Fertility and Sterility On Air - TOC: October 2025

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

• (04:48) Advanced maternal age was associated with an annual decline in reproductive success despite use of donor oocytes: a retrospective study
• (15:16) Developing a decision support tool to optimize oocyte thawing for producing at least three euploid blastocysts
• (23:47) Effect of denosumab on semen quality in infertile men selected by serum level of antimüllerian hormone: a randomized controlled trial
• (31:06) Progestin prime ovarian stimulation provides comparable outcomes to GnRH antagonist in donor cycles with vitrified oocytes
• (41:13) Impact on clinical outcomes of membership in the Society for Assisted Reproductive Technology
• (48:58) Linzagolix with and without hormonal add-back therapy for symptomatic uterine fibroids: PRIMROSE 1 & 2 long-term extension and withdrawal study
• (56:30) Cumulative pretrigger progesterone levels are not superior to single-day levels for predicting a failed cycle in fresh embryo transfer cycles

View the October 2025, Volume 124 Issue 4 of Fertility and Sterility at https://www.fertstert.org/issue/S0015-0282(25)X0010-8

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 discussions with authors and other special features. FNS On Air is brought to you by the 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, Dr. Pietro Bortoletto, Interactive Associate-in-Chief, and Associate Editor, Dr. Kate Devine.

Welcome back to Fertility and Sterility On Air, October 2025. We're on volume 124, number 4. I'm Micah Hill, the Media Editor, joined by Kurt Barnhart, Kate Devine, and Pietro. We've got a lot to talk about, so we're just going to dive right in.

In the front matter this month, we've got a nice article from Alan DiCerny, so if you're one of the hundreds of people that have been mentored by him, he's got 10 points of wisdom. I'm sure you'll appreciate the anecdotes and the wisdom from Alan DeCherney in reading that. Eve wrote an inkling, Kate, on restorative reproductive medicine.

Do you want to just give us the highlights of what he was talking about in that article? Yeah, absolutely. This is a great read for anybody in our field, and I would say many outside of our field. The inkling by Peipert, Kuhlman, and Feinberg augments some excellent fact-based resources that have come out recently from ACOG and ASRM, and essentially explains what I think we all know, but quite eloquently, that essentially what is referred to as restorative reproductive medicine is really already part of the full scope of REI practice that all REI physicians are well-trained in, but that limiting available treatment for patients with infertility only to what is described as RRM really withholds treatments that are essential for many patients to become parents.

Furthermore, there's been description in the popular press by proponents of RRM that ART is, quote, flawed and grossly unethical. These statements really stigmatize the patients that need the essential treatment of ART, and I would, again, encourage everybody to read it. There's some really excellent examples.

Of course, men with congenital bilateral absence of the vas deferens, this is the only way that they can become parents of children genetically related to them. Then they talk about other examples from medicine where, you know, we don't rely upon only lifestyle modifications to provide lifesaving and curative treatments. For example, coronary artery bypass grafting is necessary to save lives and to treat the disease of coronary artery disease, just as ART is necessary to treat the disease of infertility.

So, you know, I would encourage everyone to read this. As I've now said a couple of times, it's really incredibly well written, as well as some of the other fact sheets, again, from the ASRM Center for Policy and Legislation and from ACOG. A few of us, I think, will be on the Capitol tomorrow to really give a briefing, listen to a briefing on the importance of debunking some of the myths that the RRM proponents are putting out there.

So thank you to Ben and Eve for this outstanding contribution. And yes, of course, we need to focus on the underlying root causes of infertility. That said, it's not going to get every patient to where they want to be.

Great summary, Kate, and I really appreciate the inkling in your summary of that. I don't think we can overstate that REIs do restorative reproductive medicine every day. We counsel on optimizing natural fertility every day.

It's part of what we do. We don't push patients towards IVF, or at least we shouldn't. But IVF is an important tool that many patients need, and any attempt to limit that or stigmatize that's not what's in the best interest of our patients.

So I look forward to seeing you and others at the Capitol tomorrow and making sure that that message is heard by the lawmakers. Great, let's jump right into the science. Kate, you also have the seminal contribution this month, a really interesting read on outcomes based upon maternal age and donor oocyte recipients.

What did we learn from this study? Yeah, so this one's a little bit of an upend to what we, I think, have often counseled our patients, which is that reproductive aging in humans is attributable almost exclusively to the oocyte and that by moving to donor eggs, you know, that factor is adjusted for and they can expect essentially equivalent odds of success regardless of their age as recipients. So this seminal contribution by first author Patricia Sebastian-Leon and co-authors from IVI present a retrospective analysis of transfers of about 33,000 single blastocysts from donor eggs, all of which made it to blastocysts by day five. So in that way, they adjusted for embryo quality.

And these transfers were performed over a period of about 20 years. So long study follow-up, which accounted for the large sample size. The donors were younger than 35 years old at the time of egg retrieval and the recipients were all aged 35 to 50 years old.

All endometrial preparation was via programmed cycle with oral estradiol and vaginal progesterone and all included transfers were to recipients with a BMI of 19 to 25, so normal BMIs. The authors found no decline in success for recipients as they aged from 35 to 40 years old. However, for recipients beyond 40 years old, implantation failure, which they defined as a negative pregnancy test two weeks post-transfer increased by 4.2% per year and pregnancy loss into which they combined both biochemical and clinical loss increased by 3.2% per year, again, after the age of 40.

Live birth per transfer gradually decreased from about 46% among 40-year-old recipients all the way down to about 33% to recipients who are 50. They did evaluate patient and cycle characteristics, including BMI within that already normal range to which they limited their inclusion, fresh versus frozen eggs, fresh versus frozen sperm, and fresh versus frozen embryos, as well as PGT status, which really only about 2%, less than 2% of the embryos had PGT. They found, though, that the differences in all of the cycle and patient characteristics that they were able to evaluate were negligible and they did this by Cohen's d-index for continuous variables and Hedge's g-index for categorical variables.

And so this was a rigorous step that they took so as not to erroneously adjust for underlying characteristics that were not truly associated in a meaningful way given the large sample that they were dealing with. Importantly, they were unable to control for uterine factor, endometrial thickness, and paternal age, which I think is a really big factor to consider when we think about the clinical import of these data. It's also important to, you know, call attention to the fact that this was a really heterogeneous group of transfers occurring over a long period of time from a mix of fresh and frozen eggs, fresh and frozen embryos.

