Fertility and Sterility On Air - TOC: June 2025

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

02:17 Effects of preimplantation genetic testing for aneuploidy on embryo transfer outcomes in women of advanced reproductive age with no more than three retrieved oocytes

15:30 Using National IVF Registries to Validate Clinical Outcomes Following IVF Covered by Health Insurance 

29:38 Impact of corpus luteum number on maternal pregnancy and birth outcomes: the Rotterdam Periconception Cohort

39:15 Systematic review and Meta-analysis of the impact of the re-freezing and re-biopsy embryos on reproductive outcomes in patients undergoing freeze-thaw embryo transfer  

50:20 A blastocyst’s implantation potential is linked to its originating oocyte cohort’s blastulation rate: evidence for a cohort effect

01:02:56 Linzagolix rapidly reduces heavy menstrual bleeding in women with uterine fibroids: An analysis of the PRIMROSE 1 & 2 trials 

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 everyone to another episode of Fertility and Sterility On Air. We are in June 2025, volume 123, number 6. I'm Micah, and we're joined by the whole original crew today. We've got Kurt Barnhart, Eve Feinberg, and Pietro Bortoletto.

Good morning, everyone. Good morning, Micah. Good morning, everyone.

Hello, Micah. Nice to see you. I like that you called us the original crew.

Not that Kate is not version 2.0, but you're right, there's a certain amount of nostalgia here seeing the four of us together. I love it. We've gotten the band back together.

We're excited to have another great discussion today. We're recording on the day after Memorial Day for June here, and we just want to thank all of those who have served our country and allow us the ability to do IVF and have our freedoms that we have. We're going to jump right in.

The front matter has some really good things to read. Editorial Editor Michael Eisenberg has something on the genetics of male infertility. There's four review articles there.

Really good time to brush up on your genetics of male infertility with this views and reviews. Editorial Editor Anuja Dokras has a fertile battle over isthmocele, something I know all of us see on a fairly regular basis, especially with C-section rates being what they are. So a great discussion on should we operate or should we observe? And finally, Editorial Editor Dom de Ziegler continues the discussion around vaginal versus intramuscular progesterone and FET cycles and looks more at the systemic effects of progesterone in his inkling.

So that discussion continues. I highly recommend you read all of those things. Eve, we're going to jump right into the science.

You have the seminal contribution this month. Tell us, should we do PGT on older women of reproductive age who have three or fewer eggs or embryos? Yeah, this was a great article and I think it's really timely and it answers a good question. So the title of this is Effects of Preimplantation Genetic Testing for Aneuploidy on Embryo Transfer Outcomes in Women of Advanced Reproductive Age with No More Than Three Retrieved Oocytes.

And this was a study out of China and the objective was exactly that, to evaluate whether PGT is of benefit in women 38 and older who have one to three eggs retrieved. It was a retrospective analysis. It was over a four-year time period from 2019 to 2023.

And they compared patients who did PGT versus those who underwent a fresh transfer of one or two embryos on day three or day five. And on my first read, I was like, huh, maybe the outcomes are going to be skewed because it's one or two embryos, why not throw in all three? And in diving into the data further, I think it was one or two because that's all that was available and it wasn't due to restrictive transfer policies. So all PGT transfers were single-euploid FETs and then the primary outcome was live birth rate per cycle and per retrieval.

And then they also analyzed live birth rate per embryo transfer. So there were 727 total included cycles and of these, 298 were PGT and 429 were non-PGT. Interestingly, in China, PGT use is limited to patients with advanced reproductive age, recurrent implantation failure, or recurrent pregnancy loss, so you can't just simply elect to do PGT.

There were no differences between groups in the mean number of oocytes retrieved or 2PNs. In the PGT group, only 14% of cycles led to embryo transfer versus 84% in the fresh transfer group. When they calculated clinical pregnancy rate and live birth rate per cycle or per oocyte retrieval, not surprisingly to me, there were no differences in outcomes.

Clinical pregnancy rate per retrieval in those who did PGT was 9.4% versus 10.5% in the fresh transfer group. The live birth rate per retrieval was not statistically significant with either 8.1% for PGT versus 6.3% for fresh transfer. Then they analyzed this per embryo transfer.

So PGT not surprisingly did better with a clinical pregnancy rate of 67% and live birth rate per ET of 57%. The miscarriage rate per pregnancy was higher in the untested group, 40% versus 14.3%. And interestingly, the authors also evaluated the time to live birth in each group, showing no difference. So what are the take-home points? I really read this to say that PGT is a selection tool, and I know we've said that again and again, but in patients where there's not a lot to select, I really read this as there's not a benefit in time to pregnancy or live birth rate by using PGT in this population.

I think you can definitely still make an argument about reduction in miscarriage rate with the use of PGT. And I think given the very real emotional toll of miscarriage, I want to highlight this as a benefit. I think many patients would prefer to have these losses play out in the laboratory and not inside their bodies.

And so I think even though these data don't make a compelling argument for PGT to improve live birth rates, it does provide some value in showing benefit there. I think the other point, though, is it didn't change the time to pregnancy. So one of my arguments about miscarriage rate is always that if you have a loss, then it takes a lot of time to recover from that loss, and it may delay your time to pregnancy, but these authors really did not show that.

So I want to open it up for discussion because I think that we're going to have a robust discussion here, and I'm curious what you all think. What you said is what jumped out to me. Overall, I think it's what we would expect, a benefit on a per-transfer basis, no benefit on a per-retrieval basis, but a lower miscarriage rate.

You guys know I like to think about it in numbers needed to treat and what's the benefit. What's interesting here is if you look at the miscarriage rate, it's 14 versus 40 percent. That's a number needed to treat of only four women to have one fewer miscarriage, but that's if you look at it on a per-embryo transfer level.

If you look at it on a per-retrieval level, it was 1 percent versus 4 percent, which is a number needed to treat of 33, and that's when you're deciding to do PGT. So that's an interesting framework because that's a pretty different number needed to treat, 33 versus 4, depending upon how you look at that outcome. So I'm still trying to process how big of an effect it is, and I think that's probably why there wasn't a big effect on time to pregnancy, because at a per-retrieval level, the numbers were just low of those that got pregnant and had a miscarriage.

