Fertility and Sterility On Air - TOC: August 2024

Take a sneak peak at this month's Fertility & Sterility! Articles discussed this month are:  

04:19 Assessment of obstetric characteristics and outcomes associated with pregnancy with Turner syndrome

13:55 Effect of postthaw change in embryo score on single euploid embryo transfer success rates

22:38 Effectiveness of preconception weight loss interventions on fertility in women: a systematic review and meta-analysis

37:17 Functional evidence for two distinct mechanisms of action of progesterone and selective progesterone receptor modulator on uterine leiomyomas

43:47 Predicting risk of endometrial failure: a biomarker signature that identifies a novel disruption independent of endometrial timing in patients undergoing hormonal replacement cycles

54:28 Analysis of factors affecting the prognosis of patients with intrauterine adhesions after transcervical resection of adhesions

01:05:29 Effects of a eucaloric high-fat diet on anterior pituitary hormones and adipocytokines in women with normal weight

View Fertility and Sterility August 2024, Volume 122, Issue 2: https://www.fertstert.org/issue/S0015-0282(24)X0008-4

View Fertility and Sterility at https://www.fertstert.org/

Welcome to Fertility and Sterility On Air, the podcast where you can stay current on the latest global research in the field of reproductive medicine. This podcast brings you an overview of this month's journal, in-depth discussion with authors and other special features. F&S On Air is brought to you by Fertility and Sterility family of journals in conjunction with the American Society for Reproductive Medicine, and is hosted by Dr. Kurt Barnhart, Editor-in-Chief, Dr. Eve Feinberg, Editorial Editor, Dr. Micah Hill, Media Editor, and Dr. Pietro Bortoletto, Interactive Associate-in-Chief.

Welcome to another episode of Fertility and Sterility On Air. We're in the August 2024 edition, volume 122, number two. I'm Micah Hill, the Media Editor for F&S, and I'm joined today by my co-host.

Good morning, Pietro. Good to see you. Guys, I'm jealous.

This whole gang went to ESHRE without me. We were, before starting to hit record, we talked about the science that was seen, the stuff that's coming out. I got major FOMO.

So I heard you guys recorded a podcast episode there. We did, with the help of Kate. Good morning, Kate.

How are you? Good morning. We missed you so much, Pietro. As we were just discussing, you'll be in Paris with bells on.

And our fourth host today, our Intrepid Editor-in-Chief, who is also at ESHRE. Good morning, Kurt. Good to see you.

Good morning, everybody. I learned a lot at ESHRE. Let's see if we can impart some knowledge here from the journal and ESHRE to all our loyal listeners, some of which said hello at the booth and came up while we were recording.

It was a lot of fun. Yeah. Thank you for everyone who came by and said hello.

We recorded over 20 interviews looking at science at ESHRE and the cutting edge of medicine that was being presented there. We'll be dropping those in two podcasts as you listen to this. If you haven't listened to the best of ESHRE on FNS On Air, please tune in and listen to those episodes.

All right. We have a lot to cover today. So let's jump right in.

There's a couple of themes in the journal today, one of which is certainly weight loss and obesity. And that happens to be the views and reviews from editorial editor, Eric Widra, who says this views and reviews challenges us to reconsider approaches to obesity. The challenge includes new looks at BMI limits, which we'll talk about a little bit later, as well as the emerging role of GLP-1 medications.

Eric says this may be a revolution worth joining. If you know Eric Widra, he's a skeptic. So if he's saying that, there's certainly something there.

And there's three very good articles that cover BMI limits from Christina Boots at Northwestern that cover GLP-1 agonists and some of the new data that's coming out, or GLP-1 medications and the new data that's coming out with that, and just a general overview of obesity and fertility. There's a fertile battle from editorial editor, Madelon van Wely, talking about carrier screening and gamete donations. Both the pro and the con side agree that we should do carrier screening and donor gamete cycles, but they talk about some of the risks and pitfalls and pros and cons of those approaches.

We have inklings from editorial editor, Marcelle Cedars, this sort of continues the debate that our editorial editors have been having over the future of REI training in our country. And she definitely takes the stance that we need a three-year fellowship, that what we train in REI is getting more complex, not less complex. One of my favorite parts is she spent a couple of paragraphs talking about AI and how we need to train our fellows to understand and be masters of AI.

And it reminds me of my boss, Alan DeCherney, who always tells our fellows, you need to be the boss. You need to understand and be the boss of everything that is within the purview of REI. And if you do that, you're not replaceable.

So Marcelle really makes the argument that we should not be reducing fellowship time because it's getting more complex, what we need to train. And the final one is from editorial editor, Dom de Ziegler, OHSS should be dead. Only the obituary remains, a title taken from about 15 years ago when Alan DeCherney argued the same thing about reproductive surgery and REI.

Although I would say there's no obituary on that. People like Pietro are leading a resurgence in surgery. I wish Eve were here because I think she tells the story that it's one of her most highly cited papers was that little editorial with Alan DeCherney that we keep coming back to to say, ah, you got it wrong.

Here you are evidence of the contrary. That's right. Joke's on them.

So let's jump right into the science. Pietro, the seminal contribution you have this month, some fairly impressive or maybe even surprising data on Turner syndrome and the risks associated with pregnancy. Tell us about this new study that's out.

So the readers may not appreciate this, but we take turns assigning articles to each other where we kind of get to pick stuff that speaks to us or stuff that is within our purview of expertise. And I think most of the listeners know by now that my wife's a maternal fetal medicine doctor. So when I saw a Turner syndrome obstetric outcome paper, I was like, well, that one's mine for this month.

And I really like this paper. And I think just to set the stage for the listener, we know that Turner syndrome impacts one in 2,500 female live births. The vast majority of them are 45X, but there's also many of those mosaic phenotypes that exist.

The obvious stigmata of Turner's are the short stature, the wet neck, broad chest, wide spaced nipples. There's also nearly 100% rate of premature ovarian failure in true 45X women. But beyond the POI, nearly 50% of patients also have congenital heart defects ranging from as simple as a bicuspid aortic valve to issues with the aortic arch, as well as coronary artery anomalies.

These cardiovascular issues are so important that the actual leading cause of death in individuals with Turner syndrome are cardiovascular complications. And if you've been paying attention to the maternal mortality crisis in the United States, cardiovascular complications also happen to be the leading cause of maternal mortality. The objective of this study, which is entitled the assessment of obstetric characteristics and outcomes associated with pregnancy with Turner syndrome, is out of the University of Southern California by first author Zachary Anderson and senior author Koji Matsuo.

They sought to assess national level trends, characteristics, and outcomes of pregnancies with Turner syndrome in the U.S. They did this utilizing data from the Health Care Costs and Utilizations Project's National Inpatient Sample. This data covers 48 states and captures nearly 7 million inpatient admissions across 4,500 participating hospitals. From a study design perspective, this is probably the most ideal way to study this patient population that is rare times two, patients with Turners and patients with Turners who are getting pregnant.

I don't think you could pull this off with single institution data, single IFEF center data, one labor floor. You really need to look at a national sample to get a meaningful number. So kudos to the authors for thinking about it and having access to this data.

They specifically looked at women with a Q96.0 ICD code, which is the ICD code for Turner syndrome. They focused on women between the ages of 15 and 54 and looked specifically at the years 2016 to 2020. They tried to capture all of the obstetric outcomes of interest.

Issues with the fetus, issues with the placenta, uterine factors, delivery outcomes, as well as all the important patient level covariance. Now here's how rare this is. Of the 17 million hospital deliveries included in the dataset, 1,255 pregnant patients had Turner syndrome or approximately 7 per 100,000.

These are not patients with Turner syndrome. These are patients with Turner syndrome who are pregnant and having an obstetric event that required inpatient admission. So once the authors had access to this data and performed a very rigorous multivariable analysis, here's what they learned.