I always think about when we look at these really long study follow-up periods, whether the authors may have considered controlling for the year of embryo transfer, I can think of some biologically plausible ways where, you know, as we may be doing transfers to older and older recipients, maybe some other things are changing over that time period as well, like a shift towards using frozen donor eggs, etc. I did really love this paper, though. I have to say I liked their analysis overall.

I thought it was rigorous and their figures are beautiful. So for one thing, the simplicity of figure two, since, you know, again, there was not much for them to adjust for, given that the actual variables that they evaluated were negligibly associated with age, it just shows these beautiful curves of what recipients in this population experienced in terms of declining live birth after the age of 40, increased risk for miscarriage. And then beyond that, I also really loved figure three, which shows essentially a very nice illustration of the relative risk of their outcomes of interest and the confidence intervals relative to the null.

So Micah made me think of our conversation at Journal Club with our NIH fellows just this week. Very illustrative. So from a clinical standpoint, this is certainly hypothesis generating.

I am, for one, am not 100% convinced that if we were able to remove all the uterine factor, all the adenomyosis, which I think we all experience as something that increased with age, that there's going to be a really clear and robust association here. But I think it's something that we certainly need to look at more closely. I recommend the read in part because of a really good discussion of biologically plausible explanations of what they observed in terms of urine aging and what has been described in the literature in terms of the genetics and hormonal milieu and increased inciliation in the endometrium as potentially resulting in resistance to implantation as our patients age.

And so I'm interested to hear a little bit from this group as to how they counsel, how you guys counsel your patients as they get older. Do you tell them, oh, it's a home run once we've got these donor eggs, or do you caution them that their age might still be a factor? I want to underscore what you said, Kate, about this paper. So well done.

So interesting. And from a methodologic perspective, they really got ahead of a lot of the criticisms that people would have about this kind of article. I think the one criticism that they missed an opportunity to adjust for was the effect of a 22-year follow-up period.

So much changed in the early 2000s in our field. Media, vitrification, laboratory equipment, you name it, there's a lot there. But the figure three to me is probably the most impressive figure of this whole paper.

And take a look at those confidence intervals. They are so tight. Micah always talks a little bit about the size of the confidence interval.

Micah, for the fellows listening, how do we interpret a confidence interval that goes from 1.028 to 1.056 for implantation failure? I'd love to hear Kurt's insight as our resident epidemiologist on confident intervals, and then I'll follow if I have anything to add. I wanted to start really general on the paper, then I'll answer your question more specifically. I really think this paper was a contribution and a seminal contribution in that it challenged a little bit of a dogma.

We still might think that it's location, location, location is the most important factors. But this is telling us that there are other factors other than the egg. And in this sense, it doesn't surprise me that age does matter.

You don't stay healthy at any given age forever and just lose your quality of egg. So the contribution might be a lot less than the egg contribution, but I really believe it's there. So when I cancel my patients, this is a very good interpretation that, you know, yes, we can overcome the egg, but we can't overcome every single problem of aging and aging affects other parts of your body at different rates.

But the confidence interval is a different point of what I'm trying to make here. The confidence interval really in this case is a factor of how much data they had. So it's really a confidence around a mean.

If you looked at the scatter, like if you plotted at the numbers, you would see a much wider range. So it's really just the confidence around a generated mean, not the description of what's going to happen in real life, if you follow what I mean. So it's a mathematical confidence, not a real world explanation of what really can happen, if that makes sense.

You think we need to factor this into patient counseling? Like we have these calculators that predict patient outcomes for autologous IVF. For donor egg, I tend to just give them a sort of overall estimate of what success is for the general population. I don't know that I personalize it if the testing is normal.

Do you think we should be doing that based upon these data? It's hard, again, because this is a denominator study, right? It's talking about populations. And in populations, you have a decreased pregnancy rate with age. But in any individual, it's hard to predict, like, is it the cilia? Is it the adenomyosis? Is it your fitness level? Is it your antioxidant level? I'm making stuff up here, of course, on purpose, because everybody is going to say, but in my case, and it's really hard to say the my case, but it is really important, I think, in counseling to say, I can't guarantee the same success you had than if I had seen you 10 years ago or 15 years ago.

One of the things that I think we don't do really well in our field, but the MFMs do a lot of is evaluate uterine artery resistance. So pulsatility index, resistance index, how much blood flow is getting through the uterine artery at a fixed point. And if you talk to them, they definitely have lots of data to suggest that older mothers have more resistance through their uterine arteries.

And that may indicate issues with placentally mediated disorders in pregnancy. But might that pulsatility index or the resistance factor also indicate a certain amount of reduced implantation potential for our embryos, despite a nice 7, 8 millimeter trilaminar lining with oral estrogen. Great.

Thank you, Kate, for sharing that article. Yeah. Kurt, last thoughts on it? No, but it does, again, challenge the dogma that it's not solely the egg or the chromosomes, I should say, which I don't know if I'm going out of order here.

It leads into an article that I had, which was, again, looking at a relatively, I don't know, it's just another circuit marker, but it's one that's in our field. So I'm talking about a paper that's talking about developing a decision support tool to optimize oocyte thawing for producing at least three euploid blastocysts. Now, this paper, again, a lovely paper by Emily Clarke and others, and senior author Alan B, Copperman out of Mount Sinai and RMA.

And I'm changing the goalposts a little bit here. This is not donor eggs. This is women freezing their own eggs, and I'm using them later.

But the concept is the same. It's like, how many eggs do I need? And what goes into how many eggs do I need? And need, in this case, we're changing the goalposts from getting pregnant to I need three euploid blastocysts. And that concept of I need three euploid blastocysts came from Paul Pirtea and also the RMA group that's saying that if you do have three euploid blastocysts, you'll have a cumulative chance of having a pregnancy of upward, I have seen 92% or 93%, but anyway, in the mid-90s, which is outstanding.

Now, spoiler alert, this makes some very concrete assumptions that you need to make in a prediction model, which is that, again, all women are created equal in that you have the same probability for each embryo and that all women will have 93%. And we can talk about whether that's a good assumption or not. But this paper is trying to, again, mathematically, based on a relatively large sample size, to say, you know, if I have eggs frozen and I come back and thaw them, what's the chance that I can get this surrogate outcome of three euploid embryos, which pretty much guarantees, not guarantees, which gives you a very high probability of being able to have a baby, which is hopefully the goal of why you froze your eggs in the first place.

So, let me go into the details real quickly for you. They divided the groups of women by start age categories. I'll get back to that.

But they also stratified the group of number of people who had eggs into groups A, B, C, and D, which A is 2 to 8 eggs cryopreserved, B is 9 to 11, C is 12 to 16, D is greater than 16. I'm not 100% sure how they came up with that division, but that seems relatively reasonable. And then they actually compared, you know, everything to the greater than 16 egg group.