Yeah, and I think it also depends on what they're calling a miscarriage and how long it takes. And so are we talking about an early biochemical pregnancy loss? Are we talking about a 20-week loss? And so I think that those are very different, and I think we all know that the majority of pregnancies that implant don't make it out of the first trimester. And so I think that it's just, I think the nuance is really in the counseling.

But I will say in my practice, I think many patients, the emotional toll of miscarriage is tremendous, and I think that we need to really listen to that and really need to guide our clinical practice based on that at times. We also have to acknowledge that there's a difference psychologically for the patients in number of embers available for transfer, depending on the intent to use PGT or not. If you look at the non-PGT group, 73% of them had a transfer, whereas the PGTA group, only 14% actually had an ember available for transfer.

And depending on who the patient is in front of you, I have to imagine that a shot at goal matters a lot for a significant number of these patients, and you're removing it for 8 out of 10 patients who decide to undergo PGTA and subjecting them to another egg retrieval cycle to maybe create a euploid embryo for transfer. I'm really taken by this conversation and the evolution of this paper. I really think, you all said it's what we expected.

Talking around the country, I don't think this is what people expect. I really think that it's still lingering in our lexicon that PGTA is going to increase your pregnancy rates. I know that doesn't make any sense, but it's what practices are doing in PGT on everybody for higher pregnancy rates.

And the key here is it's per transfer. And what Pietro said is really, really important. Who are we treating, the clinic or the patient? Would the patient rather have a chance at getting pregnant, or do you take that away from them, improve your statistics, and have them do another cycle? I mean, I don't mean to be really down on this, but I think we have come up with arguments of why PGT is better because we do it.

This tells us that it is not helping the embryo at all. If anything, the pregnancy rate is slightly lower. You're taking away a person's chance for pregnancy, and there's no benefit other than perhaps a miscarriage.

But I bet we have never asked patients. We haven't had patient-centric outcomes to say, would you rather have a chance at pregnancy with a small chance of miscarriage, or would you rather take away that pregnancy in the lab? Yeah, correct. I'm going to push back on you there, because I have that conversation every single day.

And oftentimes, it's the patients who come to me wanting to do PGT who are 38 years old who have had three losses, and they don't want another loss. They would rather not have a chance at having an embryo transfer than suffering through another miscarriage. I guess the difference is the population there.

Is it people who have had three losses, which in my practice is very few, or is it people that have infertility that are presenting at 38 and 40 years old that have never had a chance? So, again, it's patient-centric, right? It really is what it is. But I think the patients are getting the wrong message here that somehow PGTA is making their cycle more efficient and better when there's no question that this diagnostic test, which is invasive, which can necessarily take away embryos that are viable because of either misdiagnosis or damage to the embryo, and you're subjecting that to patients that have very few embryos. So in my sense, it doesn't make a lot of sense to do PGTA when you only have a couple of embryos.

Exceptions, of course. You have three miscarriages, you had a late trimester miscarriage, you know, things like that. I'm not saying that, but I'm saying as a whole, this is just yet another study that says we're overusing PGTA.

Yeah. And I don't want to be very transparent here. When I see that 38 or 39 or 40-year-old in front of me where I know that they're going to get one to three eggs, my clinical practice, I do not encourage them to do PGT.

I really encourage them to do a fresh transfer and put in all embryos that are available. And I will say, I have a nuanced discussion with them about each and every one of these points. And I think that the overwhelming majority of them still push back and want to do PGT for emotional reasons.

They'd rather have a loss in the laboratory than a loss in their body. And so I think that that phenomenon is very real, but I do not encourage PGT in the low responder population. There's nothing to select from.

Right. And again, it's how you phrase it. If I said, would you rather never have a chance of getting pregnant or have a chance of a loss and still get pregnant? I don't think we've ever asked patients that question, and it's all in your counseling.

But I remember giving the boards a year or two ago, and the answer was most people with PGT-A, one embryo. And the answer was why? And it was answered, well, it's the patient's choice. If you really think that, then you really need to understand this nuanced approach that by doing PGT-A, you are actually probably reducing a woman's risk of getting pregnant rather than helping her.

Yes, some people have different choices. I'm not saying that we shouldn't use it. But this is why I've seen an evolution of PGT-A in the last five or 10 years, where it first came out.

And I remember everyone came out saying, this is improving IVF success rate. And it was because we were using the wrong numerator and denominator. Now that we've gotten back to recognizing it's all people, not just how many the embryo you're putting back, it's a very complicated situation.

And I'm glad this paper contributes to the literature. Even my mandated state, the patient's perception on PGT is actually the total opposite of the ones that you're seeing in your mandated state. It may be demographic, but that patient who shows up and has Blue Cross Blue Shield coverage and then is being posed with the question of, do I spend $2,800 out of pocket for a biopsy fee and then $250 to $300 per embryo? There's a huge $3,000 sunk cost in there for that patient to biopsy maybe one or two embryos.

And the patients that I take care of in Massachusetts, overwhelmingly, the answer is, I'd rather just do what the insurance covers. And I have six shots on goal through the insurance. I don't have $3,500 to spend in addition to what I'm already spending on deductibles and co-pays.

Yeah, and that may just be a demographic population difference. But I wonder, too, and I don't practice in a restrictive state, but I wonder, too, how PGT practice patterns differ between states that prohibit abortion versus states that don't. And these data really don't.

They don't support that argument. But I do think that that has evolved into an argument as well as termination is illegal in a number of states. This is a great discussion.

Maybe we need to have a journal club on this because I feel like we could unpack this paper for a whole hour. First shout out of the day is to Paul N. Paul listens to us in Seattle every month. And he told Eve and I that he likes it when we disagree.

And there was a little bit of disagreement there. So that's good. It's like that when we have different perspectives.

So shout out to you, Paul. Micah and I also want to give a shout out to our Brazilian colleagues. This is being recorded a whole month after we came back from the Brazilian Infertility Society meeting.

And what a warm reception. So many listeners, people who recognized us by voice and attended our in-person first ever live journal club from Brazil. A big shout out to our hosts, Renato and Juliano, but also a big shout out to all the Brazilian REI community.

Kurt, Pietro just mentioned mandated state versus non-mandated. And our next study sort of goes a little bit along that, looking at health insurance and can we use health insurance data? Is it valid? Tell us about this study. I was particularly interested in this just from my perspective as a SART person.

