Journal Club Global at 2025 Turkish Society of Reproductive Medicine Meeting

At the Turkish Society of Reproductive Medicine Meeting, with Fertility and Sterility and ASRM, panelists discussed evidence behind an association between endometrial thickness and chance of live birth.

Panelists 

Dr. Baris Ata

Dr. Erkan Kalafat

Dr. Richard Paulson

Dr. Sesh Kamal Sunkara

Dr. Alberto Vairelli

Fertility and Sterility Moderators

Dr. Pau Pirtea

All right, hello everyone. Welcome to Journal Club Global. I'm Rick Paulson, I'm the Editor-in-Chief of FNS Reports, which as you all know is the open access journal of the fertility and sterility family of journals, and it's my pleasure to moderate today's Journal Club Global.

Coming to you here in the audience and our listeners around the world from beautiful Antalya, Turkey, where we are all gathered for the 13th Scientific Meeting of the TSRM, the Turkish Society for Reproductive Medicine. And before we launch into today's topic, I'd like for our distinguished panel to please introduce themselves. So Sesh, if you would start over at that end.

Good morning everyone, and thank you for the introduction to this session. My name is Sesh Sunkara, I'm from King's College, and nice to see you all, and quite a few familiar faces. And my name is Michael Dehaene, I'm an Associate Professor at McGill University.

I'm on the Editorial Board for Fertility and Sterility Science, and the Editor-in-Chief of the journal Clinical and Experimental Obstetrics and Gynecology. I have the headset. So yeah, good morning, or it's still good morning, right? Yeah, good morning.

So I'm Baris Ara, I am an REI practicing in Istanbul and Dubai at the Koch University and IRT Fertility Clinics. Hi everyone, my name is Erkan Kalafat, we have been working with Baris and the Koch University for the last five years. Thank you.

All right, so we're going to get started on today's journal club. The article was chosen for us, and it is out of the September issue of Fertility and Sterility. And as you can see, it is entitled Increasing Endometrial Thickness Up to 12 Millimeters is Associated with Increased Odds of Live Birth Among Fresh and Frozen Thawed Autologous Transfers With or Without Preimplantation Genetic Testing.

The first author is Gingold, and it is from the Department of OBGYN at Albert Einstein College of Medicine in New York. And the topic of endometrial thickness has been a subject of some debate at this meeting, so I think it's lovely that we'll have this opportunity hopefully to be able to wrap it up. So I will do a very brief introduction on the materials and methods of this article.

As you can see, it was a SART course, National Registry, so that means it's a retrospective analysis. The dates included 2016 to 2018, so the data are almost 10 years old, not quite. And you can see they had a huge number, 182,000 patients that did 261 cycles, so that means that each patient may have contributed more than one cycle.

Interestingly, they extracted that data out of a total of 652 cycles that would have been potentially eligible, but what they did is they had to exclude some, as I'll show you in a minute, and 78,000 fresh transfers without PGT were included, 97,000 were frozen thought cycles without PGT, and interestingly, 82,000 plus thousand were frozen thought cycles with PGT, so that makes it kind of an unusual database. All transfers were included, all they excluded were cycles that had missing endometrial thickness or ones that used frozen thought oocytes. The endometrial thickness was categorized, and I want you to remember this because I think this may be relevant to the analysis.

As you can see, they had a category of less than 6 millimeters, then between 6 and 7, 7 and 8, 8 to 12, a rather broad category, and then 12 to 15, and more than 15, and they did something called log binomial regression by generalized estimating equation model, and what that means is that the binomial regression gives you, is applied to a binary outcome, which means pregnant or not pregnant, in this case, live birth versus not live birth, and then it, the regression gives you a relative risk rather than an odds ratio, and the generalized estimating equation is used when the data points are not independent. Like I said, there may be multiple cycles per patient, but again, I want us to keep that in mind because we need to go back as we look at the data, and we wonder how impactful it is as to what kind of statistics were used to try to come up with the conclusions. And they, you test the association between live birth and endometrial thickness, and they use that big fat category between 8 and 12 millimeters as the reference.

Dichotomous variables including smoking status, indication for IVFs with the different diagnostic categories, and then categorical data where age categories that you can see there, the BMI, you see that they had 35 to 40 and greater than 40, that's because it was done in the United States, and then you have continuous variables for FSH, AMH, and the number of oocytes retrieved. So, I'm just going to present the tables real quick. I'm having a very difficult time seeing it from over here, so I'll stand up.

This is supplemental table 2. I thought it was remarkable that when you look on the polycystic ovary diagnosis that it was essentially normally distributed across the thickness of the endometrium. This is contrary to my experience, because in my experience, patients with polycystic ovaries tend to sequester with a thick endometrium and not with a thin endometrium, but that was the way the data came out. Here's demographic information among these participants.

And again, BMI, you can see there's no difference in BMI across the different endometrial thickness. Again, maybe some of us have had the experience where a thicker endometrium is associated with a larger BMI, but that was not the case in this database. And here's the results.