I'll say it up front because someone's going to ask me, this is not multiple egg bankings put together. This is retrieving, you know, one set of categories. Obviously, the question should be, well, what if I, you know, do it a second time and a third time and I cumulatively get my numbers? And I don't know how far it'll be different from this paper, but this paper doesn't specifically answer that.

So, the paper, again, is well done. I'm really pleased with the methods that are coming to the papers in FNS. I mean, they're thoughtful in how they're controlling for factors.

They're very clearly describing which factors should be controlled for. And most importantly, they're telling you when they can't control for something and then let you interpret it rather than hiding it or pretending the reviewer doesn't catch it or something like that. So, the methods are well done.

They have a logistic regression. They control for lots of factors with age and BMI and year cryo. And then they come up with the following findings.

They basically say, if you just look at number of eggs, the number of eggs, I'm sorry, people that have 12 to 16 and greater than 16 have about the same chance of getting three euploid embryos. They're statistically not dissimilar. Numerically, it sounds a little different.

It's 50% for the group that have 16 eggs and it's only 27% for the group that has 12 to 16. So, the actual numbers sound pretty low. But statistically, they're saying that's the same.

And the conclusion, therefore, is if you do have these difficult counseling options and personal decisions that, you know, if you have greater than 12 eggs, you could probably just thaw 12 eggs and you could save the rest for another time if there is a reason to have another time, different partner, not sure what you want to do, et cetera. But anything below that, you should thaw all of your eggs at once to optimize your chances. That itself is an interesting consult.

Do you tell that to your most patients right now, guys? I mean, because people ask me, should I selectively only thaw six like they do in an egg bank? And I say, no, I think you should thaw them all and see what you have. I'm just curious what your guys' standard of care is. Yeah, I do the same with the only possible exception is if they are not sure whether they want to parent with a different partner in the future.

Otherwise, from an efficiency perspective. That's what this paper is basically alluding to, that, you know, if you have still questions in your plans, that you can address those questions by limiting your embryos. But to me, the take-home message was their second point, which was that when you stratify this by age, and you looked at women above and below 38, and they did look at the SR categories a little bit more specifically, the numbers were drastically different.

And so, you had a reasonable similar finding if you're less than 38 in terms of essentially the number of eggs you have, the better chance you're going to have three eukaryotic embryos. But above 38, nobody got a lot of embryos. And again, it shows us that age is really important.

In this case, they're saying, don't split your eggs. You know, the chance of you getting a eukaryotic embryo when you're greater than 38 or low, you shouldn't be saving your eggs. So, and I guess the absolute numbers, it's just not a prediction here, right? The absolute numbers, if you were 38 to 41, and you have greater than 16 eggs, which most people would be like hooting and hollering, like how well I did, and I'm so much better now, your chance of having three eukaryotic embryos is 7%.

So, we can't, you know, we can quantitate what nature dictates in terms of success here, but the quantification isn't always all that good. So, I think this is a really nice paper to help you counsel patients. It brings out what I think we were intuitively learning from this in a nice way with rigorous methods.

As I said, it doesn't include multiple egg banks and one thaw, although I'm not sure how different that would be intuitively, but again, it's just not there. And I think the limiting factor for this in my mind was pregnancy rates, because if you combine this paper now with the paper that Kate just mentioned, we didn't follow up, you know, how old were you when you actually got pregnant? And was there a difference in the pregnancy rates when you used your eggs when you were young and when you used your eggs when you were older? So, I think it goes really well into a theme here that we can, we're getting very good at taking our own data and learning things, but it doesn't necessarily always help the individual patient that's in front of you. What do you guys think? I found the three euploid embryos to be a really interesting outcome.

Like you say, live birth would have been interesting. The patients that tend to want to limit insemination, I don't know that their goal is three euploid, because they're usually wanting the pregnancy and no extra supernumerary embryos. And I understand the three euploid gets you a 95% chance, but there'll be a lot of patients, more than half, that'll have supernumerary embryos and have a baby with three euploid.

And that tends to be what this patient population is trying to avoid. So, that's sort of like they hit an intermediate target between inseminating all, which is I think what we do for most patients, or trying to limit it to one baby, which is what some other patients are asking for. Does that make sense? So, I was a little bit, I'm trying to figure out how I would apply this, I think, clinically.

What patient is the patient population where this is going to help me? I think it's asking a different question here. Can you be relatively sure you're going to have a baby, or can you be 50% sure because you have one euploid embryo? And I don't think our patients, in my experience, maybe it's the way I say it, but I don't think everybody understands odds. And when you say you're going to get one embryo and you've got a 50% chance, that's still a lot of people that are pretty angry at me that things didn't work.

Yeah. Again, I think it's a patient selection and kind of rolls into some of the other conversations that we've already had on this call, which is to say, look, what are your priorities? How do you feel about supernumerary embryos? Or do you just want it to be a home run and a one and done, and you don't mind if you don't use every embryo you create? So, a matter of, as much as we're all for standardization in general, there's still some clinical scenarios, and this is one where you really need to understand your patient's goals and meet them where they're at. All right, Pietro, we're going to jump into the world of andrology.

What is denosumab, and does it help us with sperm? Yeah, buckle up. You probably never thought we'd be talking about a chemotherapy agent to potentially help with sperm production, but here we are. So, let's talk about denosumab.

So, if we take a step back, we know that male infertility is generally considered easy to treat, right? We have so many tools at our disposal. We have millions of sperm to work with, but still, there are actually a surprisingly small number of options for men with idiopathic oligozoospermia. And when we think about that group of men, we try to think about what are the therapies available to us? There has been a nice body of actually observational research that's looked at the effect of denosumab on semen quality in men.

Not literature that I've kept up with, so I was learning about it for the first time. It showed that exposure to denosumab, a monoclonal antibody, may improve spermatogenesis in mouse and in human tissue models, and there's some good biologic plausibility for why this might be true. The RANKL pathway, normally involved in bone development, also happens to be present in sertoli and germ cell signaling.

And for those who remember their step one knowledge, this is an apoptosis regulator gene. We'll talk a little bit more about this later. So, when there's a nice body of data, both in animals and in human tissues, to suggest there might be some effect, it makes sense to prospectively try this out and see if it does anything.

And that's exactly what these authors from Copenhagen University Hospital in Denmark decided to do. They organized a phase two double-blind placebo control trial, where they planned to enroll 282 men. Unfortunately, they did stop at their interim analysis after 179 randomized men.