Well, I appreciate your interest in this because we're going to go from really clinically potentially useful to really high level here. So this is a very important study to lay the groundwork for future studies, but it's really not going to impact what you do on a day to day basis today. But listen and let it flow over you as I've said before.

So this study is using national in vitro registries and vitro fertilization registries to validate clinical outcomes after IVF by health insurance by David Suh, along with a host of people from the University of Michigan, including Erica Marsh. Shout out to Erica, who is going to be inducted into the National Academy of Medicine this year, as well as my former fellow, Marissa Weiss, when she was at Michigan. So the object of this study, the objective is pretty straightforward and some would say relatively boring.

So I'll try to make it interesting for you. So it's to evaluate whether IVF that's covered by health insurance using a national claims database can give you valid information or robust and valid information. And as a metric, they use, of course, our ongoing registries, such as the SART registry and the CDC NASS registry.

So it sounds like a strange question, but we're in an age of big data where many people are going into databases and many people are using this Optum database, which I'm going to describe in a second for medical research. The question is, can you get valid information about IVF at the SART and NASS databases, which we've had a lot around us for a long time and there's plenty of research done on them, are limited because not every variable is in the databases. It doesn't show insurance status.

So you can't really compare those that have coverage versus those that don't. And this is a way to say, well, can we use other databases to get similar information? So they looked at a large time period from 2005 to 2020, and they looked at the standard outcomes we would look at superficially from SART or NASS, which is a pregnancy rate. In this case, it was on the first embryo transfer, but not only pregnancy rates, miscarriage rates and the plurality of the pregnancies.

Spoiler alert, they found that the Optum database, which is called CDM, can obtain this information. And it seems to be similar to what we would have in SART or NASS. For example, the first embryo transfer pregnancy rate in insurance covered patients was around 62 percent, where 63 percent in SART.

The live birth rate, 45.6 versus 46.9. But that's not the point of the paper. The point of the paper is if you really want to learn this stuff, you know how they got to that data and why they believe the data is valid. Said another way, SART gives us answers because we report the data.

Insurance registries just give us billing information. Say what you want about EPIC and the electronic medical records. They really are billing electronic records.

And therefore you can therefore get billing information out of it. And Optum is an insurance database that's advantageous because it has coverage, insurance coverage, and not just the fine data sets like in SART, but many data sets. You can you can look at the billing for multiple birth.

You can look at the billing for preterm delivery. You can look at the billing for other procedures that are covered. And this Optum database, which is a kind of umbrella database of many insurance companies, is very geographically diverse and has a reasonable amount of patients in it.

And so there's a lot of information on how they got to identify a patient undergoing IVF by certain codes, whether they had a singleton birth or whether they had a twin birth or whether they were successful in their first transfer or not. That's not the point of the paper, except to compliment the authors that they did a really good job in this kind of big data science. And at the end of the day, we can basically say, can this database replicate SART or NASS? The answer is yes.

You can get those outcomes if you want to. And the CDM database is robust and valid. Now, interestingly, it prompted me to say, well, I want to know the answer.

I want to know, you know, are success rates different for people that have insurance coverage versus people that don't? And that's not what this paper can tell you. It can only tell you that you can get good quality data. I don't know which data is correct.

I don't know if they're actually the same patients. But the fact that they were stable over a decade and giving similar results shows you that the methods to get them are pretty good. Some fun facts, the NASS data set kind of across the board reports lower rates of pregnancy rates than SART and also lower than CDM.

That's interesting, kind of, in that, you know, why are we seeing a difference? And I immediately, without finishing reading the article, started thinking of reasons. You know, are people gaming the SART data, which people have been accused of for a long time? Is CDM a different population? You know, insurance patients, patients are insured, I would expect to have higher success rates because people that are insured tend to be better prognosis patients than people that are not. And I was disappointed to find out the answer was that NAS reports clinical pregnancy rates, whereas the other ones report chemical pregnancy rates.

So I had all this wonderful thoughts about what I could do with information. And I was a little bit disappointed. You know, that's really the gist of this paper.

If you really believe that big data is the answer, you really have to show that your big data can get you valid answers because of the axiom garbage in and garbage out. So even though this only found 5,000 IVF cycles compared to hundreds of thousands in the NASS database, it now opens up the ability to say, well, now I really can do some studies about the differences between covered and non-covered patients. I really can make some decisions on what it will cost if I expand coverage in my state because I can see how many people use it, how many people get pregnant, how many people need weekly cycles, how much does it cost.

So theoretically, it can really open the door for policy decisions, political decisions. If you really believe that we have a president, a fertilization president, this now gives us opportunity to say what and what that would mean and how you can do it. So that really does give you lots of information.

I want to shout out to Cassie Bullock, my former fellow, who wrote a very good inkling on this paper. And she basically says, even though it's kind of reverse, this was a smaller data set than or a smaller number of people than the SART data because it was only a subset, it still opens the door for big data. And the big data option to use data sets other than what we mandate ourselves needs to have three V's.

Variety, meaning it has a variety of settings and a variety of people. And this optimum data set really is geographically diverse. It has to have volume, just size.

And I think we can actually get to size and, like I said, ask other questions, not just did you get pregnant or not, and velocity. And velocity is important because now you really can get these answers more quickly rather than pushing on SART to give you a data set and waiting 30 years to analyze it and things like that. It also shows you the value of data.

Now, we're in a bit of a crisis here because, as you probably all know, and I talked to Dimitri Kissin just last week, who ran the NASS database for the CDC, and they have all been let go. But there is a law, a congressional law in the books, I think in the 70s actually, that we have to, it's mandated to report IVF. Now, I don't know what's going to happen with that if there's no one accepting the data or analyzing the data.

So I would argue that that registration has been really good for our field. The fact that we can help clinics keep them in line about reporting, patients can have better access to data. And most importantly, I hope everybody who listens knows the story that, you know, a decade ago or two decades ago, when we were transferring three and five embryos, the reason that the ASRM came up with a guideline to transfer fewer embryos was because we had this reporting system that says our multiple births were way too high.

And then there was a reduction and a guideline. And it was actually Dimitri's group and the CDC that came out and said, your guidelines aren't working. You know, you haven't reduced the twins as much as you'd like to think that you did.