Pregnant patients with Turner syndrome were on average older, more likely to be privately insured, resided in higher census level household income areas, but less likely to be black or Hispanic. Pregnant patients with Turner's were more likely to have a diagnosis of pre-gestational hypertension, anxiety, asthma, but were less likely to be obese compared to those without Turner syndrome. And perhaps most interesting to me, pregnant patients with Turner syndrome were more likely to have a uterine anomaly and prior pregnancy losses compared to those without Turner syndrome.

I'll put a caveat here. The association between Turner syndrome and uterine anomalies has been called into question. Some of it we think is related to the absence of estrogen at those early critical pre-pubertal stages that's associated with the finding of a hypoplastic malarian system that just develops a little bit differently.

With regard to obstetric outcomes, and here's kind of the meat of the paper, Turner syndrome was associated with an increased risk of gestational diabetes, intrauterine fetal demise, growth restriction, and placenta accreta spectrum disorder. They're also more likely to undergo C-section and experience a periviable birth. And if you're the maternal fetal medicine who happens to have stumbled on the fertility and sterility podcast, there were no cases of aortic dissection that were reported for those having a hospital delivery during the study period.

And if you remember back from your training, this is the dreaded complication with Turner syndrome. This is why Kant routinely ends up on the list of absolute or at least strongly relative contraindications to pregnancy. So I'll pause here for a second.

We've talked about how rare of an event this is. I'm going to poll my audience. Have you guys ever taken care of patients with Turner syndrome either as a resident, a fellow, or in your attending practice that were trying to reproduce or showing up for delivery? I haven't.

And I've been at a couple of big academic institutions, Brigham Mass General, Cornell, and now Beth Israel. These are pretty rare. Micah, Kate, Kurt, have you seen these patients or taken care of them? I've done end-phrasing on a couple of mosaic Turner patients, but I have not personally helped a Turner patient get pregnant.

Yes, I have, but only in the setting of a planned gestational carrier, which is actually our practice policy due to the, based on this paper, small, but obviously catastrophic risk of aortic dissection. So haven't seen or taken care of a pregnant patient with Turner syndrome. Well, like most REIs, I've certainly helped a few, mostly mosaics, to achieve a pregnancy.

But of course, I'm not taking care of them during their course. But in retrospect, they might've fit into this paper. They seem to do perfectly fine.

Which I think brings me to my next discussion point is what's the shared decision-making process like? Kate, you said that your center has a policy that you won't transfer embryos into a patient with Turner syndrome. Is that correct? That is. And it's a topic that is frequently debated.

I'd say it's one of the most frequently played group emails among all the physicians is, how about this one? Is this a suitable exception? So maybe this paper will be enough to move the needle in favor of more of a shared decision-making model as opposed to a bright line rule. I think this is exactly that kind of paper that we often involve maternal fetal medicine doctors with to kind of round out the counseling. Sure, we can help a lot of them get pregnant, but should we, and how can we best do it safely and collaboratively? This is a great example of a paper in FNS that's speaking to a couple of different audiences.

The reproductive endocrinologists were assessing their practice patterns locally, but also the maternal fetal medicine docs were looking for some counseling data to help kind of manage that pregnancy in the safest possible way. One little note that I'll make from this paper that I didn't mention was that people, they also looked at trends between 2016 and 2020, and the authors found that for every year between 2016 and 2020, there was an increase in Turner syndrome-affected women delivering in the United States. Some of that may be our doing with the advances of ART and access, but it's an issue that I think it's always good to have data to inform our counseling and our management.

So kudos to the author. Great paper. Yeah.

PHR is really happy to see this one and Fertility and I think this one will have an impact, but I want to caution people on the impact. This goes in the level of, you know, sometimes we make guidelines and we're very strict with them, and sometimes you need evidence to change that. This I think will start the change, but I don't think this quite gives us license to throw away all those kind of, paternalistic is the wrong word, all those, you know, guiderails for good reason.

But I'd love when we start challenging some of our own paradigms and guardrails, but please slowly. I think this is also worth mentioning that this is the numerator, right? We don't see the denominator of patients who are actively counseled against or couldn't get pregnant with Turner syndrome. So this happens, I think we can all agree that this is probably the healthiest of the bunch, the bunch that's likely to have the best possible obstetric outcome, albeit a very small group.

So I think to Kurt's point, take it with a grain of salt. Good paper. Pietro, my understanding is with this, they couldn't really look at mosaic or the level of mosaicism.

So that doesn't really help us as far as that goes, low mosaic, medium mosaic, high mosaic. I think the biggest issue is just how we code stuff. I think anyone who's ever done any billing in assisted reproduction knows that the codes are abysmal and we can't capture stuff well.

It's the same thing with Turner syndrome. There's not great codes for mosaic Turners. There's just the kind of the catch all 45 X code.

And I guess the other big limitation, as you said, there was no aortic dissection, but they could only capture things that were associated with a delivery event. So if someone had an aortic dissection and died, but it wasn't coded related to anything having to do with delivery or obstetric care that would have not been captured. So while it's zero out of those thousand plus, like you say, we don't fully know that denominator.

So those will not have been captured. The aortic dissection thing, the highest risk is actually at the time of delivery where you have the hemodynamic shifts. So if it's going to happen, it's typically happening during that obstetric admission for delivery or where you're experiencing those hemodynamic changes.

But certainly the postpartum appears also a high risk window for it. Great. Kate, you're up next.

We're moving on to assisted reproduction. I was just on call this weekend and a patient asked me, you know, how does the embryo look after a thaw recently? So, you know, the study that we're talking about next is looking at those changes, the post-thaw embryo. What did we learn from this study? Thanks, Micah.

So this one was called Effective Post-Thaw Change in Embryo Score on Single Euploid Embryo Transfer Success Rates. And it's from authors Bergen et al. out of RMA New York, Mount Sinai.

And so these authors performed a retrospective cohort study to evaluate the association between the delta in pre- and post-thaw, quote, embryo score. And they associated this delta with live birth for single euploid autologous frozen embryo transfer. So a large cohort, they looked at 7,750 transfers among 4,613 patients.

And these transfers occurred from 2016 to 2022. The unadjusted analysis found a statistically significant progressive decrease in live birth from group one, which was the referent. And that was the group where there was no change in pre-vit versus post-vit warming score.

And then, as I was saying, the live birth decreased progressively from group one to group four. And group two was the group that had an improvement in score. Group three was the group that had a decrease in score.

And group four, the authors state they could not score on account of the embryos not having re-expanded post-warming and therefore not being able to grade the ICM and trophectoderm. And so, again, a progressive decline from no change, positive change, decrease, and then no expansion. That said, this progressive decrease was largely attributable to significant differences in the pre-vitrification score and oocyte age among the groups.

So the authors went on to conduct an adjusted analysis in which GE was used to account for female age at retrieval, AMH, BMI, endometrial thickness, year of transfer, embryo score at time of vitrification, which was a big one, and multiple cycles contributed by the same patient. And here they found that improvement in score was positively associated with live birth with an odds ratio of 1.43, whereas diminution in score and failure to re-expand were both inversely associated with live birth relative to the referent where there was no change. And the odds ratios for those two were 0.57 and 0.71, respectively.

So it's an interesting paper. As you say, Micah, we're constantly being asked, well, how does the embryo look now? And there's fairly limited data in terms of how to counsel patients or whether we even should based on what we're seeing at that juncture. The big elephant in the room here is, of course, really not actionable at that point, right? We're not going to say, let's just toss this one and thaw the next embryo, given that we still see pretty good success rates even with embryos that don't look great upon warming.

As much as I do think this paper has useful and interesting conclusions, it also has some weaknesses. So for one thing, they are trying to validate the clinical significance of a change in embryo score. And this is an embryo score that's internal to Mount Sinai.

And while they have two publications where they validated their internal use of it, it's hard to know whether that's really generalizable to other centers. They do provide a nice figure that's from the Friedenthal publication, which they used to create this and validate this model in the first place, which is a heat map showing the relative contributions of the various contributors to the score in terms of probability of live birth. Another piece that I was surprised not to see in this paper, and I do think constitutes a pretty significant weakness, is that they do not mention whether the embryologists were blinded to the original score.