Their population of interest was men between the ages of 18 and 60, who had been experiencing fertility for greater than 12 months, who had sperm concentrations less than or equal to 20 million per ml. And importantly, and we'll talk about why this is important, serum AMH levels greater than or equal to 38 picomoles per liter. Now, we are thinking AMH in men, huh? Well, AMH is synthesized by the sertoli cells and in men, and the production of AMH is regulated by follicle stimulating hormone and testosterone.

And in infertile men, low serum AMH is linked to poor semen quality. And AMH has been shown to potentially be a useful marker for residual sertoli cell function. So when you're designing an RCT, you want to make sure you're targeting the therapy to the group of patients who have a stand to benefit from the intervention the most.

So they incorporated high AMH levels into their inclusion exclusion criteria. They did exclude severe oligospermia. So men less than 2 million, men with a history of cancer, other systemic comorbidities, severe vitamin D deficiency.

In general, these men were around the age of 34. It was Denmark. So their BMI was 26 and their median sperm concentration was 10 million per ml.

Now, what did they do? They gave these men a single subcutaneous injection of denosumab, 60 milligrams versus a placebo. And they followed up these men for 80 days. Why 80 days fellows? Well, one spermatogenic cycle, if you're going to create an intervention, the earliest you'd see a benefit from it during the spermatogenic cycle is 80 days.

All of these men did receive daily vitamin D and calcium supplementation. Now, what was the primary outcome? Changes in sperm concentration at 80 days, secondary outcomes, the obvious ones of semen volume, motility, morphology, but they also looked at AMH testes size as subgroups of particular interest. All of this to say, unfortunately, there was no difference in sperm concentrations between both groups at 80 days.

There was no significant changes in motility or morphology. However, one of their exploratory subgroup analyses, looking at men with small testes volume, less than 16 MLs showed actually a 29% increase in sperm concentrations. This increased mean sperm concentration in this group from 8.5 million per ML to 11 million per ML.

The interventions appeared to be safe. There were 29 adverse events. They were balanced between groups.

They were all mild and localized, no serious exposure concerns from denosumab. But unfortunately, listener, the denosumab did not improve semen quality in infertile men who are stratified by age and AMH. Potentially, there's a benefit for a very narrow subgroup of men who have elevated AMHs, but a smaller testes volume.

This is, I think, a hypothesis generating finding, something that the study was not powered to identify and really report on, but maybe lead to future exploratory studies for this subgroup of men. I think, unfortunately, the study reinforces that it's really challenging to find effective pharmacotherapy for male idiopathic infertility. We are still on the hunt, but I love it when we have a biologic plausibility storyline that we can follow in a medication that's already being used in other aspects of medicine, and we can test out in a group of men to see if we can make a difference.

Unfortunately, not yet. Micah, Kurt, Kate, ever used denosumab in a group of men? I have not, but I like the originality and novelty of this study. I was just curious what the group thinks about ending trials early.

It seems like it's becoming more and more common. Maybe 20-25% of the articles, trials I'm reading these days, end early with an interim analysis that finds nothing. Based upon how you powered it, I guess halfway through the study, you would expect your interim analysis to not find a significant finding.

I'm just curious on people's thoughts of when we should end trials early and what the risks are of doing that. I wonder how much of this is coming from skittish IRBs who are really looking for a hard stop, protect the patient from unnecessary additional intervention that's not showing benefit. To me, it just reinforces the need for a really great statistical plan and someone who's thinking about your trial methodology with you, because you may think you know where the cut point is, but I think having someone inform that can be really helpful to make sure that you're getting your money's worth from all the effort going into this trial.

And that's the other side of the coin, Pietro, is that you don't want to be extending a lot of effort, meaning expense and everything else, if it really isn't going to show anything. But what I'd like to just jump in is that I think it's important to accept a study that stops for good reasons, because you don't want to force people to go to the end of the study to be convinced it's a negative study. In other words, there's value in something that's futile.

Appreciate those thoughts. And their reason for ending it was well established and seemed like it was a priori, so I'm not being critical of it. I'm just curious of the experts' opinions on that.

That's really interesting. All right, Pietro, thank you for that. Kate, we're coming back to you and back into the world of ART.

They call it progestin primed. We're just going to call it the progestin protocol. Does this work in donor eggs? Thank you.

Yes, definitely a misnomer, as we have discussed. And we're back to the IVY group and back to donor eggs. So I have a theme for this podcast today.

Here, Murria and co-authors, again from IVI in Spain, put together another good study evaluating donor egg ART. This one evaluated the clinical outcomes of implantation, clinical pregnancy, ongoing pregnancy, and cumulative live birth from frozen donor egg transfers. And the exposure was whether the frozen donor eggs were derived from stimulation cycles with pituitary suppression achieved via medroxyprogesterone or GnRH antagonists.

So there were 3,600 MPA-derived donors and 5,000 antagonist-derived donors. Again, over a long, though not as long as 20 years, study period from 2016 to 2022. And over this time, the center gradually transitioned from predominantly antagonist cycles to predominantly MPA, so progestin-suppressed cycles.

The authors' GEE analysis identified recipient age, BMI, the number of mature eggs, and embryo quality as predictive of live birth. But pituitary suppression, and to me, unsurprisingly, and based on the growing body of evidence in the literature as well, was not associated with live birth or any other clinical outcome. The authors went on, again, rigorously to present a sub-analysis of 877 donors who underwent at least one of each type of protocol and, again, found no differences in the clinical outcomes.

They did find in laboratory outcomes that MPA-derived oocytes were more likely to make it to blastocyst and to result in blast with good quality morphology as conventionally assessed. They use their European standard system, but these are ABC, good, fair, poor quality embryos. Again, that did not translate into difference in the clinical outcomes.

They did a second interesting sub-study, which almost reads like an entirely different paper, where they looked at some AI technology, which are already in much more widespread use in Europe, where the embryoscope is largely used. They look at all the cycles where embryoscope was used, and they look at some AI algorithms that they applied both to evaluate the eggs as well as to evaluate the embryos. So, they use Future Fertility's Magenta system to evaluate egg quality as well as IDA score to evaluate embryo quality.

And they sort of do a pseudo-internal validation where they demonstrated that the Magenta score, the egg score, was in fact associated with the probability of the eggs making it to blastocyst. And then they went on to use then the egg score and the embryo score as outcomes, secondary outcomes of the exposure of the type of pituitary suppression. And so, you know, we can argue about whether that's a robust enough validation to consider these endpoints, but I certainly think it's an interesting diversion to read in the supplementary materials of this paper predominantly, and also just to kind of understand a little bit about what the largest center in Europe is doing pretty much standardly in terms of how they're looking at their ART cycles and how they're evaluating gametes and blastocysts.

