, which takes other hormones like testosterone and turns it into estrogen. But when we draw labs from someone with adenomyosis, they might have completely normal circulating estradiol, so your E2 levels and progesterone levels. And so your GP goes, your labs look fine, even though you're in excruciating pain. And so that explains why, but if we took a piece of tissue from your myometrium that had adenomyosis in it, then we would find a higher amounts of estrogen. Back up and talk about the technical definition of adenomyosis now that you understand all of that background information. This was formulated by bird and colleagues in 1972. The gold standard definition is the benign invasion of the endometrium into the myometrium, producing a diffusely enlarged uterus, with which microscopically exhibits a topic and non-neoplastic endometrial glands and stroma surrounded by hypertrophic and hyperplastic myometrium. And that basically means a really inflamed myometrium. That is been basically infected and taken over by the endometrium. And that is having an enlarging inflammatory response in the myometrium. And it decreases the efficacy of that muscle tissue working effectively. Let's break that down a little bit more. So, ectopic means in the wrong place. So ectopic pregnancy is an implantation in the flopian tube. So that is a pregnancy that has occurred in the wrong place. And that has negative outcomes. So, ectopic in this explanation basically means we have the endometrium growing in the wrong place in the myometrium, in the muscle tissue of the uterus. Neoplastic means not cancerous. So that's great. It's not cancerous. Hypertrophic and hyperplastic means the surrounding muscle is both enlarging and multiplying in response to the invasion. The muscle is literally reacting to the tissue inside of it. So it's saying, "Okay, well, this tissue is an effective so I need to make more." I have a friend who has adenomyosis and her IVF doctor very rudely said that she has a fat uterus and that's how she knew she had adenomyosis. And crucially, we need to understand this. It's specifically in the deepest layer of the uterine lining called the bassa-lius layer that does the invading. This is important because the bassa-lius doesn't shed during your period. It's permanent regenerative base layers and it's a layer that pushes through the boundary into the muscle wall. And there are two different types of adenomyosis we need to talk about. Diffuse and focal. And these two main forms behave pretty differently. Diffuse adenomyosis is the ectopic tissue that is scattered throughout the entire myometrium. The uterus becomes globally enlarged, heavy, and what clinicians say boggy, or in my previous story, fat, which is rude, it loses its firmness. More common in women who have uterine procedures like DNC, so a DNC is a pregnancy termination. That is surgical. So going in there, removing the fetal tissue, or cesarean sections in older women, fortuorize from the lining, pushing inward through a weakened boundary inside the outside. And so to simplify that, with this type of adenomyosis, we have damage in the internal wall of the uterus, and that may have created an area for adenomyosis to form, if that makes any sense. And so that is with surgeries, cesarean section, and sometimes birth as well. The next type is focal adenomyosis. It's also called adenomyoma. It's a well-defined mass of ectopic tissue confined in one area of the muscle. It looks almost identical to a fibroid on imaging, which is one reason why it gets missed so often. And it's far more common in women who are younger, who have never been pregnant before. And it is strongly linked with deep, infiltrating endometriosis. It's thought to arise from outward inward. So endometriosis nodules on the outer surface of the uterus that migrate inward. So diffuse is something that's happened on the inside of your uterus, so the endometrial lining side. So we've had a termination. we've had a pregnancy, we've had a C section, or maybe nothing has happened there. Maybe we've had a tiny little infection, and that's created an opening, possibly. That's one of the theories that we have for there to be adenomyosis. And diffuse means it's throughout the entire uterus. But focal is we're only seeing in one area. The tissue looks very similar to a fibroid, and it is highly associated with women who have endometriosis, they haven't been pregnant before. So that we have these two different arms that you can fall into with adenomyosis. So from the University of Paris, they published a landmark classification in 2017 dividing adenomyosis into intrinsic, involving inner myometrium with a disturbed junctional zone associated with prior surgery and heavy bleeding and extrinsic, which involves the outer myometrium with an often intact junctional zone, strongly linked to endometriosis and younger, non-pregnant patients, so women who have never, so women who have never been pregnant, never had a baby. A 2025 meta-analysis found roughly comparable prevalence between the two types. Focal at 17% and diffuse at 15% across eight major studies. So hopefully you understand that. I know it's a lot of information for you to categorize and remember, but that's what we need to remember when we're talking about adenomyosis. There are two very distinct types, and you will fall into one of them. And I think most women listening to this, if you have been diagnosed with adenomyosis, hopefully you've been explaining these two types, and your doctorate specialist has been able to explain that to you and which one you fall into and why. On the chances that they haven't hopefully, just from listening to this, you probably know which one you sit in, because hopefully you've seen your MRI or your trans-vaginal ultrasound results and you can see whether it is just adenomyosis everywhere and you've had babies and it's coming from the inside out or whether it is a singular big tissue that looks like a fibroid, but it's not. You also might have endometriosis, that's deep. Ones for trading, you might have not had a baby yet and it's coming from the outside in. Bueno, okay. I was talking about the relationship with endometriosis before, but let's go a little bit deeper. And again, I want to bridge these two conditions, but we do not ever want to conflate them. They are two very distinct diseases and conditions. Therda, Therda, cool. Both conditions involve endometrial type tissue growing where it shouldn't. Both are estrogen-dependent, chronic inflammatory diseases, both share progesterone resistance, aromatase over expression. So aromatase is an enzyme that turns testosterone into estrogen. If we have too much of that, we're taking all of our testosterone and turning it into estrogen. Abnormal angiogenesis and critically share genetic mutations. Again, the key difference is location. Endometriosis lives outside of the uterus and it can appear on the ovaries bowel everywhere where adenomyosis lives inside the uterine wall, the same tissue and it has completely different addresses in the body. As I said before, curricurance rates are very significantly high. So professor Chaparons studied from 2017. They found that 96% of patients with outer myometrial adenomyosis also had endometriosis. Across the broader populations, around 30 to 40% of women with endometriosis also have adenomyosis. That's a lot of different ways with