And since this is a retrospective cohort study, I think it's pretty likely that they were very much privy to the original score, which is a pretty significant source of bias. The other thing that points to embryologists likely having known the original score is that the overwhelming majority had the same score post-warming with only about 22 percent having gone down. The groups with no expansion, thankfully, was only 3 percent and only 6 percent increased.

Again, given that that would be a little bit counterintuitive if you're aware of the original score, unlikely to grade it better when they come back post-warming. They did a pretty rigorous analysis. They looked at the duration from warming to post-thaw grading, which we know is likely associated with expansion.

The mean time in these groups was not different between the various score groups, nor was it associated with the probability of live birth. Interesting paper. Again, not sure exactly how generalizable I would say that it was.

It would be nice if we had some clinically useful predictors based on pre-thaw evaluation that could tell us some of this stuff with a little bit more accuracy. Again, because once the embryo is thawed, the embryo is thawed. I'm interested to hear from this group in terms of to what extent are your centers utilizing post-thaw embryo assessment in any way for clinical management or patient counseling? And I think kind of as a hot topic, what about standardization of embryo grading and the use of AI to do that? And what other adjunctive embryo selection tools and technology are on the horizon for this group? I'll tell you that at Boston IVF, we don't rescore embryos once they're thawed.

We use their pre-thaw score. And the only reason it comes up is if the embryo really just failed to expand or didn't survive the thaw. Patients are provided photos at the time of the embryo being thawed.

And oftentimes, the embryologist will share like, oh, this one looks better than what it did when it was frozen or it looks perked up. But it's not something that I think changes our day-to-day practice. And I think for exactly the reason that Kate said, the vast majority of times, it's the same and very rarely does it look worse.

I'm fascinated by this paper, Kate. The whole idea that we now have a new variable to look at that gets prognosis. We can put in our AI models.

We can change the way we talk to patients. We can be optimistic. We can be pessimistic.

Yet after all of this, I'm going to transfer that embryo anyway. So I haven't figured out as much as I love the science here and that it really might matter. Of course, it might matter, you know, how an embryo freezes.

We cumulatively say, you know, embryo success rate with thawed is 99%. But there's got to be, you know, gray areas in there. Some are better than others.

So I love the idea that we're looking at this. But what do I do with that information? Yeah, exactly. And so interesting anecdote, the first abstract I ever submitted to an ASRM meeting as a resident was a paper correlating post-thaw embryo grade at NYU with implantation rates essentially.

And we found very similar things that it's highly correlated as other papers have as well. And I stood there in the, you know, exhibition hall next to my poster and got beat up over and over again by people saying, well, what am I supposed to do with this? So the short answer is it might end up to be one of these key predictive indicators. You know, you can look at your lab overall and see what your scores are in aggregate and see if you're doing things well.

But that's boring. What I want is something that'll tell the patient what to do right now. Right.

I like your idea of using image learning to be able to more accurately track this and eliminate some of that human error and subjectivity that goes into embryo scoring. I'm so glad that you pointed out the major flaw of this paper, which is that they don't mention it. So we're assuming that they didn't do it.

But the blinding to the pre-thaw score is huge. You get you totally going to anchor you in one direction or the other at the embryologist. Totally agree.

All right. Well said. Kurt, as a wise man once told me, sometimes you just have to let the science wash over you.

So that's what I did with this one. That was a great discussion. I love that.

Excellent. Excellent. We're moving on now to infertility section of the journal.

And I have the next article. It's titled Effectiveness of Preconception Weight Loss Interventions on Fertility in Women, a Systematic Review and Meta-Analysis from first author Ann Caldwell, senior author Nanette Santoro from the University of Colorado. So this is obviously a systematic review and meta-analysis.

It's looking at the effectiveness of weight loss interventions using lifestyle modification or medicines for overweight and obese patients trying to get pregnant. There are a couple prior meta-analyses that are on this topic. But they look at RCTs and data that was per protocol instead of intent to treat.

And actually, when I teach fellows about per protocol versus intent to treat analysis, this is the example that I use is weight loss intervention or lifestyle interventions. Obviously, per protocol is nice because you're looking at patients who actually did the intervention and did it as they were instructed or those who were in the control group. And so it tells you, did this intervention actually work if you did it, which is great.

But we know that in real world, often more than 50% of patients won't be able to follow through with those lifestyle interventions or diet modifications, exercise modifications. Sometimes it's more than half of them that are unable to. And so if you have a patient in front of you, what you care about is intent to treat.

If I tell the patient you should try to do this intervention, will it actually be effective for them in the long run? Because some of them will not do that. And so I thought that that was a good explanation of why they felt an updated meta-analysis was needed. They only did RCTs, and they excluded studies that had duplicate data.

And I know, Kurt, this is something that you've mentioned to me before. We have seen meta-analyses where they include the same patients twice. Maybe the authors published an interim analysis at 200 patients, and then they have their final study at 400 patients, and they publish that.

And you see both of those studies in a meta-analysis. Well, that's not appropriate. You have patients that are counted twice, and you're inappropriately weighting that study more heavily now into your outcomes as you summarize the effect.

There are actually six duplicate studies that they had. So I thought that was good that they recognized that up front and excluded those studies. They use random effects models.

And for fellows, I think it's important that you just have some basic understanding of how meta-analyses work. These are common cases of the days for the oral board examination. So when you look at your forest plot and you see your estimate of the odds ratio or the risk ratio and the 95% confidence interval for each study, obviously they never line up exactly.

And why is that? Well, one is just sampling error. I could do the exact same study in the same patients twice. It's not going to be the exact same effect estimate, the exact same 95% confidence interval, just because of random chance, because of sampling variation.

And so a fixed effect model assumes that the difference between all the studies that you're summarizing are purely due to sort of that random chance or that sampling error. And therefore, it weights the bigger studies more heavily because they're going to have greater precision in their estimate. A random effects model, which is what they used here, assumes that two things are contributing to that difference.

One is that variation in sampling or random chance. But the other is that no two studies are identical, right? They have different patients. They have different interventions.

They have a variety of things that are different between them. And that's certainly the case here. In this study, the RCTs that they're looking at, some use diet.

Some used exercise. Some use medications. Some use fertility treatments.

Some didn't. And so you have all these variations in trying to do the same thing, which is weight loss. And so a random effects is assuming that there's also between study differences.

And so it's going to give more weight to some of the smaller studies. It's not going to weight the heavier studies as much as the fixed effect model would do. So as I mentioned, these studies are very diverse.

They're very heterogeneous in what the intervention is. They're also very heterogeneous in what the control group is. There's only one of these studies where the control group is a placebo.

In some of these, the control group is going to immediate fertility treatment, whereas the intervention group is going to the lifestyle modification, and then fertility treatments in 12 weeks or 20 weeks, after whatever amount of time the intervention is. And so obviously, the difference in the control groups is important here as well. And then because of all these differences, these authors do a lot of sub-analyses.

They look at interventions that are less than 12 weeks, greater than 12 weeks, BMI under 35, BMI over 35. Was it lifestyle interventions? Was it pharmaceutical interventions? And they tried to do subgroup analyses on all of those. So what were the results? They had 16 RCTs that they included, 3,500 patients.

So it's a fairly large amount of data. When they look at pregnancy, overall, as you combine these very different interventions aimed at reducing weight loss, there was an increase in the odds or the risk of getting pregnant. So it did seem to be beneficial.

But when they looked at live birth, there was not any difference in live birth. And there was maybe an increase in miscarriage, actually, in the intervention arm. And that may have been why there was a wash when you got to live birth.

When they broke it down specifically through these sub-analyses, if the intervention was less than 12 weeks, that's where they found the benefit. Interventions that took more than 12 weeks didn't have a benefit. And if the BMI was over 35, that's where there seemed to be a benefit.