So, didn't find a difference based on pituitary suppression in either the Magenta score or the IDA score, but yes, in terms of kind of more traditional, does the egg make it to blastocyst and is the blastocyst morphologically high quality? At the end of the day, this is a reassuring study for all of those out there, which is unfortunately still the majority of cycles in the U.S. that are not using medroxyprogesterone to prevent premature ovulation in ART. And, you know, lots of accumulating data on how this is a more patient-friendly protocol, it's lower cost, it's less monitoring, it's fewer injections, but we're not using it by and large, even in all of our freeze-all cycles. So, we had an interesting conversation among the associate editors this week as well about, okay, well, do we keep talking about this? It's been shown, basically, now we're looking at all these endpoints that we don't even know, like, does this hypothesis even make sense? And the authors acknowledge that.

There's a great editorial by Chervenak et al that says, look, like, I don't understand why this would improve egg quality, but we should keep on looking at it and saying it anyway because maybe it'll make people actually do it. And also, we don't understand everything. So, interested to hear what this group thinks about this paper in general.

There's so many things we could discuss about it. You know, should we be using MPA more? Why aren't we? Should we be using all these AI add-ons? It's almost mind-boggling. I've been such a proponent for MPA protocols for as long as I can remember, as long as this data has been coming out.

And when I started our clinic earlier this month, we made the decision to uniformly use MPA for cryo-wall and egg-free cycles. This is one of those few things in our field where we did it the right way. There's a humongous body of literature, prospective RCT, different age groups, different infertility diagnosis, different triggers that have largely showed the exact same thing.

This is safe. This is effective. This is patient-friendly, non-inferior to antagonist protocols.

My only gripe is that we continue to call it priming. Who the hell decided that this was progesterone priming? Mike and I are going to go to our grave trying to fight that one. But I'd love to see more data that supports my fixed, long-held beliefs about progestin being a great option for patients in 2025 and beyond.

I really applaud the idea that you all just mentioned here about, if we find ways that are non-equivalent, that are cheaper and patient-friendly, how can that not be a plus? I just want to be careful that we keep talking about AI and all the data that's generated by AI and the embryo scope. And remember, that's never been demonstrated to actually really improve anything. So we're crunching data that ultimately hasn't been proven to demonstrate anything and making small benefits based on, again, sub-aims and some data.

So I'm not a big proponent of AI. I don't think it hurts, but I'm not a big proponent of AI if it's going to cost more and you're charging it, because I don't think that's helping people. It's almost ironic in this paper, right, that here we are talking about this protocol, too, that's low-tech, really simple to help patients in terms of their costs.

And meanwhile, we're throwing on the embryo scope, throwing on all the AI as add-ons. So maybe it comes out even, who knows? But interesting data. And thought of that irony, Kate.

That's an interesting point. Pietro and Kate, you've been huge proponents of this. Are there any holes in our knowledge gap at this point? Like, it seems like we're pretty much hitting all the main questions on the progestin protocols and it's showing equivalence or non-inferiority.

Are there knowledge gaps that we're still really missing? And patient populations, maybe, that we're missing? I'm glad you asked that, Micah. I think there's mixed data still in low responders and really not a large representation in terms of the prospective studies looking at whether this might be overly suppressive or hurt outcomes in patients who are low responders. And so I'm sure the question will be answered.

I look forward to seeing a good quality study on this question. And then the other piece is, if so, is it because we're dosing them too high? So a dose finding study to evaluate, is there a progestin dose that will prevent ovulation but not be suppressive? Or is there a sweet spot, perhaps even based on the specific population, as to what we should be doing there? I think that still remains to be seen. My one fear with this is that the pharmaceutical companies who are desperate for novelty will find a oral progestin, run a trial, and get FDA labeling for it, for IVF specifically.

And then we will all be stuck making the tough decision. Do I go with the Clomid or do I go with the Letrozole? Do I go with the one that has FDA labeling for its indicated use? Or do I go off-label and take on that counseling and exposure? But hopefully, they're slow to it. And we have many more years of being able to use this safe, effective, and inexpensive option in ART.

Yeah, sadly, I think this is going to have to be an investigator-initiated, fellow blood, sweat, and tears project. Not a lot of money to be made for the $0.25 medroxyprogesterone and proving that you only need half a tablet. So... Go hike up the price.

We have the beautiful Ganirelix dose finding study, one of my favorite studies to talk with the Fellows about. But obviously, Organon had a financial investment as they were trying to bring that drug to market. And MPA is already out there.

So I agree with you. But for those who haven't tried this protocol, I've been doing it this entire year on all of my freeze-all's. It works great.

Patients love it. And they're saving a lot of money. All right, we're going to stay in the world of ART and talk about a paper that is near and dear to my heart, the impact on clinical outcomes of membership in the SART registry.

So this is from third-year fellow Daniela Diego. She's at Emory and a couple past presidents of SART, Jim Toner, Steve Spandorfer, who between the two of them have decades of experience in registry and SART. And so basically, they were looking at what's the difference between clinics who report their data to SART and clinics who skip SART and report directly to the CDC.

So that's the essential premise of this paper. Their outcomes were what are the oversight mechanisms between these two reporting outcomes, as well as what are pregnancy outcomes, miscarriage, multiple gestation, and so on. So this is observational data from 2021.

For those who don't know, in 1992, Congress passed the FCSRA, Fertility Clinic Success Rate and Certification Act, which required all fertility clinics by law to report their outcomes to the Secretary of the Department of Health and Human Services, who delegates that to the CDC within DHHS. Now, interestingly enough, I learned this during a SART meeting with CDC. Prior to this year, we'd meet twice a year with the CDC and monthly virtually.

And during one of our in-person visits, we found out that some clinics don't report to either SART or to the CDC. And the only way the CDC can find this is by Googling and doing searches and trying to find fertility clinics who are out there that aren't reporting. So for 2021, 73% of clinics reported to SART, 18% just to the CDC, and 9% they found online were IVF clinics that were not reporting to anyone.

Unfortunately, we learned at that meeting that the government doesn't really have a regulatory mechanism to enforce that law. So in other words, if clinics are practicing IVF and they're violating the law, there's not really at this point any consequences for them not reporting. But obviously, for those clinics that don't report, we don't know what their outcomes are.

Now, 91% of IVF cycles are done in SART member clinics. So the majority of cycles are done in SART clinics. And that means that SART clinics tend to be bigger.