statistics to say, very high likelihood if you have endometriosis, you have adenomyosis and vice versa. In 2013, researchers from Northwestern University in Chicago led by professor Surtur Boulien. They found infertility and sterility having extremely similar pathophysiology, sharing somatic mutations, particularly in these KRAS genes gene. Going on from this, a 2019 study published in Nature Communications made a groundbreaking finding. Identical KRAS mutations found in the endometrium and adjacent adenomiotic lesions within the same uterus. Let's simplify that. So they found in women who had endometrial tissue and adenomyosis tissue, they had the exact same mutation in the KRAS gene. And so this is really, really important because this provides direct molecular evidence that ectopic tissue originates from the permanent base layer of the uterine lining. But they are not the same disease. Same mutation, different diseases, different locations. So we have the same mutation in different cells. So we have to remember that a lot of people might have done human biology. Remember you're in year 10, you do human biology and you're just given this blob of a cell and they're like, find the ribosome, where's the nucleus, where's the membrane, where's the goalkeeper, where's all the shit in this cell, basically? I want you to understand that that cell doesn't actually exist in human biology. There is no cell that is exactly the same. The cell in your myometrium and the cell in your endometrium are very different. So they can have the same, all cells in your body have the same genes, but it's what genes are expressed. That gives that cell its unique job and appearance. So a muscle cell is really long. They have all these myo and actin filaments, right? That will pull and push together. The cell in your eye has photo receptors. But all of your cells in the body have these exact same blueprint in your DNA on those chromosomes, but how they are expressed is different. We have cells that are very, very different and they have the same mutation and they're being expressed so that gene mutations being expressed and that's having a negative outcome on the body in different ways. A denomiotosis is invisible at the proscopy. You can't see it during surgical investigation that catches endometriosis because it's hidden in the muscle wall. This means that women can undergo surgery for pelvic pain, be told everything looks fine and still have significant adenomiotosis that was never detected. And this is really interesting because this morning I was having my little doom scroll and I saw this video of a woman in tears in her bed with all of the classic leproscopy incisions on her stomach and the caption said that she's went through this long journey to have endometriosis diagnosed and she had the leproscopy and nothing came up so they didn't find anything. So the chances of that woman having adenomiotosis probably pretty high. You might be thinking at this point, okay, the cross-gain really interesting. What's the actual origin story of adenomiotosis and this conversation in the scientific community at the moment is a huge bone of contention and my answer to this question really is we need far more research but I'm going to give you some answers from the research and theories that we do have at the moment. The first hypothesis we have is the TIA hypothesis. The TIA hypothesis. For short, this is the pro. This hypothesis is being proposed from Dr. Leiden Decker in Germany. TIA stands for tissue injury and repair theory. So the theory is the uterus generates specialised contraction waves originating from its innermost layer, the junctional zone. In adenomiotosis these waves become excessive, disordered and each wave causes microchroma in the endometrial, myometrial boundary. And this microchroma triggers a wound healing cascade involving CRH. So this is corticotropin releasing hormone and ACTH and cortisol. These are all stress hormones and inflammatory hormones. This cascade of events also activates local aromatase enzyme production, which converts androgens like testosterone into estrogen and right there in the uterine tissue. So this goes back to your labs to be completely fine. But this theory is saying if we have myometrial muscle contractions that are excessive and uncorordinated and causing trauma at that site between our myometrium and our endometrium, then this could cause trauma here. And then this is creating a cascade of events that formulate adenomiotosis. Going on from this, more local estrogen drives more uterine contractions through which causes more micro injury, which triggers more repair, which makes more estrogen. And this creates its own perpetuating feedback loop that makes it worse and worse and worse. We also have another hypothesis or theory called the EMID. This stands for endometrial myometrial interface destruction. And this is proposed by Dr. Sunway Gough in colleagues at Fudan University in Shanghai. And this was published in 2020. And they focus on injury that occurred from possible terminations, pregnancies, births, and other pelvic surgeries, like cesarean sections, for example. And how this creates a destruction in the boundary between the myometrium, so your muscle tissue and the endometrium. And this creates a cascade. So the physical destruction creates localized tissue hypoxia, so that's oxygen deprivation. So tissue needs oxygen to survive. So when we create incisions, maybe that's created a bit of damage in that area that the body can't get to and oxygenate. And so that's created localized tissue hypoxia. And that activates the HIV1 alpha. This is a hypoxia sensor protein. And that up regulates a rheumatase. And that turns more testosterone into estrogen. And that aggravates platelet aggregation and activation. That exacerbates a wound healing response. And that displaces the bachelors endometrial cells and that survive and establishes themselves in the endometrial wall. Basically, what that means is their theory is, OK, Dr. Gurnard, very interesting. What if we take into account terminations, pregnancy, c-sections, and surgeries that might have caused damage in the wall of the myometrium and the endometrium. And that's created an adverse wound healing environment that doesn't have enough oxygen. And that's created this perfect cascade of events for a denomiosis to formulate. The interesting thing about this hypothesis is that it has been experimentally validated in mouse models. So they took mice and they induced adenomyosis. In 83 to 100% of the mice, when the endometrial, myometrial interface was deliberately disrupted, they found that these mice developed adenomyosis. Pretty cruel, pretty horrible. Now studies pretty yikes, but this is experimental reproducibility is really, really significant. That their findings are significant here. We have to say, it also explains the really strong epidemiological link that we have between prior uterine procedures and adenomyosis risk, which no other theory accounts for as cleanly. So this is the cleanest, most observed theory that we have for the development of adenomyosis, but it doesn't explain for the women who have never given birth, never had surgery, et cetera. There's another theory called the outside to inside theory that was proposed by Professor Charles Capron at the University of Paris in 2017. And so this explains the focal and extrinsic adenomyosis