This is the regression curve that they were able to generate, and you can see that the pregnancy rate, the probability of pregnancy, increases with increasing thickness all the way up to about 15 millimeters. This can then be quantified. This is table 1, data on treatment and pregnancy outcomes for each cycle across the participants.

Here's the live birth, and it varies from the thinnest endometrium at 31 percent as compared to 45 percent in the 8 to 12 category. That's the reference, and actually gets up to 46 when you get above 15 millimeters. I thought it was remarkable that the total number of oocytes retrieved in each of these groups is also the same.

So if you think to yourself that endometrium is going to be thicker in somebody who has higher estrogen level, higher estrogen level associated with greater number of oocytes, you would think you would have more oocytes in the thicker endometrium. That was not the case in this case. The number of oocytes is the same across the board.

Table 2, a little busy, but I want to point out again the percentage of live birth, which they reported as 31 percent in the lowest category, and then going up to 45. This is the same data that I showed you in table 1. Here's the relative risk, and this is what I think is kind of remarkable, because they are reporting a 30 percent reduction, only a 0.7 relative risk in terms of pregnancy in the thinnest category. So this would imply a 30 percent contribution to embryo implantation that comes from endometrial receptivity, and when they look at patients that had uterine factors, remember uterine factor, that means that somebody checked the box on the SART reporting data.

So let's remember how the data are collected. Again, a remarkable difference between the thinnest and the thickest endometrium. In table 3, this was again I think part of the unusual nature of this database is that they specifically looked at patients that had pre-implantation genetic testing, and even in those you can see a remarkable difference in the pregnancy rate, the live birth rate, that is to say between the thinnest category, 39.2 percent, which is a 0.72 relative risk.

So 28 percent reduction in the probability of pregnancy with a PGT normal embryo in the patients with the thinnest endometrium. Conclusion. This is right out of the paper, an increasing endometrial thickness up to 12 to 14 millimeters appears to be associated with improved adjusted live birth rates in fresh transfers, frozen thaw transfers, frozen thaw transfers without and with PGT, although an 8 to 12 millimeter thickness is nearly as useful.

And although providers may seek to optimize endometrial thickness in preparation for FET, it remains unclear whether this is an achievable goal or will yield clinical benefits. So now we have the overall, the overview as to what it is, and now we're going to turn to our panel to decide whether this is real or whether this is going to be another example, as I said in my editorial, big data, big lies. So let's begin at the end.

Sush, what do you think? Do you believe it? Do you think this is real? I wouldn't call it big lies. Big data is certainly a strength, but as with any big data, the validity of the results depends upon the quality of the data. And given that this is a national registry, and I've worked with national registries as well, we can see how unreliable the data can be.

So that's something to take into account. Interestingly, as you showed, the various sensitivity of the sub-analysis showed similar trends. That is, increasing thickness increases live birth rates.

So whether it is fresh autologous, that is obviously without PGTA, frozen with or without PGTA, or the uterine factor, they showed all similar trends. This is very different. So after reading this paper, then in clinical practice, how do we translate into clinical practice? Do we have a clear answer about endometrial thickness and embryo transfer? Not really.

Actually, it's giving more confusing out there than giving answers, because only recently in the same journal, Fertility Sterility, a paper by Baris Atta from his team came about, where they transferred a single euploid embryo in frozen embryo transfer cycles, obviously, and they found that the endometrial thickness does not matter. So what do we make out of it? Traditionally, hope I'm not taking too much time, our thinking as physicians is that you aim for about seven to eight millimeters, and you want to go up to that, or maybe plus a few, and then you feel happy, or you feel reassured that this is going to result in a good outcome. If suppose we were having thin endometrium, say less than six centimeters, then we become a little bit anxious, and then we want to wait to see if it thickens, or to cancel it and bring back again.

And also, interestingly, although this paper went up to greater than 15 millimeters, showed that live birth rates are increasing 12 to 14.9, and more than 14.9 as well, there is not a significant increase, more of a plateau, but no decline. But traditionally, we've been thinking that if a very thick endometrium in a frozen cycle or a fresh cycle is not good too, with regards to live birth rates, it decreases live birth rates, and previous studies have shown that. So what do we make out of it? I'm not sure.

So I will, you know, there are other panelists who probably can enlighten. So Michael, the fact that all of these patterns look the same in each of the categories, do you think that's a strength, because it substantiates data, or do you think it's a weakness, that it might be implying that there's some sort of an artifact in the data? Well, you know, first I question if all the patterns look the same, because one of the things I noticed was that in the group that was 15 millimeters or greater, they had, compared to the reference group, an improvement in outcomes in one of the groups, and in the other, no, meaning it's fresh or frozen. Now the question comes up is, what's the biologic mechanism of that? I could believe that linings that were 15 millimeters or greater might hamper pregnancy and live birth, and the reason is that even myself, I once did a study where when we were doing scratch therapy, I sent, that was being done in women that had failed at least two transfers, and I sent the scratch to pathology, and then we did their next cycle without getting the results, and we looked at the pathology results of our scratches and compared them to the previous cycle, and we found that women that had maximum linings of 14 millimeters or greater had a fairly high risk of having an endometrial polyp at about 50%.