53% of SART clinics have over 500 cycles a year, whereas 50% of those that only report to the CDC do less than 100 cycles a year. So SART clinics tend to be a little bit bigger. So what did they actually find? When they looked at live birth based upon SART age, and they looked at singleton live birth, singleton term live birth, all of those were higher in SART clinics than in non-SART clinics.

And the differences ranged from 4 percentage points up to 13 percentage points. So that's absolute difference of 4 to 13%. If you think about that from a number needed to treat, that means it's somewhere between 8 to 25 women.

So for 8 women that come to do IVF, you'll have one additional pregnancy in a SART clinic compared to a non-SART clinic. Miscarriage was a little bit lower in the SART clinics, 18% versus 22%. They don't really have information as to why.

My guess might be it's PGT use in SART clinics compared to non-SART clinics. But that's just the hypothesis. I don't actually know if that's what's driving that difference.

And the final thing they looked at was multiples. And so SART clinics were having, again, 4 to 13 percentage point higher live birth. But they were having half the rate of twins in younger women.

So in both the under 35 and 35 to 37, half the rate of twins. I will say these numbers are really nice to see, around 3% for SART clinics. I think that's a lot of credit to people like Kate and Pietro, who serve on the Quality Assurance Committee and help try to drive those numbers down.

Interestingly enough, I gave these numbers in Australia a couple months ago. And they're at 2%. So they're at almost a monozygotic twinning rate for their IVF twins.

But of course, it's a mandated country. It's paid for. The government and the clinics can say, we're just going to put in one embryo.

But I'm proud of SART clinics to say that we're approaching that. We're not quite there yet. But we're getting close.

The final thing was they just looked at reporting requirements. What's similar for CDC and SART? Both do targeted validation. And both require prospective reporting.

So when you start a cycle, you've got to report it within a couple of days. That way, you can't not include cycles that maybe have a poor response and are canceled before they even make it to retrieval. I will say the validation that the CDC has is very different.

They use a company called Westat, which is their data collection company. They do a validation of the data. But it's purely a numerical validation from not physicians, not embryologists, whereas SART validation is people that actually do IVF, understand cycles, and validate at a higher level.

SART has additional requirements above CDC, such as you have to have a board-certified medical director. You have to have an MD or PhD running your lab. Your lab has to be accredited.

I learned this just a year ago. We were all surprised in SART leadership. The CDC reports if you're accredited.

But the law doesn't actually require accreditation. It just requires the CDC to report if you're accredited. So there are people that have labs that report just to the CDC.

But their labs are not accredited. You have to adhere to embryo transfer policy, minimum standards of success, and advertising policy, as well as several others. So I just think this is good evidence that all that effort that all the SART member clinics put and all the volunteers that run SART put into it does have demonstrable outcomes, as far as both the efficacy of going to a SART clinic is a little bit higher, as well as the safety, because the multiples are a little bit lower.

So I've been waiting for this paper for about a year. I'm very excited that Steve and Jim and Daniela were able to get this published. Kate, Kurt, Pietro, thoughts? You said it well.

I mean, this is important work. And gosh, kudos to the Aussies for getting down to monozygotic. That gives us more work to do, Pietro, on our committee.

There's also a really nice editorial I want to point people towards on the importance of the work that SART does. And it's heightened importance by Dan Grow, my co-chair of the QA committee, essentially highlighting that with, unfortunately, CDC being somewhat hamstrung in the current environment, SART's work is all that much more important for patient safety and really giving patients the information they need to understand what success rates they can expect. I don't think that can be overstated, Kate.

Just for historical reference, SART started reporting outcomes in 1985. This Congressional Act did not come out until seven years later, 92. And CDC did not start reporting outcomes till 95.

So I got a lot of questions as to why should we continue to report if the CDC no longer has that group there. And my answer is SART was doing this for a decade before the CDC was. As a field, we're very committed to holding ourselves to high professional standards and advancing the safety and efficacy of IVF.

And SART's going to continue to hold that mission. We would like to partner with the CDC to do that. But whether the CDC is present or not, we're going to continue in that mission.

And we've had an uptick in new SART members this year because of that. So I'm proud of that. Michael, great discussion.

I think that one thing I want to add, it's really high level. But we all need to know how important this reporting is. It's not just a burden.

It's not just a requisite. It's this reporting and the work with ASRM that allowed us to reduce the number of embryos, that literally reduced the number of twins and triplets that we have. This is good for our field, both publicly and the outer vision of our field to the public, but also to treat patients and have better outcomes.

So I hope people don't look at this as a burden to report. This is really, really important and has helped. So great paper.

I encourage everyone to read that. Great work from the fellows at Emory and Cornell. Pietro, we're totally jumping now into the world of gynecology.

And did we learn some new things from Primrose One and Primrose Two studies? I think I would be remiss if I didn't plug fertility and sterility is a place for ART articles, but also for gynecology. If there's ever something that you think is bread and butter gynecology, menopause, touches aspects of reproductive age women, this is a place where those papers can live. And I think this is a great example.

The Primrose One and Two studies have been published many years ago now, but continue to yield some very interesting data that's imminently helpful for counseling. So this is a paper by the preeminent Jacques Donnez and his group evaluating the Primrose One and Two trial data. As a reminder, Primrose One was run in the US, Primrose Two in the Europe and US.

They were both phase three trials that established the efficacy at 24 weeks of Linzegolix with and without hormonal advect therapy for symptomatic uterine fibroids. These were RCTs that enrolled over a thousand women across five arms with increasing Linzegolix doses with and without advect therapy at the different dose set points. The initial trials stopped at 24 weeks.

This is an extension following those patients to 52 weeks and then looking at withdrawal at 64 weeks. Finally, with bone mineral density, always a big concern with suppression, assessed at week 76. As a reminder, these women were on average 42 years old, BMI of 30s with a very diverse racial composition, 34% black, 64% white.

Primary outcome across both of these studies was achieving a menstrual blood loss of less than 80 mLs in a greater than 50% reduction from their baseline with multiple relevant secondary outcomes. So first let me tell you what they found at the extension going from 24 to 52 weeks. They found sustained efficacy.

There was reduction in heavy menstrual bleeding at week 52 across a variety of doses, improving at higher doses, improving at higher doses with advect therapy. Amenorrhea rates continue to be strong at higher doses and with advect therapy compared to placebo. And the uterine fibroid volume reductions were maintained, maximally seen at the 200 mg, their top level dose.

Pain, quality of life, hemoglobin and bone mineral density all continue to show consistent improvement, persisting up to the one-year mark. Now, probably the most interesting finding of this follow-up study was looked at withdrawal. So as I suspected, and I think many of our listeners suspected, if you started to withdraw medication between weeks 52 and 64, you know, looking at the first quarter of a year afterwards, symptom recurrence was rapid.