If it was less than 35, there was not a benefit. So the authors, I think, appropriately concluded that there's not a one-size-fits-all approach that we can take from this, that it's sort of nuanced counseling with the patient and shared decision-making with the patient. My main critique is somewhat, and I like doing meta-analyses, is I think these studies are so heterogeneous that combining them statistically is probably something that I wouldn't have done.

I would have just done this as a systematic review. I think it's challenging, and they did their best with the sub-analyses to appropriately combine studies that are similar. But even within those, the studies and the control groups are still very, very different.

There was a great reflection piece on this from Feng and Mol in Australia. And I really like it when the reflections don't just tell us about the paper, but really think about it in different ways. And they thought about it from a number-needed-to-treat standpoint.

The difference, while statistically significant for pregnancy, was only 4%. So for a number-needed-to-treat, you need 21 patients to get one additional pregnancy. For live birth, it's even smaller.

The difference was 1.4%, which means you need to treat 71 patients with intervention in order to get one additional live birth. And the importance on that one is it wasn't statistically significant. So if you take the lower confidence interval, there actually might be a number needed to harm by doing the intervention.

And then the other thing that I really liked is that they gave the recommendations from all the societies and even legal limits that exist throughout the world. And I think on this one, ASRM is actually fairly progressive with the most recent practice committee guideline on obesity that Carl Hansen was the good shepherd on, and recommends that—ASRM recommends that we don't limit fertility treatments based on BMI unless you can't safely do IVF at your outpatient surgical center over a certain BMI. So that's the only reason that ASRM says that you shouldn't.

But I hadn't seen a table like this that describes Canadian guidelines, Chinese guidelines, European guidelines, New Zealand, Sweden, Spain, UK, Serbia, Ireland, all of which have, in some cases, legal limits. BMI is as low as 30 on being eligible for fertility treatments. And so they challenge that, which gets exactly back to our views and reviews.

So this aligns nicely with that—the one from Christina Boots that challenges having BMI guidelines, as Kurt said, sort of maybe a paternalistic approach to who we say we will treat and who we won't outside of the safety of what we can do in our surgical centers. So that's my take on this article. I think it's helpful, but it sort of gets us back to where I think many of us were, that this is a very complex issue that's very patient-dependent, and at least I don't personally delay treatment on someone trying to make them lose weight first.

But I'm curious about the approach that Pietro, Kate, and Kurt have on this, or your other thoughts on the article. Yeah, I mean, the BMI thresholds with a legal limit of 30 makes us feel pretty liberal, even though I am constantly feeling sheepish and paternalistic for the guidelines that we have already. Our threshold at Shady Grove is a BMI of 44 for a transfer, and a BMI of 40 for procedure in our outpatient surgical center.

And so those are pretty, in my opinion, strict and a little bit paternalistic, and I think the pendulum is starting to swing the other way as more and more data come out, and it dovetails nicely with Eric Widra's views and reviews for this month. And we're fortunate now that we do have a lot more pharmacologic interventions that seem at least preliminarily safe, but then, of course, we have to be careful to keep an eye as those data unfold, and also making sure that we're aware of which of our patients are on these medications, because sometimes we won't be. Yeah, I think we've hidden behind these kind of state guidelines or surgical center guidelines, because we don't know the answer, and it's easier to say, you know, sorry, it's out of our hands.

You know, if your BMI is above this, you can't have anesthesia, therefore you can't have IVF. But the true answer is we really don't know. I mean, there's rough evidence that says a higher BMI might have lower success rate, but there's a lot of things that people have risk factors for that we can't control.

So it's one of these things where, because we don't know the answer, we tend to hide behind guidelines. Our cutoff for egg retrieval at Boston IVF and outpatient surgery center, not in hospitals 45, we interestingly don't have a cutoff for embryo transfer. That's an interesting kind of tidbit that I just learned about shady growth.

What's the rationale for the difference? Yeah, great question. So one is in case they were to need, you know, a DNC in early pregnancy or something like that, where they may be at risk for an outpatient procedure, and then also just some of the data indicating higher risk of pregnancy loss and some of the other obstetric complications and wanting to help them achieve the greatest possible probability of a healthy live birth. As Kurt says, we don't know.

And so we have to come up with guidelines and especially large centers like yours and mine, it's good to have a policy, but it's something that, you know, policies need to be re-evaluated on an ongoing basis. And we all need to remember that. And similar to the Turner paper that we saw in this same issue, there's some good examples of healthy re-evaluation.

We've had lots of ethical guidelines on this where we'd love to get our ethicists and our maternal fetal medicine and talk about BMI as a cutoff. And I've heard some really persuasive arguments first that BMI or obesity is a medical condition, just like Turner's might be, or just like depression might be, and therefore we should be treating people in the same way if you can try to get away from the stigma. But the other overriding issue is usually the active versus passive intervention.

Like every MFM is going to take care of somebody that delivers a baby with a BMI of 50 or has a DNE of 50, but actively trying to help somebody and put them in a high risk is what we try not to do as REI or have been criticized for as REIs. Anyway, having said that, I don't have an answer. That's why this is so gray.

And that's why I'm glad we're learning that they're perhaps our weight loss issues. But the most important thing is we can't stigmatize. And right now, I guess we still hide behind, as I said, these guidelines because they're definitive, quote unquote.

I think this is great fodder for a fellow debate at an upcoming PCRS or SREI meeting. It is really a difficult question. And to think of it in terms of the ethical principles of medicine, I think is the right way to go about it.

Just to add on to that ethics, we at Penn have hospital retrievals for medical diseases that require anesthesia or anesthesia surveillance. And we have many. I mean, it's a big part of our practice.

But we debate whether obesity counts because and it's two things. It's the stigma of obesity and is it a medical condition? But secondly, I hate to say this, if we extended it, we would do it purely for BMI. We wouldn't have any more time or we wouldn't have any more slots.

We would be overwhelmed with that need. So this is something we really need to think through. Mike and I were having a chat before we started the podcast today, a little bit about the GLP-1 meds.

And I think the paradigm is really very actively shifting and how I think we're going to manage obesity as it relates to access to ART. The struggle has always been how much do you delay ART by to allow for successful weight loss? And now that you can pretty reliably and pretty profoundly achieve weight loss using these GLP meds in majority of patients, I think the pendulum is maybe moving backwards where we can actually focus on weight loss, focus on health optimization and then get them to ART in a much shorter period of time. But of course, the data needs to bear it out that it actually works, that it's safe and that it's better than the alternative.

But I'm feeling actually really encouraged about how we're going to be managing obesity and the ART population in these next few years. A PHR, we're managing obesity to decrease the risks of IVF, not because we think that IVF is less successful, right? The risks of IVF actually have been published in Fertility and Sterility. My co-fellow Philip Romansky published in FNS data from the Brigham and Women's Hospital that did BMIs up to 65 in their inpatient retrieval unit.

And I think we all talk about the anesthetic risks, the anesthetic risks, it's actually exceptionally small and exceptionally safe to be able to offer anesthesia for these patients. So, I think that I've always kind of struggled with that argument where, oh, we don't want to do it because we're worried about conversion to an oral airway or intubation and it doesn't seem to be true, at least in a high-volume center with a lot of experience with it. Right.

And then we've tried in our surgeon center to use no anesthesia for our retrievals in the cases of high BMI. And I'm told it was against state regulators that said we can't even do that because it's a surgeon center even if you're not using anesthesia. But that's a risk-adverse environment.

So, anyway, there's ways to work through this. That is a robust discussion, Kate. I think you're right.

This is a perfect fellows debate for an upcoming Journal Club Global. So, we'll look for the right one. Kurt, we're moving on to reproductive science.

I know you set a high bar for science articles being in FNS. And I loved this article and reading it. So, tell us about the action of progesterone versus selective progesterone receptor modulators on fibroids.