So I could understand why, if the lining got thicker, the likelihood of a live birth would go down, but why did it only go down in one of the two groups? That's something I have a little difficulty understanding in terms of the biologic mechanism, but nevertheless, I could believe that as endometrium thickens, you have improvements in your pregnancy outcomes, but the question is, can we modify that really, right? Is it possible that we can fix that in our patients, or is that just where the patient is? Certainly patients with very thin endometriums are more likely to have some type of damage to the endometrium, possibly from previous infections or DNCs, and that that damage might hamper their ability to conceive, but then can we really, do we really believe, is there any evidence that we can improve that by raising estradiol that we give them, or doing a different type of cycle? And it's not clear that that evidence really exists, so I think what we're saying is, this is the situation our patient is in, but we may not be able to make it better. Parish, you have written on this topic, why is this data so different from your study? Regardless of the numbers, can you put my mic on? Regardless of the numbers, it's on. Regardless of the numbers, if it's 200,000 cycles, if it's two million cycles, it's two million cycles.

This is retrospective data, and to be fair, to the authors, if we go through the discussion of the paper, they have a paragraph on it, so it's retrospective data, it does not necessarily demonstrate causality. Okay, so that's the trick, that is the big data, you know, is not necessarily demonstrating causality, and you know, when we refer to big data, big data analysis is always retrospective, right? And why is it different than our findings, whereas, you know, also our two studies were also retrospective, right? One possible explanation, which I don't think is the case, is each study is a random sample, so we revolve around the true effect estimates, right? So in some studies, you may observe something slightly, you know, different than the actual effects, you know, in one direction, in some studies it could be the other direction, but I think the real difference, the real cause of the difference between our findings and most of the retrospective studies, is the differences in practice. So we do not regard endometrium per se as a problem, and once we rule out intra-cavitary pathology, once we rule out premature progesterone exposure, either in the late follicular phase for fresh transfers or in frozen transfers otherwise, then, you know, we keep transferring, and I think that reflects the natural course of events.

So it is ingrained in IVF practice for, like, more than 30 years ago, teen endometrium is a, you know, teen endometrium per se is not as functional as a non-teen endometrium, and people tend to cancel the cycles or start giving additional interventions. And that is prevalent in the U.S., how do I know it, basically? We recently published another retrospective study, again it's retrospective, it is multinational, it included more than 30,000 single-euploid blastocyst transfers, so we had RMA data from U.S., we had EV data from Spain, we had ART data from UAE. And we plotted, we had some graphs, it's in the paper, to see if the prevalence of teen endometrium was different.

In the U.S., teen endometrium in the U.S. data almost did not exist, I mean, like, you know, six millimeter was so, like, maybe one percent, I mean, you know, you remember? In Spain, it appears they put less emphasis on it, it was slightly higher. In our case, it was like seven, eight percent. So the data, as these registries are, the data is collected, is being, you know, practically distorted somehow.

Transfer cancelled, adjuvant given, and it's not criticism, I mean, I'm not saying it's medically wrong, but it's just different. And I guess the teen endometrium that accumulates in data following that type of practice represents transfers, what I can call, out of desperation. So these women should have had prior cycles somehow, and other things might have been tried, etc.

Maybe they have a genuine, you know, pathology. It's not the regular teen endometrium patient. And again, to be fair to the orders, they also mentioned, okay, say, yes, we excluded uterine factor when it was ticked as an indication.

And we assume the patients had, in circulatory pathology, like adhesions, etc., ruled out, because no reasonable physician would have done that transfer, right? But ruling out the existing adhesion is one thing, but you can't rule out a scar or, you know, scarred, I mean, dysfunction, I mean, yeah, exactly, you can't rule out a scarred endometrium. So there might not be any room for further surgical intervention, but your endometrium is already scarred, it is what it is, and that patient, unless it's ticked as uterine factor, wouldn't go into, yeah, would just go into the teen endometrium. And the other thing is, which we didn't put in the paper, because we were not able to collect the indications for hysteroscopy, when we were doing our own study, we tried to retrieve from the electronic medical records, relevant history, like if the patient ever had a myomectomy, I mean, hysteroscopic or otherwise, if the patient had operative hysteroscopy, or hysteroscopy, or he had a history of pregnancy losses, to see, you know, if my, say, theory about this scarred endometrium issue is correct, you would expect teen endometrium having a higher prevalence of higher incidence of these procedures.

And actually, it was the case, but as we couldn't document the indications, we didn't put in the paper, but my impression is in the US data, the teen endometrium category is not the same, it does not include necessarily, it's a subset of patients with teen endometrium in our data. So, Erkan, I think you have some insights as to what might be problem, or some of the confounders with the data. Oh, that's true.