89% resumed heavy menstrual bleeding within 12 weeks of stopping. Fibroid and uterine volumes returned towards the baseline pre-treatment volumes. Interestingly, pain and quality of life scores worsened from when they were on treatment, but not as severe as they were at baseline, looking at three months post-withdrawal.

And most importantly, bone mineral density improved towards baseline after drug discontinuation did not quite reach baseline levels, but showed that there was a recovery in bone mineral density, which I think was expected. I think what this follow-up paper tells us is that Linzogolix is effective long-term beyond one year at heavy menstrual bleeding, pain, fibroid size and quality of life improvements. ADBAC therapy seems to be effective, minimize bone loss and minimize vasomotor symptoms.

But what this study really draws into question is, given the very high recurrence rate of symptoms, is this chronic therapy rather than kind of acute episodic treatment for heavy menstrual bleeding? And I think that's a nuanced question, depends on what the patient's goals are, what the goal of therapy is. Is it a bridge to surgery? Is it a bridge to something else? Or is it a bridge even into menopause before discontinuation? Micah, Kurt, Kate, you guys probably don't have a ton of experience with Linzogolix in the general GYN population, but have you had patients come through your clinic asking about it who are dealing with fibroid symptoms? I have not used it at a practical level, but I think this area of literature is fascinating. I think you really described well what this study added.

Longer-term therapy is effective, bone loss is recoverable. You can minimize that with ADBAC therapy. But the big take-home that you said is that the fibroids and the symptoms tend to recur after cessation of the medication.

So it does raise that question, does this need to be chronic and long-term? And then that raises the question, do we need longer-term safety data then to say it's okay to go longer than that amount of time? If I put my GYN surgeon hat on, this is a therapy that I've used as a bridge to surgery, as a pre-optimization step. I haven't used it as chronic therapy because most of these patients who I'm seeing are trying to conceive. But if I'm trying to get someone to a surgery that's a little less morbid and pre-optimized their hemoglobin quality of life before surgery, a couple of months of this therapy, if they're not in a rush, can be a real game changer for patients compared to our conventional Lupron option that we've historically had.

I'm pleased to see this data is seeing the light of day because I really thought this class of medication would be more of a game changer than it is. I mean, I really thought it was one of the few novel therapies we've had in my lifetime. We've been using the same drugs again and again and again.

I'm a little disappointed that... I shouldn't say disappointed. I mean, again, in my career, fibroids have moved out of general practice and to the general, but that said, I mean, the science still shouldn't be strong and we still shouldn't be using it. And PHRE hit the nail on the head in that it's because most of the people we see are trying to get pregnant.

And this is temporizing at best, but it really works and the data should come out. I hope this drug becomes more widely available and we can actually use it. I think, unfortunately, this whole class of medication still suffers from the, it is inexpensive and tough to get phenomenon, which is frustrating for people in women's health who are trying to utilize some of these novel therapies.

Sometimes they're just left with Lupron because it's what their insurance will cover, which sucks when we know that there's something more efficacious and patient-friendly. Isn't that terrible? Hasn't the system just betrayed us in this? And again, we've got a novel therapy for the first time in a long time and it's become niche because of how insurance companies handle it. It's just disappointing.

Well said, but big shout out to the authors. This is Mike and I were talking before the podcast started. If you're gonna go through the effort of organizing one big RCT, in this case, two very large multinational RCTs, it's great to be able to have some questions that are answered after the fact.

And I think long-term extension is a great one, but I think the part that I'm really delighted to see is the withdrawal period and data collection during that time to really inform counseling. Well said. All right, we're down to one last article.

This is in Research Letters. This is one of my own prior fellows, Major Meghan Yamasaki, U.S. Army, stationed out in Tripler, Hawaii. So she's suffering there.

She serves our country. This is sort of a labor of love article that Kate and I have been working on for a decade. So this is looking at premature progesterone levels, something that both Kate and I have been interested in in our careers.

And during the fresh cycle, if progesterone goes up prior to trigger, that advances the endometrium and those embryos don't do as well with the fresh transfer. And those patients probably benefit from a freeze-only approach. Our hypothesis was that cumulative progesterone over several days could also be bad.

So maybe you're riding below those published thresholds of 1.5 or two, but you're doing that consistently for two or three days. Is that cumulative exposure enough to advance the endometrium? This is just a good lesson for all fellows. This was an oral abstract we had a decade ago at ASRM that showed that day three test was better at predicting it than the one day test.

But that fellow never wrote up the paper, never published it. So we have a list of these papers, Kate and I do, and Meghan took it on and got it published. So I'm really happy with that.

So this is a retrospective cohort study looking at U.S. fertility patients over a decade, 15,000 IVF cycles, looking at one day progesterone on the day of trigger or the three days cumulative exposure, which is just day of trigger, day minus one, day minus two, adding those three progesterone levels up. I will say that this went through a really great revision. And so this is kudos to the reviewers and the editors.

It actually changed what we said. They critiqued what our threshold analyses were and the way that we found that. So we adjusted our analyses based upon their recommendations, and it ended up moving the findings to the null.

So essentially we found that both the day of trigger progesterone and the three days were very predictive of failure to have a live birth. Once you were over 1.8 on the one day level or 4.4 on the three day levels, you had a 10 percentage point reduction in live birth. So you dropped from about 38% live birth down to 25, 26% at either of those thresholds.

But the next step was to say, is there any value in this test versus the other ones? So now we're starting to look at predictive values as we've talked about, and how do you test tests? How do you compare two different tests to each other? So we looked at positive, negative, predictive value, sensitivity, specificities, area under the curve, when the tests were discrepant, which test was right, which test was wrong. And for all of those things in this study, it ended up being the same. So essentially the two tests performed the same.

There wasn't any additional value of doing the three day test. Now this was an interesting lesson to me in threshold analysis and how you determine where to set a cut point for the test, because the initial analysis we did, did show that the three day test was much better. When they were discrepant 10 to one, the three day test was predicting the patients that failed to get pregnant better than the one day test.

But when we move that threshold, and it just moved like by 0.1, based upon the reviewers and editors recommendation, that moved the analysis to the null. So we went from a number needed to treat of 33 with the new test to gain one additional pregnancy to a number of 30,000. So it essentially became a null finding.

So it's just an interesting lesson in how you can find the points you want, depending upon how you do your analysis. I have to say I've cut this data 100 different ways. And probably 90% of the time, it does show the three day test is a little bit better.