You're right, Mike. FNS has a high bar for basic science research. Not that I don't think it's valuable, but there are many other journals that can take on and are very basic science-focused.

But my associate editors do a really good job of picking out what they think are impactful and interesting articles for our audience. And I think this is one of them. This is a very common area that we should all know about.

So, the title of the article is Functional Evidence of Two Mechanisms of Action for Progesterone and Selected Progesterone Receptor Modulators on Uterine Myomas. It's by Dr. Milewska and Rahman. They're out of Poland.

And it's, again, a very good basic science article. So, I don't know how much introduction they need to give to fibroids. I mean, we all know what fibroids are.

They affect many aspects of reproduction. They're really still poorly understood. In my career as medicine, we didn't really know what they are now.

Now there's some literature that I'm not going to go into too deeply, but it's fascinating that we think that perhaps they may be somatic mutations, and there may be other, obviously, aspects of reproduction that influence them. You know, if you ask any medical student, they'll tell you they're estrogen dependent, and they're dependent on reproductive hormones. But I think what's underappreciated is the impact of progesterone as well.

So, there's also been a wave that I wish was stronger, but there was a wave of sperms, selective progesterone receptor modulators as therapies for endometriosis and for progesterone. We could have another podcast on why some of these didn't make it to market. The short answer was there was a signal of safety in some of these, I'm told, perhaps due to a side chain on some of the molecules.

And there's a big debate in the FDA on whether they could be moved forward or not. But one that is commonly used, mostly outside the United States, is illiprestyl acetate. And this is the one that was used in this study.

And basically, it was looking at the—trying to figure out what exactly these sperms are doing that might affect progesterone growth. So, that was a long introduction to say this study investigated the molecular mechanisms, and in particular, they were looking at the extracellular matrix, which I think defines fibroids. We all know that they grow with estrogen, but it really is its independent extracellular matrix that makes it a solidified, you know, solid tumor, different from the myometrium in general.

So, this study looked at explants. It basically looked at 100 fibroid explants from women treated with illipol acetate and 100 without. And it also had a handful of controls where they looked at healthy myometrium and endometrium, just basically to see.

So, for those of you with a basic science background, please delve into this paper. There's a wonderful figure that shows all the proposed mechanisms and how it works that I can't describe on a podcast, but it's something you should probably hang on your walls to impress your fellow colleagues about how you understand the molecular aspects of fibroids. But in general, what this said was that it's—if you really go back to your boards, there are two types of progesterone receptors, A and B. Actually, there's more than that, but the A and B are the more common ones.

And then the other question that people have all the time is, is it working on the cellular surface receptor or is it a nuclear receptor? In this case, it's looking that the mechanism is both, which some people found surprising. They thought it would be one or the other. So, very, very high level.

Progesterone B receptor downregulates the growth of fibroids or the action of progesterone on growth. And that seems to be agonized or improved with UA. So, that seems to be the main mechanism.

Whereas the PRA receptor is, in a sense, upregulated and is less inhibitory. They also went into a little bit more of a mechanism that I wasn't aware of. They said that the main mechanism for extracellular matrix growth and remodeling is through the TGF beta receptor or the mechanism and a new pathway that I'm less familiar with called SMAD3, also important in the proliferation, the growth, and the development of extracellular matrix.

So, in aggregate, I think we knew this, that sperms are very good at limiting growth and proliferation, especially in the extracellular matrix. They really are very successful in papers if you look in Europe, and it's not little used here in the United States. And this study basically elucidates a molecular pathway involving progesterone and fibroids, suggesting that, again, progesterone is very important in fibroid development, and it's not just estrogen.

In terms of theory, they may consider that there may be co-treatment of sperms. In other words, not just the generic shut off everything, the analogy of pulling the, instead of turning off the light switch on your table in your bedroom, the progesterone receptors might be cutting off the electricity at the street level before it goes into your house. So, they're saying that maybe the combination of that with specific targets of a TGF beta or SMAD3 might further revolutionize the treatment of fibroids with medical management.

So, again, nice paper. It's a really good review for all of us to remember how fibroids work, and it really goes much more deeply than I had ever remembered seeing a good, this isn't a review paper, but it brings you back to the mechanisms of fibroids. And it's a well-done basic science study.

Those belong to, in FNS, they belong to be published, and I feel like I learned something from it. I don't think I'm going to change the way I treat fibroids yet, but not every paper in the literature has to directly impact care. This is a scientific advancement, and I applaud the authors for publishing it.

Yeah, Kurt, I loved figure four of this paper. You know, they have the typical figures from a basic science paper showing all their results, but then they have this very nice figure four that sort of shows the mechanism of, as what you mentioned, the PRA receptor versus PRB, and then phosphorylation of SMAD by one versus not phosphorylation, and then how it activates VEGF, IL-6, collagen deposition. I thought that this was really a fantastic basic science paper that also helps us understand clinically what's happening when we use these medicines.

I can see you're going to be pimping your fellows in no time at all based on this. Absolutely. All right.

Thank you for that, Kurt. Kate, we're coming back to you now. To me, this was the hardest paper to understand this month from a method standpoint, so tell me about predicting the risk of endometrial failure in this paper.

I agree. There were some gaps in terms of being able to understand exactly how they reached their conclusions. Certainly, a topic near and dear to me, and that's the topic of recurrent implantation for endometriosis.

I think it's important to endometrial receptivity. This one was entitled Predicting Risk of Endometrial Failure, a biomarker signature that identifies a novel disruption independent of endometrial timing in patients undergoing hormonal replacement cycles with first author Diaz-Gimeno. The authors conducted a prospective multicenter study of patients at five clinics in Spain.

The patients underwent mid-luteal endometrial biopsy and transcriptomic assessment of 404 genes using a, quote, supervised AI-generated model. They called this model the endometrial failure risk panel. The authors correlated gene expression patterns to outcomes of the first single embryo transfer among 217 patients.

Of note, these first single embryo transfers could be fresh or frozen, and there's no mention of the breakdown by PGT or not. What they found was that only 26 percent of the women who had a, quote, poor prognosis profile based on the endometrial failure risk panel had a live birth from that first transfer. That was in contrast to 78 percent in those whose endometria showed a, quote, good prognosis profile.

So, importantly, and this is something that a really good commentary by authors Pirtea and de Ziegler and Toner and Sokteang put forth in response to this paper, 74 percent of the samples analyzed had been found to be poor prognosis based on the endometrial samples. So, that is quite high, and that's despite only 40 of the patients who were enrolled having previously met criteria for recurrent implantation failure as defined by two or more unsuccessful transfers. And so, the study population was presumably also heterogeneous.

We don't have a ton of detail about their prior ART histories, but it included patients that had either two or more unexplained implantation failures and or, quote, a medical indication for endometrial assessment. So, neither of those is defined, though we don't know what medical indications could have qualified for endometrial assessment, nor is it totally clear whether they defined prior implantation failures as complete lack of implantation versus, you know, failure to achieve sustained implantation versus failure to achieve live birth. And again, heterogeneous population, we're not really sure about what proportion in each of the groups, meaning poor versus favorable prognosis, had PGTA-tested embryos to transfer.

So, the authors also importantly report that, quote, endometrial timing correction was performed. So, actually, what they mean by this is that the majority of the genes out of those 404 that were established in their model, and my interpretation is this is the way in which it was supervised, is that they had sort of an a priori feeling about the genes previously demonstrated in the literature as associated with the implantation window. And that was sort of superimposed on the genes that the model had selected and weighted as being associated with implantation separate and apart from timing.

And they referred to the report then that results after this, quote, endometrial timing correction as a report that could identify endometrial disruption rather than endometrial displacement. So, in this way, they described this as a novel diagnostic that shows essentially a resistance to implantation separate and apart from any aberration in the window of implantation. And so, one would conclude that they're suggesting patients found to have a poor prognosis endometrium with this platform cannot be, quote, fixed by changing the timing of their transfer, unlike the ERA that we're all familiar with.