We recently published a new study on this. It was a very large data from RMA New Jersey, from US, Spain, and ART Fertility Clinics in Dubai. And our results may seem to contradict this recently published study, but I don't think that's necessarily the fact.

And I have some points to make, but they would be better if I have some slide decks, if you could open up, thank you. So, this is a synopsis of the study. Richard already summarized the study, so I'm not going to go over it, but I would like to emphasize a point, because this is a point that reviewers give us a lot of feedback, and they don't really let it go, which is the endometrial thickness measurements, and when they are exactly made during the cycle.

So, in this study, it's taken as a convenience measurement, meaning they only took the available measurement closest to the transfer. And whenever we are publishing something, the reviewers actually don't let it go. They want to make sure that we present the data that's actually made at the day of transfer, or closest to it.

And this is the principal findings of the study, and actually, some of these findings back parish up about some potential other problems that the thin endometrium may be indicating, which is, so they did find a positive correlation between the EMT and female age, which is already telling us with thin endometrium, maybe something else is going on with the patients. They have higher rates of previous full-term deliveries in those with thicker endometrium, more good prognosis patients. Higher rates of diminishing ovarian reserve, uterine factors with thin endometrium in this study, which is, again, poor prognosis with thin endometrium.

And finally, they have a higher rate of tubal infertility with higher EMT. So, this is already giving us a picture that the endometrial thickness is maybe indicator of some other factors than endometrial thickness itself. And they actually show that across the spectrum, almost up to the 15 millimeters, the live birth rate is increasing significantly.

So, which is actually makes me curious why they capped it at 12 millimeters at the title, because their analysis actually shows that it goes up until 15 millimeters. And I would like to make a point at this stage, because the factors they adjusted for is age, ovarian reserve, and infertility indications, but they didn't adjust for embryonic quality parameters, which we did in our analysis. And this is our from study, not from the study, but from the study data that I just recently prepared.

And it's showing us the endometrial thickness categories and transferring a grade A ICM embryo. I did a little bit of plot tricks, so the difference looks a little bit more exaggerated than it actually is. In the lowest category, it's 25 percent.

One in four patients have a grade A quality embryo. And when we go up to the 15 millimeters of endometrial thickness, it's almost half of the patients. So, there is a correlation between endometrial thickness and the embryo quality that's being transferred.

So, when you don't adjust for that, maybe the effect comes up with more than, like, you know, it actually is, that maybe can be attributed to the endometrial thickness alone. This is what Baris was talking about. This is the distribution of the endometrial thickness categories in different centers in U.S., Spain, and art fertility.

And art fertility is special among these clinics because they don't necessarily cancel a cycle based on endometrial thickness. And when we look at that at the lower end, the yellow one is the art fertility. So, these lower endometrial thickness categories are more prevalent in a setting where you are transferring regardless of endometrial thickness.

So, what we are doing when we do the cycle cancellation is some sort of an intervention bias. We are taking maybe some of the normal prognosis, borderline patients, and we are pushing them rightwards. And what we are left with in the lower end is those with truly messed up endometriums or some sort of surgical problem with their uterine cavity, which is obviously dragging the live birth rates down.

And do their findings actually contradict ours? Not necessarily. Actually, we did find, for example, in the program cycles, the success is going up even in endometrial thickness categories above 11 millimeters, which was not the case with the modified natural cycles. And there is a distinction I would like to make about, like, you know, is big data lying bigger? Not necessarily, but I would like to make a distinction between observational data and interventional data.

And does this graph that we are seeing that the endometrial thickness is associated with higher live birth, does that mean canceling a cycle, doing some sort of undefined intervention, and transferring a subsequent cycle is better than transferring right alone? These things are, do not, like, you know, they are not the same. They are studied in different study settings, and the right one is studied in a randomized interventional setting. And this is as old as the time, which is association does not imply causation.

But when it comes to endometrial thickness, we seem to be forgetting about this, because to say that canceling a cycle and transferring a subsequent one by doing something additional is efficacious, we need to have some interventional evidence. But does that mean endometrial thickness does not matter at all? No, not necessarily. I agree that it's a prognostic factor.

In fact, we did look at it in our study, but it's not really a strong prognostic factor. When we add it on top of everything else we made at the time of transfer, the embryo quality, the infertility indication, the age of the female, the BMI, the type of transfer. When we add endometrial thickness on top of that, the difference in the predictive power as measured in AUCs is less than a point percentage.

I mean, we had an enormous amount of data. It was almost insignificant. But does it make a better model? Yes.

How much better would it really make a difference in clinical practice? Probably not. So would I cancel based on thin endometrium? I need more data. This is circumstantial.

There is no interventional evidence backing that practice up. We can make a distinction between a normal looking and abnormal looking endometrium. Like, you know, would you transfer an endometrium, an abnormal looking one? Then again, what's the underlying problem? Is it amenable to some sort of correction? So there are a lot of questions we need to ask.