And they came back with a second guideline. So this is a real success story in medicine that registration has really improved our field. That's why I'm saying it's so important to see this data from the big side.

And then the last V that Cassie suggested in this idea why this paper is so important is inevitability. I know the V's in the middle. But, you know, we're going to be using this data forever and ever because of how difficult it is to do randomized trials and how expensive it is.

And you could argue about lack of generalizability is in some cases. So I hope you hear a little enthusiasm in my voice because this was a very technical paper. Data sets are vigorous, rigorous and valid.

And we can trust papers in the future. So that's why this is kind of a landmark study as a methods paper rather than changing your practice at the moment. Did you guys get anything more out of the paper that you want to mention? I wanted to push back on you, Kurt.

You said that the reporting still has a significant amount of value. Let me play devil's advocate for a second. Think about the cost for reporting per clinic and the burden to report per clinic.

If this insurance claims database is giving you very similar information, do we need individual clinic level data? What's what's missing from the insurance database versus our SART inputted data? So thank you for that softball question, because I know you think that reporting is a good thing. So there's a couple answers to that. One, this paper is only going to tell us how to use insurance claims database at a high level, which is de-identified and won't be clinic level or won't be patient specific.

Whereas the SART reporting data is clinic specific and you can really use it for other purposes. How good is your clinic? Keeping your statistics valid, comparing patients back and forth on which practices, which are in themselves, are very, very important. And I would also push back.

IVF is a field where this stuff should be reported. Many things in medicine are reported and the cost of reporting SART statistics is minuscule compared to the overhead for doing IVF and very, very well worth it. I don't buy that argument.

People give it to me a lot, that it costs me so much to report SART. No, it doesn't. It costs you maybe an FTE or maybe a tweak in your medical record.

I know you don't want to pay it, but the value is really, really important. Yeah, you knocked that softball out of the park. Thanks, Kurt.

Micah, I'm curious on your thoughts as the current SART president, but I agree with Kurt here. I mean, I think that there's tremendous value in reporting. I also think that there's tremendous value in sort of our society's owning our data and not relying on insurance companies to collect these data.

So I'm curious on your perspective. Big picture, I think this is a nice study because I see this as complementary to the SART data set. This gets us, as Kurt said, some billing information, some other things that we don't capture in the SART data.

I completely agree that SART data reporting is a huge success story for our field. SART was, as Kurt sort of alluded to, reporting data for about a decade before the CDC did. And then that collaboration with the CDC coming in and really putting their weight into what SART and ASRM are recommending is really the impetus that helped drive down those multiple gestations.

So I see all of those three as complementary to each other. SART validation and quality assurance of their data is very different than what the insurance companies do and what CDC does. And so I think there's specific value that SART brings.

What really also made me happy in this is we know that, as Kurt said, patients with insurance are probably pretty good prognosis in general, if you look across medicine. And also Optum has guidance on limiting the number of twins. So I was really happy to see that SART live birth and SART multiples sort of mirrored the Optum standards.

In other words, SART member clinics are engaging at the standards that insurance companies would set if they come in for good practice and for limiting the risk of multiples. And I'll just allude to there's a SART paper that's under review now that shows that SART reporting clinics actually have higher live birth and lower multiples than the clinics that choose not to report to SART. So in other words, there's some potential value in just the standards of being mandated to follow ASRM and SART practice guidance.

That's probably a good thing for the outcomes for our patients. So I said a lot to your question, but those were all my thoughts on that paper. I really enjoyed reading this.

Yeah, let me let me clarify just a couple of really minor things. So this paper tells you how to use Optum to get the data. The insurance companies are not giving us this data.

There is no dashboard. There is no way that they're publishing this. This is a methods paper to say, if you get hold of Optum, which you can, this is how you go through it to ask your questions.

So it's a real medical methods paper, so to speak. Insurance is never going to report success rates at clinic level. And that's up to us.

That's why I think we need to continue to do that. And I really think, you know, I don't know if the Hawthorne effect applies here, but when people are watching, you do better work and you're more ethical and the data is more reliable. All right, Pietro, while we still eagerly await the NATPRO study, we have another one here looking at the corpus luteum and outcomes.

Tell us about this. And boy, do we eagerly await the NATPRO study. I've been asking questions about it for the last couple of months.

I heard enrollment's done. We want to know the results. Spoiler alert, I think it's going to be a null finding for a bunch of different reasons we may talk about still on this podcast.

But let me tell you about another paper that's kind of trying to understand the impact of the corpus luteum a little bit better. This is an article by Joni Koerts et al. from the Netherlands.

It's entitled The Impact of Corpus Luteum Number on Maternal Pregnancy and Birth Outcomes. If you've listened to any podcast in the last couple of years, you know that we talk a lot about the role the corpus luteum has in implantation. You've also heard us talk a lot about how ART pregnancies are known to carry higher obstetric risk.

And we've all been trying to figure out why that is. And we've all kind of centered around the idea that maybe it's the presence or absence of the corpus luteum, the associated hormonal milieu that we create by having that corpus luteum present and ultimately how that all impacts maternal adaptation and placental development leading to these placentally mediated disorders. This study was observational.

It came from the Rotterdam Periconception Cohort, which has many thousands of pregnancies delivered in the Netherlands. This specific study included 1,800 singleton pregnancies and stratified them on three criteria. One, was there a corpus luteum present or absent? If there was no corpus luteum present, it was defined as an artificial cycle or what we call a program cycle or more appropriately called a hormone replacement cycle.

Two, whether or not it had one corpus luteum, this is what they entitled as a natural conception or a natural cycle FET or said otherwise a non-hormone replacement cycle. And then finally, cycles in which there was more than one corpus luteum. These were the ovarian stimulated or fresh embryo transfer cycles with a big data set and lots of variables.

They were able to perform multivariable logistic and linear regression. They adjusted for age, BMI, nulliparity, as well as all kind of the things that you would want adjusted for from their obstetric history. Here's what they found.