And so, the authors further go on to report that this endometrial failure signature had a median accuracy of 0.92, a sensitivity of 0.86, and a specificity of 0.84. And they say that these values were established using a stratified five-fold cross-validation process that was repeated 100 times. Now, to really get to the clinical data of this paper, there are plenty of beautiful figures as to what genes were involved and how the RNA-seq was done and how the model was created, but the clinical data are actually found in Supplemental Figure 5. And so, here we get a little bit of a clearer sense of patient flow and what the sensitivity and specificity may have been. I tried to calculate sensitivity and specificity the old-fashioned way based on these data looking at the outcomes of the first transfer.

I got pretty close to what they got, but not exactly. So, I'm not…and, of course, we always have the question in these studies that are diagnostic accuracy studies where what we're trying to predict is live birth is which one is, you know, a positive versus a negative disease state versus test outcome, and that's really just semantics. That said, it does seem to be a fairly sensitive and specific test, but it leaves a little something to be desired.

So, for one thing, it's really not clear how they validated this in the first place to me having read it multiple times. And the other thing, and this is pointed out really quite nicely in the commentary by Pirtea et al., is that it's not…it's still not clear that a true resistance to implantation exists. You know, in H&R very recently, actually from the same group, different authors, Gil et al.

showed that there was a robust probability of live birth out to five transfers. So, that would argue against a true biologic resistance to implantation separate and apart from the anatomic factors that we all know about. And then, interestingly, I actually calculated the live birth per transfer from that supplemental figure five going out to nine transfers, and the probability of live birth for the fifth through ninth transfers were 67 percent, 51 percent, 61 percent, 58 percent, 52 percent, 75 percent, none, and then 100 percent, but the none was, of course, out of six transfers.

And so, really, that does not accord with the author's supposition that 74 or 70…I apologize, 78 percent of these patients have this poor prognosis pattern. It's not really clear in this setting what that could mean or how it would be actionable. So, I think it's an interesting paper.

I'm not sure how I would be able to apply it clinically at this point. I certainly hope that before this product comes to market, there is some pretty rigorous validation done. And to the author's credit, they did respond promptly and relatively comprehensively to the request for further information and stated that they do plan to validate it further, and they do not plan to bring it to market anytime soon.

Thank you, Kate. I think I understand that paper a little bit better now that you described it. The breakdown in the supplemental figure five just continues to add more data that patients with prior failures tend to do well when we do the same thing again.

So, maybe doing the same thing again is not the definition of insanity. Maybe it's the definition of what we should be doing for a lot of these patients. Yeah, when it comes to recurrent implantation failure, we don't know if it's real, and the better part of Valor is to keep calm and transfer another embryo.

Yeah, the problem is convincing our patients that, which is feeding into why we want an answer, we as clinicians want an answer, and why we want someone or something to blame. This is a really tough topic because as an editor for a journal, I get a lot of papers on recurrent implantation failure. And if I don't even know what the entity is, and if I can't define the entity, and everyone's defining it in different ways, how do I know what you're proposing as a treatment actually worked? This is a really important but difficult area.

Over the last couple of months, I've really tried to take a proactive approach about getting ahead of recurrent implantation failure in my counseling with patients. So if I have you play numbers to transfer, I tell patients, we're going to transfer three of them before we even talk about changing anything or just doing an evaluation. And we're not going to freak out after the first.

If it doesn't work, we're not going to freak out after the second. If you had sex twice at home in the last 12 months, and you didn't get pregnant, you wouldn't freak out. So we're not going to freak out.

And I have found that kind of setting the stage that three you play transfers before you start to readdress stuff. It's really helpful. In the same way that we talked to patients about let's do three to six IUIs, and then let's regroup and figure out what we change.

I think this is no different. And I think we could all probably be doing a little bit better job of just tempering expectations and setting the stage for what the next three months could look like for that patient to avoid the ERAs, the receptivas, the hysteroscopies, the chronic endometritis eval, kind of that whole rigmarole that we all go down and find very fruitless. Yeah, but Pietro, I'm a really impatient guy, and my patients just won't tolerate this.

Kurt, we just have to, I think, double down on how we set expectations for patients. The Amazon Prime generation, which I am one of them, wants things tomorrow. But if we tell them, listen.

Can I order endometrial receptivity from Amazon? If it were up to them, I'm sure they'd let you. Coming soon. I wouldn't be surprised.

Great discussion. Pietro, surprisingly, you assigned the articles this month, and you assigned yourself the reproductive surgery article. Tell us about it.

Yeah, you know, again, with great responsibility, with great privilege comes great responsibility, and I see a surgery article, I'm snapping it up. So apologies to Micah, Kate, and Kurt. This is a cool paper.

For those who have listened to the podcast and know me, I think a lot about uterine adhesions. I do a lot of uterine adhesion surgery. I spend a lot of time trying to counsel patients about how we avoid them and what they mean once we have them.

And in full disclosure, I'm a site PI on a multicenter adhesion prevention gel study and consult for a company that's developing this product. We, of course, are not going to be discussing this study or this company, but we are going to be talking about adhesions and why adhesions are so vexing for so many of us. From a recurrence rate, this is still a major challenge.

We think we can lyse adhesions pretty well, but re-adhesion rates are up to 62.5% reported in the literature, which, of course, varies based on severity, the number of prior corrective procedures. But we've all tried different things. We've tried intrauterine devices, we've tried balloons, we've tried adhesive barriers or gels.

Modest benefits have been reported in the literature for these different modalities. But nonetheless, intrauterine adhesion recurrence is high, and an estimated of 14 to as high as 48% of patients experience re-adhesion formation after these adjunctive therapies. This study from China, entitled Analysis of Factors Affecting the Prognosis of Patients with Intrauterine Adhesions After Transcervical Resection of Adhesions, aimed to explore these factors that influence prognosis after lysis of adhesions.

They also analyze reproductive outcomes and provide guidelines for improving outcomes. They took patients from 2018 to 2022 at a single center that were undergoing hysteroscopy for moderate or severe adhesions that were confirmed on office hysteroscopy. These are all patients who were actively trying to conceive and had no prior history of intrauterine adhesions.

In total, over four years at the single center, they had 292 patients who were included. These are all patients who underwent an index hysteroscopy in the operating room with lysis of adhesions, followed by a repeat office hysteroscopy, typically around two months after the index procedure. All of these procedures were performed under either spinal or general anesthesia, utilizing ultrasound guidance, and all of these procedures, interestingly, collected an endometrial biopsy for CD138 seeding.

I think this will be an important point that we'll talk about at the end, which I think may have potentially changed my practice, or at least got me to think about it. After the adhesions were lysed, patients all received an intrauterine adhesion barrier gel, along with estrogen and progesterone therapy. Patients also came back to the office 10 days after their initial procedure and had an intrauterine balloon dilation.

So, imagine placing a 16 French Foley through the cervix into the uterus, inflating it just to try to get the cavity to expand and lyse any filmy things that were starting to come together. Technique that's been described before, not super patient-friendly, but reasonably effective. So, what did they find? Approximately two months after the hysteroscopic adhesion procedure, 17.8% of patients had adhesions show up on their post-operative office hysteroscopy.

The adhesions that returned were, on average, much milder, so they used the American Fertility Society classification, mild, moderate, or severe. Pre-treatment scores were eight, post-treatment scores were two, and subjectively, patients report a significantly improved amount of menstrual flow pre- and post-procedure, which is always a nice bio-assay for what the endometrium is doing and what the outflow tract is doing. Now, here's really the most interesting finding of this paper that now makes sense, but I hadn't really seen it been reported before.

The risk of adhesion reformation in intrauterine adhesion patients who were found to have chronic endometritis on biopsy was 26.5 times higher than in those where the biopsy did not show any of those CD138 positive cells. Now, people have looked at the relationship between inflammation vis-à-vis the plasma cells and adhesion formation, and they found that the expression of uterine transforming growth factor, which promotes fibrosis, inhibits extracellular matrix degradation, is elevated in the endometrium of patients with adhesions and chronic endometritis, and the expression of matrix metallochronosis that stabilized fibrosis was reduced. So, there's something here about having adhesions and a concurrent inflammation, not necessarily infectious inflammation.