specifically. So deep, infiltrant endometriosis nodules on the outer surface of the uterus migrate inward through serosal service into the outer myometrium. And this explains that these women might not just have a molecular mechanism at play here, but a physical one as well. But kind of the same theory as the previous theory we spoke about, what about if we have a tissue obstruction in the area of the uterus that creates the perfect environment for adenomyosis to form, that kind of goes on from that, but it's looking at endometrial tissue infiltrating from the outside in. There's also the embryonic origin theory. This explains that misplaced embryonic pluripotent cells, so remnants from the mullery and ducts from the uterus during fetal development are already present within the myometrium from birth. They later differentiate into endometrial glands and stroma under hormonal influence. This is supported by cases of adenomyosis in adolescents who have had no prior pregnancy and no prior uterine procedures. And finally, our last theory for the origin of adenomyosis is the stem cell theory. So multipotent adult endometrial stem or progenitor cells undergo unregulated proliferation beyond endometrial myometrial boundary. So that basically means we have some cells in the endometrium that might be proliferating at a rate that is unregulated and it starts to cross the bounds from the endometrium to the myometrium. So this is an insight to out kind of theory around adenomyosis. So there's all theories. One of them has been proven in mouse studies. None of them have been proven in women. You know, it's, I don't know how we can prove any of these theories in women. I'm not a researcher. I'm sure they're really interesting and ethical ways that we can do that in vitro. So taking uterine tissue and myometrial tissue and looking through microscopes and applying adenomyosis tissue or creating wounds or something else that we can test these theories and prove these theories, but it's really important that we look into them. And I think the other thing that's really interesting about all of these theories is that they're kind of all going in the same tangent, but they're looking at different elements of it. There is a Zen Buddhist understanding of the truth and how everyone grasps a different part of it. I was told this story as a young girl where we have five blind monks. One of them has the trunk. One of them has a foot. One of them has the tail. One of them has the ear and one of them has the body. And each of them are going to have a very different story to tell. One will say it's hairy and thin. One will say it's really strong and large and bulbous. So the foot. One will say it's flexible and mid-sized, but quite strong. One will say it's flimsy and thin and large. And all of them are true, but all of them are picking up different elements of the truth. And I think that's what all of these different theories are representing really is different elements of and theorizing what could have caused and what is the origin of a denomiosis. It's really interesting research. And I'm really grateful for these researchers for doing what they're doing. As we were speaking about previously, getting a diagnosis for a denomiosis required something pretty significant, losing your reproductive organs. Because the only way to examine the reproductive organs and your uterine tissue was to take it out, put it under a microscope, and then diagnose you. The classic histopathological definition, defined by Bird and his colleagues in 1972 as endometrial glands and stroma to be present at at least 2.5 millimeters below the endometrial myometrial junction in the muscle wall. Some pathologists use four millimeters, others require involvement of more than 25% of the myometrial thickness. And so this lack of standardization still causes problems today. So basically, everyone's using different metrics. It's not really great. I think we do need to come up with a standardized definition and diagnosis of what is adenomiosis and what isn't. I personally favor the percentage because what we know from this podcast sofa is that adenomiosis can thicken the wall because the myometrium reacts to the adenomiosis in a way that creates more muscle tissue. So what happens if we have a woman that has only been exposed to adenomiosis for five years in comparison to one who's been exposed to it for 25 years, we can probably guess that that woman who's had adenomiosis for longer probably has a larger uterus, right? So inflammation makes the uterus larger and boggy, right? We're using the four millimeter mark really work for both of these women. Probably not. Will a percentage work? Yes, I would say so. But there's probably problems with that metric as well, but I think everyone needs to get together and decide. But in order to do that, we need more far more research. So because endenomiosis was only studied in hysterectomy specimens, it was framed as a disease of the older woman in their 40s simply because those were the women who were getting hysterectomies. The entire evidence base was built on a biased sample and this bias is still today, shaping clinical training, patient dismissal and research investment for decades. But it's not like that anymore. We now have an imaging revolution with come a really long way with MRIs and trans-vegenal ultrasounds. In 1987, who landmark MRI studies by Tongashi and colleagues in Japan and marking colleagues in the US, demonstrated for the first time that MRI could identify adenomiosis in living women without requiring surgery. And this at the time was genuinely revolutionary. In 2015, Muser consensus, so the morphological uterus sonographic assessment was published by Van Den Bosch and colleagues in the ultrasound, an obstetrics and gynecology. This was the first standardized terminology for describing adenomiosis on trans-vegenal ultrasounds. And it changed what ultrasound could diagnose. I have to say though, pretty big gap between 1987 and 2015. You guys couldn't get together faster, no? Okay, let's find. In 2022, they revised the Muser definitions via modified delphi process. It's a formal expert consensus in methodology and this introduced the critical distinction between direct and indirect ultrasound features. And the paradigm shift also happened shortly after this. Adenomiosis can now be diagnosed in living women who want to preserve their uterus at any age, non-invasively. This is a huge, enormous deal. So what is a sonographer looking for when they're looking at a woman that possibly has adenomiosis? Number one is myometrial cysts. A small fluid filled space within the muscle wall. These are dilated, ectopic, and dematerial glands. This is the most specific feature on ultrasound. If you see this, you're most likely looking at adenomiosis. The second is hyperecogenic islands. These are bright spots within the muscle wall representing ectopic endometrial tissue. Remember, ectopic means it's not supposed to be there. So endometrial tissue inside of the myometrium that's not supposed to be there. It's the most sensitive direct feature and its sensitivity is approximately 69%. And there are some other indirect features that your sonographer might pick up as well. And these are generally how your myometrium is reacting to the adenomiosis. So number one is the muscle looks disorganized and non-uniform. This is the single most