There's kind of two top line findings. In the cycles where no corpus luteum was present, the hormone replacement FET cycles, they did see a 2.6 fold increased risk of gestational diabetes, interestingly, and the trend towards increased preeclampsia risk with an adjusted odds ratio of 2.02. In the cycles where greater than one corpus luteum was present or fresh transfers, they showed a reduced risk of preeclampsia with an adjusted odds ratio of 0.36 and a slightly longer gestational age by a couple of days. One interesting finding that I haven't seen reported in the literature before is that in male fetuses within that group, there was a trend towards lower relative birth weights, suggesting that maybe there's some sex specific fetal programming that's linked to this luteal hormonal exposure.

Maybe. I haven't seen that signal show up in other papers. I thought that was interesting.

So why does this matter? I think this is another piece of the puzzle that shows us that there may be a connection between corpus luteum number and exposure and maternal and neonatal outcomes. But in no way do I think is it causative or explains the mechanism or gives us any information that we can say we should not be doing the hormone replacement cycle because X, Y and Z. I think we still have lots of theories. Is this being driven by angiotensin renin? Is this being driven by relaxin? Is this all just spiral artery invasion and remodeling? This paper does not give us those answers, but it continues to say we should pay attention to this because there seems to be a signal there.

And again, the NATPRO study, I think is going to be very helpful, but I don't think is going to answer that question either. With in light of all of the data that we have and kind of the signal from retrospective data, I'd love to hear from Eve, Micah and Kurt, how do you talk to patients about the importance of the corpus luteum when you have the patient in front of you who can choose how to conceive, be it in a hormone replacement or non-hormone replacement cycle? Does that cardiometabolic obstetric risk factor into your counseling at this point? I mean, I talk that the data is preliminary and I'm not entirely sure what it's going to show overall because I think that the data are mixed. Again, it's a nuanced discussion of regular cycles, not regular cycles.

As I see it, I think that program cycles are easy in terms of scheduling, but harder in terms of the need for PIO. Natural cycles are fantastic when cycles are regular, but can be more burdensome to the patient in terms of additional monitoring visits. And truthfully, our lab, it's a little bit of a burden to our lab to have this inconsistency in scheduling of natural cycles.

But I really have a detailed discussion with each patient and try to select what resonates the most for them and try to meet their goals. I've got lots of patients who very much want a weekend transfer because of work schedules. And the only way to really guarantee that is a program cycle.

I have a lot of patients who really want a more natural approach. You know, I certainly discuss the data, but I think that at this point, it's it's too early to be definitive. Would a subcutaneous progesterone commercially available in the United States change your counseling and how you bring patients towards or against the hormone replacement cycle leave? I think it would.

I mean, I think the PIO is a huge detriment. People really don't like it. And I think that the need for partner administration or other person administration, it is very difficult to self-administer intramuscular glute PIO.

And I'm saying that from personal experience. I think that will be a game changer. But I still like I really do like natural cycles.

But I don't think that they're the right move for every patient. Pietro referred earlier to the NATPRO study. I think now he's referring to the PROGRESS study, which will finish enrollment this month in the US.

Very large multi-center study, which will look if we can get FDA approval for a subcutaneous progesterone. So, Pietro, reading between the lines, you seem to sort of say that there's a signal here that you think is true, but you think the big RCT is going to be null. Why do you seem to say two disparate things? If I'm reading between the lines, why? Thanks.

Thanks for that, Micah. I think the devil's in the details and the methodology. So in my view, looking at the general population's obstetric risk, most pregnancies are pretty low risk and safe.

And I think the NATPRO study using a unselected general population is going to have a hard time having these big outcomes that you want to report. And I think the as a result, you're going to have a muted difference between groups conceiving in the hormone replacement versus the non-hormone replacement cycle. If I were designing the study from scratch and could wave my magic wand, I would want to take an at-risk patient population.

So I would want to take that PCOS patient who is anovulatory or oligoovulatory. I would want to take them because I think they're going to be more likely to have the outcome of interest. They're going to be more likely to have these negative obstetric outcomes, diabetes, growth restriction, hypertensive disorders of pregnancy, even prematurity.

And then I would want to randomize those patients to the hormone replacement cycle versus inducing ovulation using letrozole and see if I can create an environment that's better for that pregnancy and for that patient that offers some risk reduction through the presence of that corpus luteum in the letrozole induced non-hormone replacement cycle. That's where I think we would actually see some benefit. But that doesn't mean I'm not excited about NATPRO.

I think at the very least, NATPRO is going to give us some very useful point estimates, implantation rates like birth rates, miscarriage rates between hormone replacement and non-hormone replacement cycles. I think there's a lot to look forward to, but I'm not expecting it to show a difference. Micah, you bring up astutely, you know, a tale as old as time, which is we have a theory that makes biological sense.

There's some observational data to suggest that it's true. But the logistics of a randomized trial actually demonstrating that are low. There's so many trials that have failed to do it, not because it's not a good idea or not even because it's not true, but because it's hard to enroll patients or you get the wrong patients or you make the wrong assumptions.

So I think we're going to be stuck. And I look forward to this. Right now, like Eve, I treat the numerator.

I treat the patient in front of me. Is it easier for you to manage your schedule or do you prefer a natural one? There's no information that says natural is bad or worse. So, you know, that's a discussion versus the denominator.

Can we show public health wise that one is better than another? And that's a harder question. I hope we get an answer. But I, like Pietro, suspect that we might get a mixed answer or not a definitive one.

A wonderful discussion and a continuing great topic. I'm sticking in ART and we have another topic that we're all very used to dealing with. Should we freeze an embryo and then thaw it and rebiopsy it if we didn't get PGT results the first time or it's inconclusive? What's the effect of double freeze, double biopsy? And we've had this discussion with source papers before, but this month we have a systematic review and meta-analysis.

This is from first author Yang, senior author Ma out of China. And they sort of have two questions. One is specifically what I said.

You did PGT the first time. You only have one embryo left. It's inconclusive.

Do you thaw it, rebiopsy it? But then this specific meta-analysis sort of morphed into the bigger combinations that you can get to and just any embryo that you need to freeze and thaw twice, whether you biopsy it or not, and all the possible iterations that you can have in there. So this is a meta-analysis. They're obviously looking at observational data.

I think we would all agree it's unethical to randomize an embryo that's been biopsied and is normal to rebiopsy it, refreeze it versus not rebiopsying it and refreeze it. So we're never going to have RCT data on this. So we just have to accept that observational data is the best that we're going to have.