Chronic endometritis plasma cells can be infectious and non-infectious, but it seemed to portend a significantly worse prognosis if at the time of adhesion formation there was evidence of plasma cells infiltrating the surrounding endometrium. That is a really interesting finding that we'll get back to, but people also want to know about what happens to these patients when they do get pregnant. Well, around 51.8 percent of these patients became pregnant with a live birth rate of 74.6 percent.

Those numbers are pretty high. If anyone's ever taken care of adhesions or looked at the reported literature, that's higher than I would have expected, but kudos to them. Now, here's where I think our jaws start to drop.

So, of the live births, 14 percent were preterm, 83 percent had c-sections, and probably the most devastating two numbers that I'll read to you all day, of the 85 deliveries, 48 percent of patients experienced obstetric complications, the most common of which was placenta accreta spectrum disorder occurring in 29 percent of patients. And if you remember back from your days on the OB floor, placenta accreta spectrum is rare, occurs at 0.5 to 1 percent of the general population. That's a crazy high number.

This is not new. This number has been reported before. Groups from Boston, Keith Isaacson, Peter Bofill, and Human Reproduction have reported this number.

I think this number has to give a lot of us pause, and I think Eve and I have talked about a lot this on the podcast. We've talked about it on the sidelines. Yeah, we can lyse adhesions.

Yeah, we can get patients pregnant. But if we're not counseling them appropriately about the risks of that pregnancy and communicating those risks effectively to their obstetricians, we're doing these patients a huge, huge, huge disservice. So, to me, the biggest takeaway from this paper are twofold.

One, should we start biopsying the endometrium at the time of lysis of adhesions, particularly if we think it portends a worse prognosis for their postoperative adhesion reformation? Maybe, got me thinking. But two, does treatment of those adhesions, either treatment of the chronic endometritis, either empirically or once the biopsy comes back, does that change the prognosis at all? I think that question needs to get answered. I don't know.

Can't just biopsy for biopsy's sake. But really, the final part is, how do we more effectively communicate that, yes, we can get these patients pregnant, but what does the obstetrician need to know about these patients once they show up in their practice? Placentic creatine spectrum disorder is devastating. It's associated with a significant morbidity and mortality.

And are there things that we could be telling these docs beforehand, preparing them for the more appropriate delivery setting, delivering in a major academic institution with the creatine spectrum disorder protocols in place, a blood bank? I'm really kind of thinking a little bit more about how I can do that when I'm getting ready to discharge patients to OB. So two big head scratchers from me. I'll shut up for a second because I'm sure Kate, Curtin, and Micah have something to say about it.

What did you guys think about this data? Yeah, I agree with you. It's not surprising, but it is always humbling to see these obstetrical outcomes in these patients. And so I couldn't agree with you more as we discussed, I think, in the podcast last month, that we just have to make sure that we counsel patients about this exactly as you say.

The other thing that I just wanted to give a plug for is the importance of studying these interventions in the context of clinical trials. This was a study out of China. There are ongoing recruiting clinical trials in the United States evaluating these adhesion barriers and specifically this hydrogel system.

And so if you have a patient that's interested in this, encourage them to enroll. And part of the argument we had with this company that's putting on the trial is that we don't need to stop at adhesion formation or reformation postoperatively. We need to follow their obstetric outcomes and they've listened and they're now tracking what happens after the fact, which I think will be helpful.

Yeah, great modification. Pietro, you obviously do a lot of these surgeries clinically. What's your preventive method that you use most commonly? I've historically been very frustrated with intrauterine balloons.

I think the Cooke balloon that we all kind of intellectually like because it looked like the shape of the uterus, it probably filled the lower segment and the cornea a little bit better is no longer available. Some of us still have some old stock in our surgery centers and use them in select cases like we do. The intrauterine Foley balloon kind of sucks.

I think if you have a big central midline adhesion, it could be helpful just for physical distention, but if it's anywhere else, you're kind of in a world of hurt. Sometimes a nice big gauge Foley is helpful to prevent the lower segment, the outflow tract from re-stenosing or re-adhesing. So I'll use it there.

I like estrogen and progesterone. I think it's benign. I think it intellectually makes sense.

There's some data to suggest that it helps. We don't have access to intrauterine IUDs here in the United States, although some people do buy a Paragard and take the copper off and do it that way. So I think all of us are really hungry for something else, which is why I wanted to participate in this multi-centered perspective, randomized trial, looking at adhesion prevention barriers to see if there's something better that we could be doing for women.

But there's some groups in Europe that are working on stem cell therapy, injected either into the sub-endometrial space or infused into the uterine artery with induced pluripotent stem cells. I think there's so much that could potentially be coming out. So I'm more excited than ever.

I think the same way that we've been doing it has not worked. We're kind of on the brink of some better therapies. An age-old problem.

I'm glad that we're seeing some new data to quantitate it for us, but it would be great if we could solve it. Yeah. So Pietro, you mentioned that they comment on the American Fertility Society score.

I just have to say that goes all the way back to 1988, which American Fertility Society was the precursor of ASRM. One of my favorite books is from Alan DeCherney, which talks about the history of our society. At one point, we were the American Society for the Study of Sterility, A-S-S-S, until Dr. George Speck stood up and said, we should not be known as a bunch of asses.

And so we came up with a new name, which is now the American Society for Reproductive Medicine. That definitely sounds better. Ain't that right? We've come a long way, baby.

We shouldn't be acting like that either. No, we should not. All right, Kurt, we have one more article.

And one of my favorite sections of the journal that you have brought forward are the research letters. And we're going to talk about one of the research letters. There are actually three this month, but we're sticking with this sort of theme of obesity and sort of metabolism with this one.

So tell us about this final article we're talking about today. So a research letter is a full publication in fertility and sterility. It is cited the same way.

It is credited the same way. The idea, though, of a research letter is that it is a brief articulation of your science. It could be a very focused paper with a single finding, or in this case, it could be a reanalysis of another study with a second important finding.

So I just wanted to let readers know that if you get asked to revise it to a research letter, it's not a demotion. It's actually, we like the paper. We just think it could be stated a little bit more concisely.

So this particular research letter is the effect of a eukaloric high-fat diet on the anterior pituitary hormones and adipocytokines in women with normal weight. So I learned a new term from this paper. There may be something called referral metabolic syndrome.

Guys familiar with that? Heard that one? No, I hadn't heard that one yet. So the theory was in a previous publication by these authors, Tai Nguyen is the senior author and Annette Santoro, they demonstrated that there may be a syndrome with obesity that affects the reproductive hormones coming from the pituitary gland or vice versa. We don't know the cart and the horse in this case.

So the idea that you might have a decrease in LH amplitude, which ultimately might give you a decrease in LH levels, a decrease in corpus luteum function, a decrease in progesterone, and therefore a greater negative feedback of estrogen causing suppression. So I've always had this idea, and Dr. Santoro and groups have helped crystallize it with me, that not all ovulations are the same, not all corpus luteums are the same. Just because you have progesterone doesn't mean it's the same metabolic function of the menstrual cycle.

And I learned early in my career when I was looking at progesterone-only contraception that affecting the pulsatility of LH can have huge effects. You know, Depo-Provera works by stopping all pulsatility from the hypothalamus, and at lower levels, birth control pills and less concentrated progesterones can just affect the pulsatility and therefore changing the ability to ovulate. So it's not inconceivable that obesity might have some of these same functions.