sensitive overall feature for adenomiosis. Acoustic shadows rating it in a fan or ray pattern from the endometrium into the muscle. We generally also see a asymmetric myometrial thickening. So one uterine wall is significantly thicker than any other. Usually in the posterior wall. So posterior means behind. So this is the uterine wall that's closest to your spine. The uterus becomes round and spherical rather than its uniform normal hair shape. So generally we see a uterus is kind of top heavy and it's lighter down the bottom because it cinches in and your cervix is smaller than the top of your uterus. So generally we start to see a sphere or an oval shape instead of a pair. Obviously it's going to be that irregular junctional zone. So the junctional zone, remember, is inside of your uterus. So it's that junction between the muscle tissue, your myometrium and your endometrium. So if we see a bit of a blur here, that's pretty obviously going to be adenomiosis. Alongside this, trans-lisional vascularity. So this is blood vessels running through the lesion on a Doppler ultrasound. And so this helps differentiate adenomiosis from fibroids where blood flow runs around the outside edge of the lesion rather than through it. And so this is really important to know. I'm going to read this out again because a lot of the time that women go in and have an ultrasound or an MRI, they're just told they have fibroids and they might be fibroids that but also might just be adenomiosis. So I'm going to read that out again. Trans-lisional vascularity. Blood vessels running through the lesion on Doppler ultrasound. That helps differentiate adenomiosis from fibroids where blood flow runs around from the outside edge of the lesion rather than going through it. It's really important to remember, ladies, if your synographer is like, oh, okay, that's a fibroid. I want you to ask, is there, any translational vascularity that you can pick up on a Doppler ultrasound. Yeah, okay, cool. So that is ultrasound. You're so clever going in with all of that information. Let's talk about MRIs. Number one, the junctional zone thickening 12 millimeters or more on a T2 weighted MRI image is the most established criterion that we have for a denomiosis using MRI as a diagnostic tool. A junctional zone under eight millimeters generally allows exclusion of a denomiosis. If your junctional zone is under eight millimeters, you might not have a denomiosis. It could be something else. Overall, we find the MRI performs with its sensitivity at 78 to 88%. So it's pretty accurate in finding a denomiosis when the healthcare specialist knows how to use that technology. Notice how to read through the imaging, which they're highly trained. I'm sure they know how to do it. So what happens if you go through all of this and you're told that you don't have a denomiosis, but you still think you might have it. Number one, operator dependency. So ultrasound diagnosis is only as good as the person performing it. Most general stenographers and gynecologists have not received specific training in a denomiosis ultrasound features. So when you're on the phone to your practitioner, healthcare professional clinic, blah, blah, blah, blah. I want you to ask, is the synographer, organicologist trained specifically in a denomiosis diagnosis through ultrasound or MRI? Yeah, that's a good one to ask. That's a yes or no. There is no gray in that. They've either been trained or they haven't. And if you can't get a clear answer, take that as a no. You know, that's an email. You know, of course, these people are really, really busy. Get them to email you back and say, I'd love to know and ask for the piece of paper that says that they have done that training. You don't want to pay for a treatment and a diagnosis where they actually haven't done that training, right? So it's pretty easy to do Google a bunch of people, gynecologist and stenographers in your area call the mall up, email the mall up. Have you been trained in this? Yes or no. Number two is fibroid confusion. I just spoke about this before. Adenomiosis and fibroids frequently coexist. They cause similar symptoms like heavy bleeding pain in large uterus and they look very familiar on basic scans, differentiating between them requires expertise and knowledge of specific imaging features. So again, going back to what I said before about the translational vascularity might go back a few times, write that one down. Okay. Number three is symptom normalization. Sevilla period pain and heavy bleeding are routinely dismissed as normal. Dr. Hetchman in Australia has spoken about this in her clinical work. Women are told their experience is just being a part of being a woman. It is not number four. No blood test exists at the moment for the diagnosis of adenomiosis. There is no validated biomarker for it. You cannot order a blood test that will validate it. And number five, it's invisible on a laproscopy. So adenomiosis sits inside of the muscle wall. It is not visible at the surgical investigation that catches endometriosis. Let's go through the symptom profile. I'm sorry we didn't do this earlier. I didn't realize it was so far down in my notes. I digress. Number one is heavy menstrual bleeding. It's the most prominent symptom. Flooding, large clots soaking through protection. Your ear is lasting longer than normal. Menorrhea. So severe, progressive, worsening period pain. And it often does not respond to over the counter pain relief. Approximately 20% of adenomiosis patients have dysmenorrhea that is specifically refractory to NSAIDs. So these are non-inflammatory aids. So your neurofin, your ibuprofen. Chronic pelvic pain. So non-cyclicle constant discomfort that is not limited to a period. And so that is one of the main distinctions we have between endometriosis and also adenomiosis to a centigree. Women who have stage one or stage two endometriosis will generally have pain leading up to your own lap period. Women with the latest stages of endometriosis have pain all the time. Women with adenomiosis have pain all the time. They have pelvic discomfort all of the time. It is not localized to any part of their cycle. Alongside this pain during sexual intercourse and when you're pain, pain when you're going to the bathroom and passing stool, pain when you stand up, pain when you sit in a certain way. This just pain. This just constant pain. Subfatility and infertility. And this is because the endometrium is basically invading the myometrium and that negatively impacts fertility. We will talk about that soon. This is really important to say though that sometimes women are completely asymptomatic. Approximately 30% of women with adenomiosis do not have any symptoms at all. The disease is silent and they may be diagnosed incidentally when imaging is performed for another reason or they have a hysterectomy. Right? And that's pretty interesting because we do have research that shows that most women have endometrial tissue that grows outside of uterus but the difference between a woman who has endometriosis and a woman who doesn't is that their immune system can clean it up and get rid of it and put it back in its place really quickly. Whereas women with endometriosis have a immune system that's gone haywire and cannot get rid of endometrial lesions and they continue to grow and they just generally have an inflammatory environment and a more