From a methodologic standpoint, I like that they're sort of carrying on Kurt's mantra that we should look at the most quality data that we have. And so for observational data, they looked at the Newcastle Ottawa score. And if it was low quality, those studies were excluded, meaning a score of less than four out of a scale of 10.

So they're including at least low-moderate studies, hopefully mostly moderate studies. As I said, this paper sort of morphed into a much bigger combination as they looked at the source data. So you have studies that were slow freeze, slow freeze, slow freeze, VIT on the second one, VIT, VIT in both of the freezes.

You have studies that are PGT, studies that were not PGT, studies that were not PGT in the first cycle but were in the second biopsy or second thaw. And you have cleavage studies versus blast studies as far as embryo transfer. And we have four primary outcomes, live birth, clinical pregnancy, miscarriage and implantation.

Well, when you combine all of that, you end up with 55 potential comparisons. And so this really became a pretty large study looking at a lot of different types of studies and a lot of different outcomes. The final thing that they did from a method standpoint was if the I-squared, which is a measure of heterogeneity, was over 50 percent, they did random effects.

If it was less than 50 percent, they did fixed effects. I don't agree with that, and I'll explain at the end why, but it's just the approach that they used. And then, as I said, there's a lot of potential confounding between these studies because they're all over the map as far as what type of freezing they did, whether or not they did PGT and where they transfer their embryo.

So to try to adjust as best they could for that confounding, they did sensitivity analyses limiting those. So what did they find? They found a ton of papers, 28,000 meeting their inclusion criteria from their initial search, which is huge. They had a very broad search.

It actually made me think, could we use AI to help screen papers for a meta-analysis? I don't know how you read 28,000 abstracts, but out of that, they got down to 25 papers, and on those full papers, 19 had eligibility. So a fraction of 1 percent of those 28,000. And everyone who's ever done a systematic review is shuddering at the thought of screening 21,000 articles on Covidian or you name it.

Oh, gosh, AI for sure. Yeah, exactly. So maybe a potential use of AI.

We'll see. Obviously, it would have to be validated. So I said there's 55 potential comparisons.

They end up talking in their text about 32 of these actual comparisons. What did they find? In general, I think it's what we would all expect, lower clinical pregnancy, lower live birth if you do double freeze. And that was pretty consistent across all the analysis.

Interestingly, no difference in implantation, but maybe that was power because not all studies reported that, and an increased risk in miscarriage seemed to be reported across a lot of these studies. Now, as someone who likes doing meta-analyses myself, one thing I like looking at is the forest plot and just seeing are these studies pretty consistent? And really they were. So just looking at live birth, there's 18 studies, 15 of them are in the direction of a negative impact, three statistically significant, 12 weren't.

But 15 out of 18, that's over 85 percent of the studies showing something in the same direction. So I think that's convincing. So what did they conclude? Well, they conclude that this shows that there's a decrease if you double freeze an embryo.

And I think we all probably see that clinically. Certainly, if you biopsy it twice, there's probably a decrease as that trophectoderm takes two hits. Now, they do conclude a little bit stronger than that.

They say, therefore, you should not ever do this. I don't know that I quite agree with that. So let me just take live birth on the double PGT embryo.

So this is the worst case scenario. You biopsy it twice and you freeze it twice. The odds ratio is 0.66. If you have a 50 percent live birth in your clinic with PGT euploid embryos, then doing this would reduce that to 40 percent.

So you still have a 40 percent live birth with that embryo. Yeah. Is it statistically reduced? Yes.

But if your option is doing another cycle to get more embryos versus biopsying that, I would say 40 percent if it's euploid on rebiopsy is probably worth doing. And then the second thing they say is that if you do end up rebiopsying it, you should run the genetics in-house so that you can transfer it fresh on that second rebiopsy rather than freezing it. They don't actually have that in their data because that's not an actual outcome in their data of people doing the PGT in-house and transferring it without that second freeze.

And I think most clinics, at least in the U.S., don't have that potential in-house to do that. So I think that was maybe a little bit of a strong statement. But the big picture, I think this study confirms what we agree with in talking to people around the country and looking at our own data sets.

There's probably somewhere between an absolute reduction of five to 10 percent in the success of an embryo if we have to thaw it and rebiopsy it. So I think it's a question to talking to the patient about how many embryos do we think we get if we do another fresh cycle to try to get more versus should we use what we already have in-house? And at least in my experience, most patients would rather use what we have in-house, understanding that there's probably a reduction or potentially just transferring that embryo without biopsying it, which some patients will choose to do. So I have some comments on the statistics, but I'm curious on the clinical aspects.

I think there's kind of two hits here, right? One is the freeze and unfreeze. The second hit is the biopsy. In your mind, Micah, do you think that if you simply had to freeze and unfreeze an embryo, we have as much of a negative impact or any impact at all on that embryo? In my experience, that embryo does pretty well being frozen and unfrozen, particularly if it doesn't have to be rebiopsied.

I would agree with that statement. I think I saw Kurt and Eve's heads nodding as well. Yeah, I would think it's probably the biopsy.

That's the second biopsy is probably the bigger hit. I do, and I would totally agree with that statement. I will say, and again, I think it's all in the counseling, but there are times where we have patients who come back and they didn't do PGT and they want to do PGT for various reasons.

Sometimes it's a newfound translocation. Sometimes it's a newfound single gene disorder. Sometimes it's, you know, they want family balancing.

But I think that it's in the counseling. And I think for the patient who has very few embryos and is over 40 and those embryos may represent their last chance at having another child, I strongly discourage it. But I think for the patients who have lots of embryos who are trying to do PGT for other reasons, like I think as long as they understand that there is a reduction in success, I think, again, it's all about informed consent and shared decision making.

And just two quick statistical comments. Six times in this paper, the author said something was higher or lower when it wasn't statistically significant. In one of those cases, the confidence interval was 0.2 to 2.8. I don't think we can say with any confidence that something is higher or lower when we have that big of a confidence interval.

So just for fellows, as you're writing papers, you're sort of tipping your hand at which direction you want the data to go when you say something's higher or lower, when you have that wide of a confidence interval crossing one. The other thing is just on random versus fixed effects. Just remember that random effects is assuming that each study is asking a slightly different question in a slightly different way.

So, yes, they're all asking the question freeze twice, but we're using different types of vitrification. We're using PGT. We're not.