We need to make a distinction between what an observational data is telling us and maybe not try to drag it to the interventional space. That would be my most important message for today. And these data is not necessarily contradicting ours.

I see it like, you know, when I look at the numbers, they are mostly telling the same story, maybe with a few asterisks about how their results should be interpreted. Thank you. Thank you.

That was very insightful. So I want to invite the audience to come up to the microphones and to ask questions of our panel. As you're coming up, Catharine, what do you think about the magnitude of the decrease? So we've been talking qualitatively that thicker is better than thinner.

But what about the magnitude? Is the endometrial thickness play a 30% difference in terms of the implantation rate? What do you think, Sesh? And then we'll ask Dr. Picasso. That's a good question. As I think everybody has alluded, with regards to the thin endometrium, because it's observational data, it's from the SART data set, you do not know if there's any underlying reason for the thin endometrium.

So if there is anything like intrauterine adhesions or any uterine factors that are causing the thin endometrium, that could be a potential cause for the magnitude indifference between the thin endometrium and the 8 to 11.9 millimeters endometrium. So that could be an underlying reason, because we do not have data. There are variables that we do not have.

The other thing, it is interesting to note that even if the thin endometrium, of course they exclude in this study, they exclude an endometrium two millimeter or below, but even if the thin endometrium, say four to less than six millimeters, the live birth rates are not that low. They're 31% and odd. So it is not that dire.

So if we have a woman, of course there is no underlying pathology that needs intervention, but if you have a woman who has an endometrium of this thickness and there is nothing that we can do further, you probably tried before cancel and this is the maximum you get, it is not dire. They still have a reasonable pregnancy or live birth rates. That's something that is very interesting.

Dr. Rakowski. So thank you. So full disclosure, I'm an embryologist.

I've never measured the endometrium, but it's always struck me as I've watched physicians do it as to how actually inaccurate it is. It looks incredibly inaccurate to measure. So I have a couple of comments about that or questions.

When you measure it, do you just measure in one particular place or do you look in many places across the uterus and get sort of an average? And in terms of the data that was presented from the SART registry, because of this potential variation in measurements to the discussion about differences across countries from Barish's presentation particularly, I just wonder whether they did any sub-analyses of the data by program, because I would imagine that different programs are going to measure it slightly different from one program to another. And in the United States, there are some very, very large programs that will contribute a large percentage of the cycles versus the much smaller ones. So I would have loved to, if they didn't do it, I'd love to see a sub-analysis to actually, by center, to see if they actually got similar results.

Thank you. So Michael, you can do the measurement. That's fascinating, Barish, and I think that's true in the United States.

If I get an endometrium that's less than six, I keep moving around. I keep looking. I keep looking.

Oh, there it is. There's the seven millimeter. What do you think, Michael? No, you know, I think they're all very interesting points.

I think that we know from evidence in the literature that if you have different people measuring the endometrium, you'll get a different result. So there is observer variability, which is one factor. And in this study, they did include patients who had had multiple cycles, a small percentage of them.

But the implication of that is that they then included the patients that didn't conceive, who are more likely to have thinner endometrium, maybe overestimated the role of the thinner endometrium. There is another study of about 30,000 cycles where the last author is Emery Selley, that's published, and Barish is actually one of the authors on that as well. And they looked at the area under the curve and receiver-operator curves for the role of endometrial thickness, and they found that, you know, it was between sort of 54 and 59.

It wasn't a huge factor in having outcomes. And again, as Sesh said, we have these patients with very thin endometriums that go on to live birth. So there's some question by including patients multiple times if they didn't overestimate the role of the thinner endometrium.

So before we go to the next question, I just want to say the endometrium is supposed to be measured in the sagittal plane in the thickest part of the endometrium. So it is not an average, and you have to be very careful about how you hold the probe, and that's the way it's supposed to be done. But then it depends on the position of the ultrasound versus the position of the uterus.

Is it perpendicular? Is it at an angle like that? Barish, you were going to add something. May I sort of respond? It's an extremely valid question. It's something we've questioned, is it possible that the Americans, the Spanish, and are we measuring it differently? Is it possible to show the graphs again? I mean, I think it's impossible to tell if it's the case without going back to the images.

But if you look at the distribution patterns, you have the yellow bars where we claim that we're transferring regardless of thickness, they seem to be distributed. So it's like a bell curve. The other ones, they're skewed on one side.

So I think we can't rule out measurement differences entirely, but I think it's mostly affected by the difference in practice. And indeed, if you pay attention, whenever you're reading a clinical IVF paper, take a look at the exclusion criteria. You'll see when they define the patient, these people are, even in some endometrium studies, I was so surprised when we wrote the critical analysis paper on endometrial thickness studies, in some endometrial thickness studies, patients with thin endometrium were excluded.

And your decent, the decent live birth rate. So in Istanbul, in the paper we published from Istanbul, the live birth rate without PGTA at all per transfer was 41.7 percent or something, when the endometrium was six or less. And in the UAE data with euploid transfers, it was 49 percent per transfer when the endometrium was six or less.