hyperestrogenic environment that is conducive to further endometrial growth. But sometimes women with adenomiosis just don't have any symptoms. Talking about fertility, there is something called the JZ fertility predictor. So this is the junctional zone. Remember that zone between your myometrium and your endometrium. Researchers have found that the junctional zone average exceeding 7 millimeters with a maximum exceeding 10 millimeters predicts implantation failure in IVF with a 95.8% accuracy. So what does that mean in English? So if your junctional zone is 7 to 10 millimeters wide or exceeds it, then your chances of having implantation failure with IVF specifically is 95.8. I don't know any research that speaks about junctional zone fertility prediction in association with natural conception. I guess that's kind of hard to predict and study. I'll be it not impossible. This means that finding an MRI or an ultrasound could tell you even before you start an IVF cycle. That implantation is extremely unlikely without intervention and yet this is not routinely measured in most fertility clinics. So if you have the symptoms that we just spoke about heavy bleeding, dysmenorrhea, chronic pelvic pain, pain during sex, during pooing, during wing, etc. If you've tried falling pregnant for a few years and you haven't fallen pregnant, I would definitely present to a clinic with a sonographer and MRI, a clinician who knows how to work that machinery and technology to find and treat adenomyosis and rule it out. Because otherwise you are going to spend thousands of dollars on IVF that was never going to be effective. I have a whole episode with Dr. Rebecca McKenzie Proctor, an amazing IVF clinician and gynecologist, no BGYN, love her. She talks all about it and she says, and I quote, "It doesn't matter how many IVF cycles I give you, it doesn't matter how many healthy embryos we have. If your body and your uterus is not hospitable to pregnancy, it's not going to do any good. So it's actually better for us to figure out what's going on and get the foundations of your health good before we fall pregnant." And I think that's almost the antithesis of IVF in a way and how it works as a dare I say multi-billion-dollar industry. You know, there's a lot of impetus for IVF doctors to just put you through another round, another round, another round, another round and not actually investigate what's going on. Okay, you could have the healthiest embryos in the world. I'm sure your genetics are absolutely fabulous and your partner's great, right? But if you have a denomiosis, the chances of miscarriage with IVF are almost 100%. So it's worth looking into. I spoke about this a little bit before and the difference between endometriosis and adenomiosis and the main difference that we know between them is localization versus systemic. So endometriosis is systemic, it affects the entire body and we generally see that the entire body is hyperestrogenic. If we look at a blood result from a woman who has endometriosis, it's very, very likely that her E2, her estradiol levels are going to be through the roof. But if we look at someone's blood results and they have adenomiosis, it might not be that way. Their E2 could be normal, they could have fairly normal progesterone and that's the clinical distinction we have here. Is that hyperestrogen is localized in adenomiosis? Here's one of the mechanisms we know about. We have spoken about a few of them, but let's introduce a few more. There's an enzyme called the CYP19a1. This is also known as aromatase. I did mention this before and it is highly expressed in adenomiotric tissue. And its job is to convert androgens like testosterone into estradiol. The interesting thing about aromatase here is that generally we don't really ever find aromatase in muscle tissue. It's kind of weird that it's in muscle tissue and that's one of the diagnostic criteria that we have. If we find aromatase in endometrial tissue and myometrial tissue more specifically, we know that there's going to be a lot of dysfunction here because we don't really ever find it there. Which means its presence is pathological. So it causes problems. Simultaneously, the enzyme that normally inactivates estrogen in the uterus is called HD17B2 or 17 beta hydroxy steroid dehydrogenase. Whenever you hear dehydrogenase, it breaks the hormone apart. So this enzyme, its whole job is to find excess estrogen and say I'm going to get rid of the, I'm going to digest you, put you into circulation because we don't actually need too much of the around here. But in women who have adenomiosis, we see in the tissue that they don't have enough of this enzyme. So it means that we have a lot of aromatase in an area it shouldn't be turning testosterone and androgens generally into estrogen. And then the enzyme that we generally see in tissue to turn estrogen into non potent form and non active form is inactive and we don't see a lot of it around here. So we have a localized hyperestrogenic environment. So putting that simply, estrogen is being manufactured too much by a rheumatase and we don't actually have the enzyme to get rid of it properly. So this is why in adenomiotic tissue is swimming in estrogen that it is made for itself that makes the condition worse while circulating estrogen levels in your bloodstream are completely normal. This is why when I talk about adenomiosis I don't ever really talk about estrogen dominance because estrogen dominance is a systematic issue from multiple different standpoints but in adenomiosis it's very very localized. You can get rid of all of the estrogen circulating in your body and it might have a little bit of an impact on the local environment in the Miami-Trium but overarchingly it's not going to have that much of an effect and it might actually negatively impact the rest of the body because estrogen isn't evil, okay? It's not an evil, horrible hormone, it's amazing. We need it. There's a reason why women postmenopausally will have HRT and will introduce it synthetically in their biology because it's wonderful but in this instance too much of it can be really really problematic. Alongside this as well what researchers have found in adenomiosis tissue is that number one we have lots of aromatase making lots of estrogen from testosterone and we don't have enough of this dehydrogenase enzyme that's getting rid of that excess estrogen and also the receptors that receive estrogen are really really sensitive to that estrogen which means that these receptors are having up regulated ability to respond to estrogen. So all three receptor types that we know of for estrogen ESL1, ESR2 and GPER are expressed at significantly higher levels in adenomiosis than in the normal Miami-Trium. So in layamans terms when we look at biometrial tissue in women who don't have adenomiosis they have a normal amount of receptor proteins there. For ESR1, ESR2 and GPER, okay, normal amounts but when we look in biometrial tissue from women who do have adenomiosis what we find is that we have far more of these receptors. So we have maybe even if we theoretically have a localized environment that has a normal amount of estrogen with women someone who has adenomiosis they still have more receptors which means that that same amount of estrogen can attach to more receptor sites and they can have a more profound estrogenic effect in the local area. ESR2 is particularly