We're transferring at different stages. We have different patient populations. So random effects assumes that our studies are heterogeneic, even though they're asking the same question.

Fixed effects assumes that they're all the same. The only difference is sampling error. Clearly here, we can tell that the difference between these studies isn't a sampling error.

It's that the studies are just different. So you should probably use a random effects model. Why does that matter? Random effects models will have wider confidence intervals, and 11 of their 32 comparisons would have not been statistically significant if they had used random effects models.

And so it would probably not change the overall conclusion of the study. So I don't think in this case it really moves the needle, but it's just sort of style points. You want to use the test that's most appropriate to the population of studies that you're looking at when you do a meta-analysis.

Yeah, Michael, why do you think that they flip-flop between the two methods? I don't think that I've seen that before within a single meta-analysis using both fixed and random effects models. Most guidance on this will say, look at the studies, and if they're heterogeneic in their methods, use a random effects. But you will see some places in the literature that says, look at the I-square, and if the studies are heterogeneic statistically, then use random effects.

But the I-square just tells you how different are your bars on the forest plot. Is the outcome heterogeneous? It doesn't tell you that the studies are. And so I think that latter is the inappropriate way to do it, but there are papers to support the way these authors did it.

So it's not like it's wrong, I just think there's a better way to do it, a more nuanced way to do it, if that makes sense. And that begs the question, you know, listeners are going to say, well, how did this paper get into fertility and sorority if they're showing their bias and misrepresenting their data and using the wrong statistical methods? Well, the answer is not every paper is perfect. It's never going to be perfect to get through the system.

And that's why you listen to us to find out, because you have to decide when you read a paper, is it high quality or not? I mean, so this is going to happen again and again, but you heard it from us, and mostly Micah, that this is the way you can review a meta-analysis and say whether this is a robust answer or, hey, I like that. I learned something, but we're not quite there in the truth yet. Thank you for that, Kurt.

And again, I want to emphasize overall, my minor critiques don't impact what I think the message of this paper is. I think this is a consistent effect across the literature, but the effect is probably somewhat on the small side. And so that nuanced counseling is important.

Eve, we got one more in IVF. We're looking at blastocyst implantation potential. What did we learn from this paper? This is really interesting.

So the title of this paper is a blastocyst implantation potential is linked to its originating cohort's blastulation rate and evidence for a cohort effect. And this is by David Huang and others from UCSF and Alife. So the objective was to look at a cohort's blastulation rate and to investigate if blastocysts originating from different follicular cohorts have variable implantation rates.

The group hypothesized that intrinsic differences exist in an embryo's chance of success based on its originating follicular cohort. In other words, all euploid blastocysts do not have an equal likelihood of achieving a live birth, and that likelihood is tied to the blastocyst conversion rate of the cohort. So in this study, they use the term blastocyst progression instead of blastocyst conversion.

But blastocyst progression is the number of blasts divided by the number of 2PNs. Euploid blast progression was defined as the total number of euploid blasts over the total number of 2PNs. Day 5 blast progression was the total number of expanded blasts on day five divided by the total number of 2PNs.

And day 5 euploid blast progression is the same, but for euploid blasts. The hypothesis was generated based on some other data that showed fertilization rates were associated with subsequent implantation and transfer of a fresh embryo in a cycle that led to multiple supernumerary embryos had higher odds of implantation compared to those cycles with no surplus embryos. This was a retrospective study using data over a 15-year time period from March of 2008 to January 2023 at UCSF.

They only used patients whose outcome was completely tracked from retrieval to transfer. So banking cycles and cycles with no blast development were excluded. Logistic regression models were used to assess the relationship between known imputative IVF treatments and subsequent implantation after ESAT.

There were a total of 4,292 blasts transferred, and they included results from over 3,000 stimulation cycles in 2,600 unique patients. And of these, 2,703 were euploid from 1,961 oocyte cohorts in 1,600 unique patients. The mean age of this population was 36 years, and then for all ages, the median number of oocytes was 17, median number of 2pns was 11, and median number of blasts was 6. So as expected, these numbers were highest in younger patients and lower in older patients.

And you guys know I love to say this, but age is queen. And oocyte age and number of oocytes retrieved were positive predictors of implantation after ESAT. An increase in blastocyst progression was significantly associated with an increased odds of implantation.

So this is really the crux of what they found. In the multivariable logistic regression, when they adjusted for oocyte age, number of eggs retrieved, blast morphology, and blast ploidy, overall blastocyst progression rate, DeFi blastocyst progression rate, and euploid blast progression rate, those remained independent predictors for subsequent implantation after single embryo transfer. So I wish our listeners could look at Figure 2, but I would encourage everybody to go back to the original paper and look.

But this is broken down by morphology of the embryo and probability of implantation is plotted against blastocyst progression rate with a linear relationship. So poor embryo morphology embryos overall had the lowest implantation potential, or they had lower implantation potential, than good morphology embryos. But those with the highest blastocyst conversion rates had higher odds of implantation.

So to put some actual numbers on this, a poor morphology embryo with a 20% blast progression had a 33% chance of implantation compared to a 70% chance of implantation from a good morphology embryo with 100% day five blast progression. Because they had multiple cycles from the same individual, they were able to evaluate differences between cycles. And interestingly, the parameters did not change much in these couples.

And so they demonstrated that a follicular cohort quality was not critically modulated by IVF stimulation parameters. So the same individual had similar blastocyst conversion rates cycle over cycle. So I think overall it's a fascinating study, and I think it really challenges the idea that all blasts, especially all euploid blasts, are created equally.

And I think this can help us to evaluate some of our more challenging IVF cases and look not just at the embryo that was transferred, but the cohort from which that embryo arose. I also wonder if it's generalizable to other centers who make culture blasts differently than UCSF does. Does group culture make a difference versus individual droplet culture? And I think it would be really fascinating to look at the cohort effect in split donor cycles, where one donor is shared by two or three couples.

How much does the sperm contribute to this, and can we gain a better understanding of male factors? I think this can also be really valuable with donor egg banks and decision making about selecting an egg lot. So I think it really challenges the notion that all euploid blasts have a 70% implantation rate. And when we look at these patients who have repeated IVF failures, I think this is just another parameter that we can look at that may help us to understand perhaps why.