So even if it is maybe a little bit less, which wasn't the case for us, but still, it's very decent. Question. Okay, I'm Doris Makridzianakis from Greece.

Looking at the endometrium, one parameter is the thickness, but we all know that it's even more important, the pattern and the ecogenicity of the endometrium. So maybe it's very simplified to looking at the implantation only on the thickness. And the second thing is about aging that it was mentioned.

It is not the thickness, the important thing, but mostly the decisionalization through aging that is not taken into account. So what do you think about this? Erkan, you want to take the endometrial pattern question? Oh, well, I mean, in the studies, we are like, you know, methodologically, we are saying that everything was normal. Some of the indications like, you know, uterine surgeries or like, you know, the abnormal looking endometriums were excluded at the time of transfer.

So these results should by default apply to standard clinical scenario where endometrial thickness is always measured with an accompanying normal looking trilaminar or like, you know, appropriate endometrium. So, I mean, yes, that could be a factor explaining why maybe some of the, like, you know, endometrial or lower thin endometrium categories are probably associated with lower live birth. But in these studies, allegedly, this shouldn't be the case.

Yeah, one of my problems with the pattern is it depends so much on the angle between the ultrasound probe and the uterus. And if the uterus is perpendicular to the ultrasound, you will get a, the spiral arteries are lined up with the ultrasound. You get an entirely different echo pattern than if the uterus suddenly is in the axis and you are looking down at it and you get this homogeneous pattern.

And if you just adjust the patient or the patient empties her bladder, suddenly you have a different pattern. That's my problem with the pattern data. And it's not that it's not true.

I just said, I think it's even more difficult to standardize than measurement. Question? Erkut Attar, Istanbul Yeditepe University. So, I just want to know from all of you, I mean, what are the qualitative differences between thin and thick endometrium? Let's say, what are the molecular differences between thick and thin endometrium? This is very much important.

Quality is important. So, what we are missing in thin endometrium? Let's say, what sort of cytokines or the other molecules which are, let's say, LIF or MCP1 or the others, those are the essential molecules for implantation. If they are expressed well in thin endometrium or not expressed well in thick endometrium? MCP1 is one of the most important and also there are some more I can talk about this.

But first, I believe we should do studies, some molecular studies between thick and thin endometrium. Then we can discuss, you know, if implantation occurs in thin or thick endometrium. That's my idea.

Excellent point. Michael, do you have data on molecular biology and endometrial thickness? I usually keep that in my pocket, but I won't pull it out today. You know, it's a great question, right? I don't know an answer to it.

What I do know is that when I have patients with, you know, persistently thin endometrium, I often put in a hysteroscope. And I'm amazed at how many of my patients have had their endometrium amputated. It's not that they're scarred to resect.

It's that you look at parts of the uterus and the endometrium isn't there. And, you know, I don't have a great offer for them, right? There's no easy fix for this. There are all kinds of things people are trying, but I don't think any of them are established yet.

And, you know, when I see it, I always think, well, we have to be very careful when, you know, as gynecologists, we perform a curettage. We want to do as little damage as we can. And I think that's important.

When I was talking about scar tissue before, this is really what I was talking about, was when you look inside and you find something you can't fix, but you also see the endometrium is damaged. Baris Shigat. Obviously, sounds a relevant question, and it brings other questions.

One, what is a thin endometrium? So where do we start looking for the differences? I mean, five versus eight, six versus nine, eight versus ten, et cetera. So the thin endometrium concept has been around for more than 30 years now. Actually, there are molecular studies, you know, claiming consistent or different findings, but actually what we've always been questioning is, even if it matters, it may matter to some extent.

I mean, some of them, there might be something genuinely wrong with thin endometrium in a subset of patients, but is there a threshold, is there a cutoff where you should modify your clinical management, which you can only determine by the clinical data? If you see, you know, if there's a sharp drop in chance of live birth, if it's, you know, less than whatever number, then you would start looking at, you know, molecular characteristics or whatever, you know, different pathogenic mechanisms between the two. But we keep, despite we are keeping saying thin endometrium, the definition of thin endometrium varies between six and 14, one, four millimeters in the studies. And, you know, there's an impressive paper, but as a clinician that comes across, you know, patients every day, I was worried a bit when I read the title.

You know, when it says it keeps increasing until 12, and in my opinion, you know, a lot of transfers being denied, you know, cycle after cycle, because it's not seven or six or eight, depending on the opinion of the clinic. Now, you know, as obsessive as we are, you know, like striving for the perfection, you know, appreciate precious embryo, a lot of, you know, like the patient is spending a lot of money, I want to be successful statistics. I hope we don't start, you know, going to 12 now, because if you look at the distribution, with the same logic, we would cancel like what more than more than half of the cycles now.

So we first need the definition, I think, to do those studies. Yeah, just a quick comment, if you allow me, I mean, to do this. Can I? Quick comment? Yes, but there's a question behind you, so very quickly.