Anyway, this study was to go take it one step farther and to study a high-fat diet that happens to be 48% of the calories made of fat, but eukaloric, meaning you're taking normal women giving the same amount of calories, you're just really increasing the amount of fat they have, and they wanted to see if there was an additional effect on anterior pituitary hormones. So basically, the study looked at a small number of women, but in a pre-post fashion, very good human physiologic study, and it noted that there was some decrease in LH and FSH, but there didn't seem to be much of a change in some of the other pituitary hormones. There was a modest decrease in cholesterol that was statistically significant.

There was a modest decrease in T3 that was statistically significant, and a trend in the lower end growth hormone, but many of the other hormones like adiponectin, IGF-1, leptin, prolactin, TSH were essentially unchanged. So they concluded that a high-fat diet can affect the anterior pituitary in a sense because we're looking at LH function, as I mentioned before, but it may be cell-specific. It's not global.

As I mentioned, perhaps the effect might be due to not just the anterior pituitary, but other ways that progesterone is synthesized, going again to its pulsatility or even its effect. So it's not just directly on the anterior pituitary. So I liked the study in that it made me rethink the physiology of human reproduction and the effect of obesity.

I don't think they found exactly what they were looking for with a slam dunk to say that obesity has an effect globally on the anterior pituitary, but still so much to learn about the interplay and obesity and reproduction, again, or vice versa, because we don't know the cart and the horse. And I was very pleased to put it in the same issue as all these other articles on obesity to help us think through this problem. So I hope you enjoyed this issue and the science that we put into it.

Kurt, I love the research letters that you've added, and we just should acknowledge Irene Sue, who's the editor of this section, who does a phenomenal job. It's a really quick, digestible way to read a simple concept from someone without going through a full paper for these kind of manuscripts. And this important finding, you could argue it's a negative finding, but this important finding deserves to be published.

And having it in a full-length article wouldn't do this justice, or I'll put it in the positive, putting it in a concise, small format does it better justice than writing a full article that's updating findings from a previous study. If you continue to scan down towards the end of the table of contents, there's one section that I think deserves special attention this month. The video articles, and I know this is an audio podcast, I wish I could show you what I'm seeing, but the three videos this month are actually tremendously cool in very different ways.

You know that all of our video articles are hosted on YouTube, they can be seen on our social media channels and on the FNSMATE website, but three videos I want to point out to you. One, an article entitled Neo-Neovagina Creating Technique Based on a Fascial Cutaneous Flap for Malarian Agenesis. Imagine taking the skin from the inner thigh, rotating it around, creating a neovagina and tucking it in.

Exceptionally cool procedure. Two, there's a video on using ovarian tissue biopsy for cryopreservation using a V-notes approach. Instead of performing a laparoscopy to harvest ovarian tissue for ovarian cryo, using a natural orifice procedure through a colpotomy to be able to do it.

Really stinking cool. And then the last one, Kurt, here's your ectopic pregnancy paper for the month. Hysteroscopic subchorionic injection of methotrexate followed by laparoscopic excision of the gestational sac for management of cesarean scar ectopic pregnancy.

An innovative dual approach for a challenging pathology. Three really cool videos that I encourage everyone to just spend eight minutes watching on our YouTube channel. I think you'd get a lot out of it even if you don't perform these procedures.

Outstanding. Thank you, Pietro. Kurt, we have about two minutes left.

The final thing in the journal this month is an expression of concern. And I know you've been dealing a lot as editor-in-chief of focusing on integrity of scientific publications. And there have been some retractions from the journal.

There have been some expressions of concern. Would you just take 60 seconds and just tell our listenership, why is this an important thing? Why have you been focusing on it? What's an expression of concern mean? How should we pay attention to these? Yeah, thanks, Micah. I think this is really important.

It's come to our attention recently that there is literature that's published that is not correct. In some cases, it's wrong. In some cases, it's a mistake.

But in some cases, it's hard to believe it's fabricated, that the study actually never happened. It kind of really amazed me that the prevalence of this. So what do you do if you find that a paper can't be trusted or does not belong in the scientific literature? The most dramatic ability is to retract it.

So that basically means you're saying, we made a mistake. This article shouldn't have been published. It's no longer in the scientific literature.

Now, you know, an accusation of scientific misconduct is huge. And you need a fairly high burden of proof to understand or retract something. So if there's a separate way of identifying it, that's called an expression of concern.

So in this case, there's probably been an allegation, or I know there was an allegation, that there might be something wrong with this paper. It was investigated. I'm sorry, it was investigated.

And while we can't, while we, the royal we, can't prove that it is factually incorrect or fabricated, we think there are enough errors in it that we're telling you as a reader, be careful. When you read this or interpret it or include it in meta-analysis, you should have concern. And that's what an expression of concern is.

It should travel with the article in PubMed. And I'm telling all you folks, when you do a meta-analysis or look at your research for journal clubs, you should actually actively look to see if there's an expression of concern and make sure an article is not retracted. So in Fertility and Sterility, we are actively looking to correct the scientific record and have had some already.

And this is an example. And we will continue to do that because we want Fertility and Sterility to be the trusted source of reproductive medicine and science. And something that's published in Fertility and Sterility should carry the appropriate weight and be relied upon.

Thank you, Kurt. I know we hadn't planned on talking about that today. We hadn't discussed that, but I appreciate that.

And I think all the readers of FNS appreciate sort of your leadership, not just within our society and our journal, but globally on the research integrity topic. Thank you. We'll end the podcast talking about an exciting opportunity that we want to share with our listeners.

Fertility and Sterility has long had a group of volunteers who are professionals in the field, contribute as editorial editors, associate editors, interactive associates, but we've noticed that there's an increasing need to bring new ideas and new people into the fold. As a result, Fertility and Sterility and the family of journals has decided to organize a FNS editorial fellowship. It was created with the purpose of identifying junior or senior clinicians, researchers, embryologists who hold a particular interest and promise in being involved in the academic publishing process.

The goal of the fellowship is to recruit one fellow per year to participate in a years-long, in-depth academic publishing experience that's going to expose them to the review process, the academic journal management process. And this individual is going to work closely with the editor-in-chief, as well as the editor-in-chief of Fertility and Sterility family of journals and reports, science, and reviews. The position is going to be entirely remote.

The position is going to require participation at editorial board meetings, management of articles, providing support for the editorial board, and identifying and implementing a longitudinal improvement project on behalf of the journal. If you're interested in applying, applications are now open. The position is going to run from October 31st, 2024 to October 31st, 2025.

And like I said, an entirely remote position for people who are actively in training or nearly or out of training and not in their career, wanting to be more involved in the process. To apply, you can send a CV and a cover letter to fertstert at gmail.com. And in that cover letter, please make sure you share your interest in why the fellowship is of interest to you, other things that you have going on during this year, and reasons why you think you'd be a great fit for us. The application deadline is August 31st, and anything that you submit, we'll take a look at and hopefully announce our very first inaugural FNS editorial fellow at the ASRM annual meeting in Denver.

You've probably guessed it, but we could be talking for another hour. There's so much stuff that we love about the journal and so much stuff in this month's edition that kind of tickles us and gets us excited. But we'll have to wrap it up, and we'll come back to you next month with the September table of contents, and then eventually the live from the ASRM annual meeting podcast, which I know has been a hit historically in the past.

By the time this podcast is published, you'll probably also be able to listen to the live from ESHRE podcast recording. I know Micah and the FNS team are there recording a series of interviews live from the meeting, hearing about the current science and hearing from our European colleagues. So just more great content for all of our listeners.

Until we meet next time, that's it for me, Kate, Kurt, and Micah. Bye-bye. Thank you very much.

This concludes our episode of Fertility and Sterility on Air, brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine. This podcast is produced by Dr. Molly Kornfield and Dr. Adriana Wong. This podcast was developed by Fertility and Sterility and the American Society for Reproductive Medicine as an educational resource in service to its members and other practicing clinicians.

While the podcast reflects the views of the authors and the hosts, it is not intended to be the only approved standard of practice or to direct an exclusive course of treatment. The opinions expressed are those of the discussants and do not reflect Fertility and Sterility or the American Society for Reproductive Medicine.