striking so it's barely detectable in normal Miami-Trium in normal women who don't have adenomiosis yet it is strongly expressed in adenomiotic glands and stroma. So the disease has essentially created a tissue that barely responds to estrogen before has now transformed it into one that is really hypersensitive to it and so erometase is elevated at both the gene level and also in the protein level and so this elevation is confirmed in multiple studies and you might be thinking how can this happen what we do know is that erometase can get switched on by a gene called NR5A1. This is also known as stereodotic factor one or SF1 so let's use SF1 for short. This is normally silenced by DNA methylation in healthy endometrioms but in when we look at adenomiosis stromal cells NR5A1 becomes D methylated so we removing the methyl group from it. So when we add or remove methyl groups we're activating it or deactivating it and this case what we're seeing is that NR51 becomes D methylated and therefore it's active and once it's active it attaches to a aromitase and it turns the aromitase gene on so it's more active and it turns on its ability to take all of this androgen in the body like testosterone and turn it into estrogen. Hopefully you followed that I know it can be a little bit confusing. Okay so let's put everything that we've learnt today together and I just want to say as well everything we know so far there is solid science but there's also a mix of theory so this is just what we know. I might come back to this in like five years and say oh I was wrong about this I was wrong about this I was wrong about this so if you ever find new research that competes with or is in direct affliction with what I'm saying on this podcast please let me know about that research I would love to know I'm just reporting on what we know so far I digress. Let's talk about the precise sequence that formulates adenomiosis so number one injury at the junctional zone so prior surgery other initiating event it could be that theory where we're seeing really disorganized intense contraction that can cause injury at the myometrial junction. This triggers a release of inflammatory cytokines that's activated by white blood cells and immune cells at the side of damage so this up regulates a key enzyme in prostaglandin synthesis which is associated with contraction of the cell. Then going on from that we're seeing the PGE2 so that's a prostaglandin turns on the aromatase gene and transcription through specific molecular pathways specifically the PGE2 to cyclic AMP also known as CAMP protein kinase A and this activates the transcription factor SF1 and that binds to aromatase promoters that expresses aromatase and that increases local estradiol production step four. Going on from that more local estradiol drives increased ERB expression so that's the receptor for estrogen and alongside this with the upregulation of that receptor we're decreasing progesterone receptors and we're seeing more progesterone resistance so that's happened next we have local estradiol upregulates oxytocin receptors on myometrial cells and that creates more oxytocin receptors which creates more responsiveness to oxytocin and that increases more distorted uterine contractions if you didn't know oxytocin is a hormone originating from our brain and it organizes contractions in uterus oxytocin is really really important in childbirth and also during your period when we are contracting the uterus in rhythmic it's supposed to be rhythmic it's supposed to be coordinated events that opens up your cervix and sloths out the endometrial lining but what we're seeing here is we're seeing all of these events happen so we might have had already maybe we had some oxytocin problems or maybe we already had a tissue injury that's created more inflammation white blood cells present that has created an environment where creating more estradiol more estradiol is creating more oxytocin and that oxytocin means we're creating more receptors for that oxytocin and that oxytocin means that we have more and more uncoordinated strong painful contractions in the uterus and that creates more junctional zone injury so that means more inflammatory markers like C.R.P. and macrophages and other white blood cells and we can go back to step two right so the cycle perpetuates itself this disease is not simply something that develops and then stays the same it is living it is breathing it is developing and it generally worsens over time it actively maintains and expands itself through its own inflammatory output and inputs I spoke about prostate glandans before and I think it's really important that you know a little bit more about them so they are the clinical drivers of pain and bleeding so COX2 is significantly upregulated so this enzyme drives the overproduction of prostate glandans that cause the most severe symptoms there are lots of different types of prostate glandans okay we don't want to demonize prostate glandans generally prostate glandans are a peptide that lives in your pelvis and it is either made from omega-6s or omega-3s so it has an omega-6 or omega-3 backbone and what we generally find is the ones with omega-6 backbones generally make the uterus contract in an un-rhythmic non-coordinated very painful fashion and so that's why we know that women who have a dietary intake of more omega-6s generally from really processed ultra-processed food will have more painful periods because of that over production of that really nasty prostate glandan in comparison to other prostate glandans that have omega-3 backbone that seem to create more of a harmonious contraction environment so they're more efficient so we actually get the endometrium out in a more orderly fashion and they don't over contract the uterus in a way that causes more pain. PGE2 is a prostate glandan as we described above as I described before it's both a product of the inflammatory cascade and it's also a driver of aromatase so it turns on aromatase it's pro-inflammatory pro-proliferative and directly drives the self-amplifying cycle there's also something you need to know called the COX2 inhibitor so this has been studied in a denomaiosis and it's been shown to reduce estrogen production fibrosis progression and epithelial to mesenchymal transition so these evidence shows how central COX2 pathways are to the disease alongside this we're generally seeing that a denomaiosis is characterized by a lot of inflammation and when we talk about inflammation I'm not talking about oxidative stress oxidative stress and inflammation of very very different pathways in this though we're seeing the inflammatory micro environment is really rich in cytokines and immune cells and so I just want you to understand immune cells are your white blood cells and they release cytokines that are inflammatory inflammation is a tool used by your immune system JAK2 and stat 3 signaling pathway to promote cell survival and inflammation when we see higher IL-6 we generally see lower IF IVF pregnancy rates and this is direct line from the inflammatory environment to fertility outcomes there is another cytokine here IL-8 this is generally elevated and promotes two key processes so chemotaxis so recruiting more immune cells to the site which means more inflammation and more cytokines and angiogenesis, which stimulates new blood vessel growth to sustain the ectopic tissue. And