Okay, so as long as, I mean, we don't take care of this question, we cannot be able, we will keep, I mean, discussing the same question again and again, years and years in my opinion. We have to have something to talk about. Question.

Can I comment on something Barish said? I think it's more than even the cancellation, right? I think it's the fear that there will be centers that say, well, your endometrium is 10 millimeters, and you'd do better if it was above 12. So I'm going to try to raise your estrogen and thicken you even more. But again, right, this is different, right? I don't think anybody in the study whose endometrium was 13 millimeters got there because they had previously had an endometrium of 10, and then the doctor raised the estrogen.

So we don't know that that would offer a benefit. By raising estrogen, in some ways, could even be detrimental. Well, that was Erkan's last slide point.

Yes, exactly. It's not intervention. And by the way, in this paper, even though in the conclusion, they do not advocate intervention, elsewhere in the paper, they do suggest that maybe you want to be pushing for the 12.

Yes, question. In order to cancel the embryo transfer, how long, how many days, and how high should we give the estradiol before we give up? Okay. Sesh, would you? The question? How, before you cancel the cycle, what do you have to do? So we'd published a study probably more than a decade ago.

This is a retrospective study looking at how long you give the estradiol and does it matter with regards to pregnancy outcomes. And this is a single center study. We found that if, and this is in program cycles, so if you were to do a down-regulated programmed FET cycle, then it did not matter.

But if you were not to use down-regulation, then after 20, 20 days, more than 20 days, then the pregnancy rates went lower. And that was published in Fertility Sterility quite some time ago. But then again, you have to bear in mind it is a single center study.

And I just want to make a comment about the paper. And given that you are the editor-in-chief for Fertility Sterility Journals, I think the title of the paper is good for headline grabbing, but it is, it can cause, you know, many of us, you know, don't go beyond the title and some go to the abstracts and some don't go beyond. So the title is slightly misleading in the sense that if you just look at the title, then many of them might think, oh, we have to aim for 12 millimeters.

So maybe something that you might be able to comment, you know, you make the title attractive to grab the attention, but it might not be, it might be slightly misleading. I will share with you, so my journal is less than 10% the volume of Fertility and Sterility. So it's very easy for me to read all the articles and it's very easy for me to stay, not very easy, but relatively easy to keep going back to the author saying, no, you can't put that in there.

No, I read that again. No, that title is misleading. I don't think you can do that with Fertility and Sterility that gets 3,000 submissions a year.

So it's a, that's where the big influx of data actually makes that more challenging. All right, we're down to the last eight minutes. Oh, last question.

All right, last question. And then we're going to let the panel have a last word here. I was, I was just intrigued by what Erkan said about the association between embryo quality and fin endometrium.

Apparently those are cycles where there was no PGTA performed, or I don't know whether embryo quality on top of the PGTA duploidy status of the embryo was also assessed. What is the plausible explanation for this? I think the explanation, because even in this study, they're showing that with fin endometrium, you have older female age, higher rates of diminished ovarian reserve, more uterine issues, and maybe some other poor prognosis factors they didn't have in the data set. So actually fin endometrium comes with a whole other separate baggage of issues, which may be uterus or embryo related.

When you account for all of that, you are diminishing that association between endometrial thickness and live birth. And there are obviously some other factors that we are not even aware of yet. Like, you know, so endometrial thickness may not be an end in itself, or also an indicator of other prognostic factors.

So maybe if you were to find that and account for more stuff, maybe that association will diminish to almost nothing. So the association is, I think, coming from other issues like age, indication, or just like, you know, some other confounders that we are not aware of. All right.

We're down to the last five or six minutes. So I'd like for each of our panelists to have their last 60 seconds or your final thoughts on the paper or on endometrial thickness or what's important in reproductive medicine today. Would I change my practice based on this paper to aim for 12 millimeters? No, not necessarily.

It's a good paper, but what is reassuring despite, you know, it is, I mean, we're critically appraising the paper. It's not a bad paper. It's not the best paper, but it is a paper like every other paper.

And would I cancel a cycle when there is no underlying pathology or nothing underlying if it is six millimeters? Not necessarily. Maybe the first time to give the benefit of the doubt, but if it is persistent, not necessarily, because as the data showed, despite the six millimeters in this group could be underlying pathology, they still had good, decent live birth rates. Michael? Just to add a little bit to what Sesh said, even, you know, with some pathology there, if you can't fix the pathology, the options are either to transfer into that patient if you can't thicken the endometrium or a surrogate.

And surrogacy may not be palatable for many of our patients. It's quite expensive. In some places it's not permitted, depending on government regulations.

And as such, you know, even with, we have to accept that this is the situation of the patient. And nevertheless, we have to remember that there were a significant amount of live births in the people with the very thin endometriums. Baris? Before giving my remarks, would you promise me you will give your remarks as well? You've been moderating wonderful passively, but everyone is talking about your receptivity talk yesterday, which I unfortunately missed.