So if I'm planning on doing a fresh transfer, and I'm already drawing blood, it doesn't really cost us anything extra. We don't charge the patient extra, I don't think to get that extra progesterone level. So I'll do it.

But do I think a clinic needs to implement three day testing if you're not already doing that? No, both tests are of value and seem to have similar value. How much the value is similar is just all in how you slice the pie. I love this.

And I love that this was a labor of love for many years for you guys. Particularly now that it ended up as a research letter. I think this reinforces that every good idea finds a home.

Infertility and sterility in research letters are a wonderful place for short, singular findings that are relevant and worth sharing to end up. I had a couple of questions for Micah and Kate. One of the things that I've always kind of mused about in fresh transfers is, does the aggressiveness of stimulation modify some of this effect? So when Cornell, which historically has done a lot of fresh transfers, stimulates, they always prided themselves as saying we under stimulate, we stimulate very gently and we never really get progesterone rises.

And they did a lot of internal validation with looking at progesterone levels and fresh transfers and saw that there was no effect with elevated progesterone levels, probably because they didn't see a heck of a lot of them. Talk to me a little bit about the effect of stimulation in these progesterone levels. Are you seeing it more often in certain patient groups than others? Can we minimize even having to check progesterone levels by just more mildly stimulating these patients who are trying to get to first transfer? Great question.

100% there are extrinsic and intrinsic factors that play into where someone's progesterone ends up. How many follicles do you have? Those are progesterone producing, estrogen producing units. The more you have, the higher it's going to be.

I think there are some intrinsic things in patients with their polymorphisms and just their steroid pathway enzymes. And that causes some patients to pull things through to estrogen better than others. And then the extrinsic factors are what we do to those follicle stimulating units.

How much do we drive it? And then how much LH activity we have. There's good data out of RMA and from Richard Scott that shows that using LH, and that makes sense from the steroid pathway helps pull that substrate through and get you more to estrogen rather than progesterone, changes the Delta V to Delta IV pathway of those steroids. So yeah, there are both those extrinsic and intrinsic factors.

And certainly I think a gentle stimulation, if a fresh transfer is the goal, can help you achieve that. Certainly using something with LH activity can also help you achieve that lower progesterone. Kate, what do you think? Yeah, I can't say it better than that.

I would also call attention to, this is something that we have looked at also in separate publications is the effect modification of high serum estradiol concentrations and the progesterone being elevated prior to trigger is independently associated with the negative impact on implantation. And it's another, I think, Cornellism, Pietro, that the embryo can wait for the endometrium, but the endometrium can't wait for the embryo, right? And there's a nice commentary on that. I just got a shiver down the back of my spine when you said that.

Right. But I mean, it's true time and time again in FET and IVF. And I think it's a good way to explain it to fellows.

So sorry for the PTSD that I think I just... Yeah, you did. ...may have flared there at you, but it's a good way to remember it. Yeah, why is my heart rate elevated all of a sudden? One of the things I've always, I've seen people do during these stimulation cycles is when they're utilizing low-dose HCG is crank up the low-dose HCG dose towards the end of these cycles where a fresh transfer is kind of being planned for.

I think to Micah's point to really shift that ratio of recombinant FSH to LH activity. And what I've seen when I've checked these progesterone levels is that you can actually get them to bend and in some cases, even plateau, not super consistently. I think there's definitely some batch effects of reconstituted HCG that's low-dose towards the end of a cycle after it's been in a vial for 10, 11, 12 days.

But it seems to be one of those kind of clever tricks that we can do in fresh transfer cycles is really crank up that low-dose HCG at the end for using it as monotherapy. That's your next study, Pietro. Well said.

And love the persistence, get it published. Another great example, too, of, again, how the peer reviewers, I think, elevated a paper. And a good reminder that you don't have to find a positive finding to get published.

As an editor, as a writer, as a reviewer, I love null findings. I think those also help advance our field. So don't feel like you have to find something and p-hack to try to get the positive finding to get something published.

Almost all our papers today were negative studies. Yes, they definitely were. They have value.

Absolutely. So as always, there's a whole bunch of other great stuff in the journal that we didn't cover. Kurt, there are four expressions of concern this month.

So sometimes we have some retractions. Sometimes we have expressions of concern. Can you just remind us, in general, when the journal or the publication committee says there's an expression of concern? What does that mean for us as readers and researchers? Yeah, sure.

So first, I want to make a shout out to ASRM and the Research Integrity Committee that takes research integrity very seriously. So when we get an allegation that a paper may have had errors or may have had integrity problems, it gets reviewed by a group of people that thoughtfully go through it. If they really feel the paper can no longer be trusted, that data can't be scientifically backed up, then that paper is actually retracted.

That's what a retraction is. You can no longer have confidence in the findings, so therefore remove the literature. But short of that, you might find that there's legitimate problems with the paper, some of which can be addressed or explained, but it really makes the findings questionable or put it this way, you should look at that paper differently and have a concern about that paper.

And that's what a letter of concern is. I think we should all be looking at these categorizations because it's really important. I still believe we have the best peer review literature in the world and we should continue to, but not every paper is created equal.

And sometimes people are finding inconsistencies, errors, or even fabrications or such. And we should keep that in our minds also, not because we shouldn't trust the literature, but because when someone finds an error and we bring it out, then pay attention to it. Thank you, Kurt.

I appreciate the rigor that you as editor-in-chief and ASRM with the Research Integrity Committee have showed in this area. I think that's very helpful for our field. So we are in October, which means we have ASRM 2025 coming up.

We will be live in San Antonio. We have some great F&S lineups. We have the best of F&S.

We'll have all of our editor-in-chiefs picking out their favorite articles from the last year over our family of journals. So come hear those authors talk about it. We'll have a journal club on how we emulate clinical trials with some world experts.

I'm very excited about that. Hope everyone has their cowboy hat and is ready to come to the gala. And we will see you all at ASRM 2025.

Looking forward to it. Bye, Micah, bye, Kate, bye, Kurt. And a big shout out to all of our listeners down under.

Eve Feinberg just traveling back from the Australian Society meeting in Adelaide and wanted to make a big shout out to all the loyal listeners down there. Until we see you next month, bye-bye. 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, Dr. Adriana Wong, Dr. Elena HoganEsch, Dr. Selina Park, Dr. Carissa Pikny, and Dr. Nicholas Raja. This podcast was developed by Fertility and Sterility and the American Society for Reproductive Medicine as an educational resource and service to its members and other practicing clinicians.

While the podcast reflects the views of the authors and the host, 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.