this helps build the infrastructure the disease needs to survive. There's also TNF alpha, IL-1 beta, TGF beta-1, and CD68 positive macrophages. We also see mass cells appear in the earlier stages of adenomyosis disease progression. We generally see them elevated in what researchers call the transitional lesions that are pre-adenomyotic tissue at the junctional zone, where they release inflammatory mediators, roster glandans, and I did speak about this before, but I think it's really important that we nail it down, because everyone's talking about insulin resistance, everyone's talking about estrogen dominance. The next wave is going to be progesterone resistance. Everyone's going to start talking about this, because that is something that we're seeing more research released on, and more practitioners understanding and putting into their practice. So, look out, I'm calling it. In a year to two years, this is going to be the next thing, is progesterone resistance. So, progesterone functions in a way that counterbalances estradiol. It limits endometrial proliferation, so it slows down the progression of the development of the endometrial lining, so it says, "Hey, hey, hey, we don't need to proliferate this much, okay? We're just going to calm down. We're going to keep everything cool, calm and collected." That's progesterone. It supports proper cell division for implantation. It keeps the inflammatory environment in check, so it's generally anti-inflammatory, so it calms down your immune system a lot. But in a denomiosis, we generally see that progesterone is, we're seeing a progesterone resistant, basically, and that means this counterbalance is completely broken. In a localized area of your myometrium and your endometrium, estrogen just runs wild. She doesn't have her friend with her to say, "Hey, can we go home?" It's 5am in the morning. The town's on fire. That's what progesterone's doing. We don't have that friend around, so estrogen is just running rampant. The specific isoform that's the most deficient here is PGRB. This is a progesterone receptor isoform B. So PGRB is the functional, is the functionally active form that mediates most of progesterone's anti-proliferative effects. So its expression is significantly reduced in adenomiotic stromal cells. What that basically means is progesterone attaches to this receptor, and that receptor creates an environment, and that receptor mediates responses inside of the cell that are anti-androgenic and calm down prolyphrine effects in the endometrium that are going a little bit too far. This is deficiency is epigenetically driven. So DNA methylation and histone modifications at the PRG gene promoter silence its expression in adenomiotic cells. The gene is there, it's just been switched off at the epigenetic level. If you remember before, we're talking about the CRARS mutations that we see in both adenomiotic tissue and also endometriosis tissue. It's found in 37% of adenomiosis cases in the landmark 2019 Nature Communications Study, and it's directly linked to functional progesterone resistance. So CRARS mutant adenomiotic cells show low progesterone receptor expression, and crucially, the most commonly used for progesterone adenomiosis. In CRARS mutant adenomiotic cells, we see generally a low progesterone receptor expression, so we're not, we don't actually see a lot of progesterone receptors being made and expressed at the cell membrane. And so maybe this is what explains for women with adenomiosis, if they're given progesterone, so synthetic progesterone through hormone replacement therapy, they're just not responding to it. It's because the hormones there, it's just we don't actually have receptors to receive the hormone. Another thing that we need to remember alongside this, we spoke about this before, is one of the estrogen receptors ERB, so it's overproduction creates an underproduction of progesterone receptors at the cell membrane site. So the estrogen receptor that is most upregulated in adenomiosis actively dismantles the progesterone receptor. It's almost like adenomiosis as a disease has protected its fuel supply and has gotten rid of the thing that's going to stop its progression, which is progesterone. To pull this all together, all about progesterone resistance, without functioning progesterone receptors, estrogen proliferative effects go unchecked, and the process by which the endometrium prepares for embryo implantation cannot occur properly. Progesterone, pro pregnancy, progesterone, creates an environment in the uterus, and in the endometrium, that is progressive towards the motion of possible pregnancy, if it isn't there, then estrogen actually isn't capable of doing it on her own. Okay, so we've spoken a lot about the pathophysiology of adenomiosis. I could talk about this forever. I think I'm going to write an article and release it on my Patreon and Substalk, so go over there and subscribe to both of those. It's a paid platform because I put a lot of work into these articles, all of the resources of it. I think I will include a lot more. I just feel like I can't talk about too much more here. I feel like it's going to be three to four hours. I probably will include genetic predisposition. I'll include vascular changes and fibrosis, fertility, and a few other things, but I just want to look at treatment options specifically now. So number one is non-hormonal treatments, and the first one is ibuprofen, so NSAIDs. They inhibit Cox-1 and Cox-2 enzymes, and that reduces the prostaglandin synthesis, and therefore uterine contractability and inflammation. So this decreases the pain. So the reality of this is approximately 20% of patients have dysminaria, that is refractory, non-responsive, two NSAIDs. So if you do have a denomiosis, NSAIDs will work 80% of the time, but for 20% of individuals, it will just not work at all. And that's not because you're not taking enough ibuprofen. It's because the disease has generated a prostaglandin load that exceeds what the standard doses are able to suppress. Next, we have trans-examic acids, so this is for controlling the amount of blood you're losing, even hybids that break down of blood clots in the uterine lining, and reduces menstrual blood loss volume. It's more effective than NSAIDs for heavy menstrual bleeding specifically. However, it does not address the underlying disease mechanism. It does not reduce pain, and it has a limited role in a denomiosis management overall. It's really important for women who have a risk of eye-indeficiency inemia, or if you're just hemorrhaging every single time you have a period, this can be really great once you have a period. When you're leading up to your period, and on your period, if you have a really, really heavy bleed, the next is hormonal treatments. If you have a denomiosis, you've been offered the combined oral contraceptive, which is an oral contraceptive that you take every day, and it contains synthetic esteridial and progestin. It suppresses ovulation, things endometrium and reduces estrogen-driven proliferation of ectopic tissue. In a randomized controlled trial directly comparing deenogest to combined oral contraceptives, it showed that deenogest was superior for reducing dysmenorrhea, heavy menstrual bleeding, and uterine volume, and uterine artery blood flow in adenomiosis. The role then for combined oral contraceptives is reasonable starting points