So I'm curious to learn what you do too. And this may sound sensational. I mean, I've published retrospective studies as well, but I think, you know, maybe we should stop publishing retrospective studies on endometrial thickness, right? Because if you look at the results, so there's a Canadian registry suggesting, you know, nine millimeters is wonderful for fresh.

Then another millimeter is great for frozen. And then, you know, one says, you know, over eight is okay. Then now it's 12.

Another paper can come up 10. So these are all, you know, one distorted by practice, then depends on how you categorize, that depends on how you analyze. None of the retrospective studies, unless you've been transferring regardless of endometrial thickness, tells you what's really happened.

And if we will invest effort and time into the issue, you know, someone should bother to do a prospective study without changing anything based on endometrial measurement, thickness measurement, then we can really understand, you know, if there's anything about it. And until then, I regard it as a screening test. You know, we've all been saying the same thing.

To have a screening test, what you're looking for should be prevalent enough to screen for it. Then it should have a relevant burden to screen for it. Then there must be something you can do about it, which is acceptable.

So, you know, you can improve the overall results by screening and diagnosing and intervening. I am not aware of an intervention that reliably increases endometrial thickness, even if I cared for it. There is no data so far showing that if you can thicken a thin endometrium, it performs better.

And we are all clinicians, we're in the real-life world. You know, the patients use ChatGPT now instead of Google. Everything is everywhere.

So, my point is not just close our eyes, you know, just keep transferring one after the other regardless of everything. So, if you're worried about endometrial thickness, you know, or if I'm worried about endometrial thickness, what I do is I review the patient's chart. You know, did I rule out intraocular pathology recently? Is there something I might be missing? I mean, did she have a prior cycle? Was it thicker? Was it thinner? Was there something different? And if the pattern is good, if I'm confident in this, then, you know, we'll have a small talk.

If she's uncomfortable about it, it has to be a joint decision in general. I mean, I can never guarantee success with a transfer, right? Then what I was, oh, you told me, you know, six millimeters wasn't a problem, but I'm not pregnant now. It has to be a joint decision, basically.

So, you know, here's the data. Here's how I think. If she wishes to try something different that is acceptable, like, so we did natural cycle, can I do an HRT next month? Sure, it's okay.

But I've seen patients, their cycles have been canceled month after month, you know, crying in the office, you know, my physician denies my transfer because my endometrium doesn't get to seven. It's been six months, right? So, that makes sure the patient is not getting pregnant. So, you know, we should just be reasonable.

That's how I think. Thank you. Erkan? My final comments is basically rehashing what Baris just said.

So, the question of is endometrial thickness associated with live birth is a settled one, and I think we should stop making studies about this because study after study after study shows, yes, there is an association, but the more important question is, is there something you can do about it? Is there a reliable way of thickening the endometrium? Is the endometrial thickness in itself is the putative mechanism for increased live birth? Is there an intervention that will increase the live birth rates? There are ways to do it in observational setting, which nobody has done so far. I did review a few studies, and I think more studies asking that question, is there an effective intervention for this sort of patient population, will be the future going forward. And if somebody is brave enough, which I think is a little bit premature because as Baris said, I think there is right now no reliable evidence showing doing X increases endometrial thickness or live birth.

So, maybe after investigating some of these questions in the observational setting, the question will be finally settled by an interventional trial showing whatever we think is going to work will actually work in this population. Well, so I guess I get the last word, and I will share with you that I agree with all of you. I think that it is very difficult to alter the endometrial thickness.

I use the endometrial thickness as a diagnostic test, same as the rest of you. If it's thin, you have to go look and make sure that there is not scarring or some other kind of lesion inside the uterus. The other thing I worry about is whether the patient is actually absorbing the estrogen in an HRT cycle.

So, get a serum estradiol level, maybe switch to patches. The advantage of the patch is that the estradiol level is more or less constant during the day. When you're taking pills, then you don't know how soon after they take the oral medication you're supposed to do the E2 level.

I think it's also okay to extend the estradiol stimulation. I said that yesterday because it is estradiol that is, in fact, inducing progesterone receptors. It is the progesterone receptors that we need to achieve endometrial thickness.

I'm also very happy that no one on the panel said anything about PRP. I don't know whether this has happened in Turkey yet. My god, platelet-rich plasma now is being marketed like it's the new snake oil in the United States, and you can inject it into the ovaries, and you can inject it into the endometrium.

It is an absolute disaster. I am, we're about to publish, I think, a paper on bilateral ovarian abscess from somebody injecting PRP into the ovaries. So, there's some horrible stuff that's going on elsewhere in the world.

You did not hear it here today because PRP doesn't do anything for the endometrium, in case you're wondering. So, we're going to wrap that up. Thank you all.

I want to thank our distinguished panel, and I want to thank all of you, ladies and gentlemen, here in the audience for coming and listening to yet another lecture and another debate on endometrial thickness, as well as our listeners at home and around the world. Thank you again. We are adjourned.