for mild symptoms in younger patients who also want contraception. I have to say this. This is from the research I have here. It is not a first-line treatment for moderate to severe adenomiosis. If you have a health care provider that's offering you this, when you're experiencing really severe adenomiosis, it might not be an effective treatment option. I said this before, dynogest, I think a lot of people are like, what is that? It's a synthetic progestin. When we take it two milligrams a day, it is the most studied. It is the most studied oral progestin that we have. At two milligrams, the mechanism is, as a fourth-generation progestin, it's highly selective for progesterone receptors and anti-proliferative, and it basically dampens the effect of ectopic endometrial tissue. In 2017, there was a double-blind, multi-center placebo-controlled trial, and it showed that dynogest in two milligrams daily produces a mean visual analog scale pain reduction of approximately six points on a 10-point scale. In English, that basically means we have women presenting with an 8 out of 10 on the pain scale with adenomiosis, and when they started taking two milligrams of dynogest, their pain went from an 8 to a 2. That's pretty significant. There was greater pain relief in patients with more severe baseline pain, with longer treatment durations. In 37% of patients with the crars mutant adenomiosis, dynogest anti-proliferative effect is specifically diminished due to epigenetic progesterone receptor silencing in the crars mutant cells. This is a potential explanation for non-response to dynogest. 30% of the patients who have adenomiosis, who have this gene mutation, might not respond to this treatment at all because they are resistant to progesterone. So this is what we were talking about before. You can have the progesterone there in the form of dynogest, two milligrams a day, but if you don't have the receptors for progesterone, it's not going to be effective. There are other progesters that you can use as well. Any TA, five milligrams a day, drospirinone, four milligrams a day, does a gestural, which is 75 micrograms a day, can all be used as well. In 2025, there was a long term study released by Vanacucci and colleagues. They followed 140 patients for three years on various different progesters, of which we've just named. And they showed effective long-term symptom control and the value of switching between progesters when one becomes less effective or less tolerated. Another treatment option that is often offered to women with adenomiosis is the marina, and it releases lavender gestural locally into uran cavity. And this induces endometrial atrophy, reduces blood flow, decreases estrogen receptor expression, and these effects extend into the adenomiotic tissue within the muscle, which is really significant, like that's pretty amazing. Carly considered the most effective first-line medical therapy for adenomiosis overall, and it's based on evidence from three of follow-up studies showing significant reductions in both pain and bleeding and measurable reduction in uterine size. The next is GNR H agonis, so GNR H can add a tropin releasing hormone. This is This is a hormone that allows your body to release other sex hormones. So both females and males have it. So this is an agonist though. So we're decreasing the GNAH working in the body, attaching to receptor sites, etc. So a GNAH agonist will down-regulate GNAH receptors in the pituitary gland, and that creates a state of profound pituitary suppression, and that dramatically lowers estrogen and progesterone to surgical metaposal levels. It's important to note here that there is an initial flare effect in the first one to two weeks where estrogen surges before suppression kicks in. So the U-dryne volume in this treatment is reduced on average approximately 311 cubic centimeters to 221 cubic centimeters after three to four months of treatment, and there is significant symptom relief here as well. But the side effects we have to note, when you are on a GNAH receptor agonist, you are basically put into a state of metapos, right? So you're going to have all of the symptoms. So you might have all of the symptoms of metapos, which is hot flashes, vaginal dryness, mood destruction, and critically bone mineral density loss with prolonged use, because estradiol will work with the osteoblast, which are the cells in your bones that create bone mass. So it's not a really great option for long-term treatment. And so that's why it's only given at a duration of six months to met. And it's used strategically in IVF, puts you in a metaposal state to kind of calm down the adenomyosis tissue, and then hopefully that improves your IVF outcomes later on. Again, I know someone who was put on this treatment. There's a newer generation of GNS, GNRH agonists, but these ones are called antagonists. So the key advantages over agonists is oral transmission rather than injections. It's no initial estrogen flares. It's dose dependent on estrogen suppression and it's rapid reversibility when stopped. But again, they're only recommended a six-month period of time. So again, short periods of time these are given, because they have really quite serious negative long-term side effects. Something else that you might be offered is an endometrial ablation. So this destroys the surface uterine lining to a depth approximately of four to six millimeters. And the idea of this is that we're basically removing the layer of adenomyosis tissue. Women within trinzy adenomyosis have a 33% rein-tevention rate following ablation versus 8% in women without adenomyosis. So 33% of women who go through endometrial ablation have to have treatment again later on. Ablation can paradoxically worsen pain by creating scarring that traps the ectopic endometrial glands within the muscle wall, concentrating inflammatory environments, and ablation is not recommended as a primary treatment for known adenomyosis. There's also lots of different surgical techniques that women can use if they want to keep their uterus. They don't want to have a hysterectomy, so the triple flap method, which was developed by Dr. Osada, also known as the Osada technique that involves bisecting the uterus, excising endomiotic tissue from within, and then reconstructing the uterus using overlapping flaps to maximize remaining muscle integrity. And finally, we have hysterectomy. This is the only known cure that we have for adenomyosis, which is the full removal of your reproductive organs. The 2020 Kaiser Permanente U.S. population-based study from 2006 to 2015 found that 82% of women diagnosed with adenomyosis ultimately had a hysterectomy. This is the current standard of care and practice, if not in all of the guidelines that we have. There are emerging interventional treatments, so uterine artery embolism, high intensity focused ultrasounds. There's also novel therapies in the pipeline, because adenomyosis is still burgeoning in the research. It hasn't yet reached my scope, and I don't actually feel comfortable providing any resources on what you can do about it, but I just hoped that this helped you understand the disease, how it progresses, and giving you some little easter eggs on what you can do to diagnose and treat this. Thank you so much for taking the time out of your busy day to listen to this episode. 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