So I want to open it up for discussion. Was I the only one who was listening and thinking, boy, I wish we had time-lapse information on morphokinetics of these embryos? I know I sound like a beating a dead horse here, but don't you think that that would add a little bit more depth to this blastocyst progression discussion that we have in cohort effects? Are you going with your time-lapse again? Are you trying to throw softballs at us yet again? I'm trying to see how this lands, so I'm lobbing it up to the group. I'm not sure that would make a difference.

I'm not sure that that would help, because fundamentally, I guess you could understand where in the blast progression things were slower, like what time points they were slower. But I think it is really interesting, and I think we've all had these patients who have a lot of eggs, who maybe have one blast from that cycle. So 30 eggs, 27 mature, and one blast.

And when that patient doesn't become pregnant, I don't know, I mean, I think it's just interesting data that that one blast may not have that 65% likelihood of live birth that we think of it. And so it may not be as shocking that they didn't achieve a pregnancy in that particular situation. I certainly agree with it on a fresh cycle.

With those patients who we get our FERT report on a daily basis, and those patients where we have a fresh transfer on day five, and then we see that there are six, seven, eight blasts frozen, I will say that is an optimistic sign. When I see that in advance of the pregnancy test, I think it is a good prognostic sign. So I think that the underlying thought behind this hypothesis is really well stated.

And I think this is a fascinating concept, and I have long thought that not all blasts are created equally. I think not all eggs are created equally, and that's part of my hesitation with things like cofertility or split donor cycles, because not every egg has the same potential. I was going to expand it.

I remember years ago, we had this consensus about recurrent implantation failure. And the consensus in the room was that, let's make the assumption that all blasts are the same if they're euploid, and if you can get three euploid blasts, you're going to get nine-plus success rate. But there was a big discussion in the room without data that there really was a cohort effect, and that we might mandate that you have to have different cycles, or age mattered.

And I think both of those things matter. It's nice to see literature coming forward to say that I agree with you, all blastocysts are not created equal. There's some emerging literature that the more blastocysts you have, the higher your euploidy rate is, which is interesting, goes back full circle to our argument that if you have a small number of embryos, it might be another reason not to biopsy.

But anyway, I think it's true. I think you can't just say genetics are everything. I biopsy that therefore success is X. I think there's a lot more subtlety to it.

And I'm glad literature is coming out to show it. Way back in 2013, and we published an article out of Shady Grove data that looked at the number of supernumerary blastocysts and showed the exact same thing. So an odds ratio of 1.06 for each additional supernumerary blastocyst that you had.

Here, it's looking at a different marker of the same thing, blast progression rate or percentage, and it's showing odds ratios of like 1.05 to 1.1. So I think it's consistent with sort of what, as Kurt's saying, what's been shown in the literature. It's just asking the question with a slightly different metric, number of blasts versus percent of blast conversion. But the effect, I think an important point is that the effect size is relatively small.

An odds ratio of 1.05 isn't a huge effect size. So I understand why sometimes we counsel a patient, it only takes one, because we all see that patient that gets one blast and they do get a live birth. So I still think you can be reassuring to a patient that it only takes one if they have a low number of embryos.

But you can also reassure a patient with a lot of blasts that it's probably a very good prognostic sign, although the effect size at an absolute ratio is going to be relatively small, but it is there. Mike, I think you guys are really uniquely positioned at Shady Grove where you do so many split donor cycles or shared donor cycles to look at that blast progression rate from different partners and to see what those differences look like. And is it really the egg? Is it the sperm? Wrote it down as a research idea when you said it, so thank you.

I just wanted to bring it back to one more clinical tidbit or detail. This was the argument we had about, again, recurrent implantation failure, that I really think if you just put three embryos back from one cohort and say, yep, she has recurrent implantation failure, you've really not considered the fact that that cycle could have not been optimal for lots of reasons. So this is one of the few times you're going to hear me say, maybe you do need to do another cycle before you blame the patient for having an inadequate endometrium or something like that.

It could be the cohort of blastocysts or the cohort of eggs you're working with. Yeah, I've seen that again and again. I've had a couple of patients who have a live birth from their first transfer from that cohort.

They go through, they do a couple of FETs, nothing's working, we're throwing up our hands, and they do a second retrieval and boom, pregnant again. So again, I will say it again and again, a euploid blast is not a euploid blast is not a euploid blast. I don't think that they each have independently the same likelihood of success.

I remember you saying this earlier, Eve, you said it quickly before, but if I've got a split donor cycle, I want the first six eggs. I don't want six through 12. And I don't know that there's any way to do that, right? So again, even when you're using eggs for donor, not every egg is considered equal, but they're sold as equal.

So again, there's lots of subtlety to this conversation. Just to the great reflection that was on this piece from Dr. Carrion and Meseguer, which basically says perhaps we could use these data to refine our prediction tools for patients. While the effect might not be huge, certainly it would give us a more accurate estimate, as he's saying, maybe not all blasts or all euploid blasts are created the same.

And so maybe this would give us post-retrieval information that we could use with new modeling tools to help counsel patients. So I thought that was an interesting reflection. Pietro, take us home.

We're talking about a GnRH antagonist and uterine fibroids. Yeah, this is your reminder that fertility and sterility certainly takes papers on fertility and contraception, as the name implies. But we also really like gynecology papers, papers that look at menopause, papers that look at non-fertility-specific outcomes.

And this is a great paper by the giant Jacques Donnez entitled, Linzagolix Rapidly Reduces Heavy Menstrual Bleeding in Women with Uterine Fibroids. I think suffice it to say we know fibroids are common and the most disruptive symptom that women experience with them are often heavy menstrual bleeding, which has a pretty significant negative impact on quality of life. This study was trying to look at specifically pharmacologic therapies for the treatment of heavy menstrual bleeding.

This is not a double-blind, placebo-controlled phase 3 trial. It is a pooled analysis of two multicenter, double-blind, placebo-controlled phase 3 trials, Primrose 1 and Primrose 2, great trial names. And the investigators tried to assess the onset and maintenance of clinically significant heavy menstrual bleeding in over 1,000 women, treating with varying doses of Linzagolix, which as many know is a generator receptor antagonist, both with and without hormonal add-back therapy.

And for those who may not be familiar with Primrose 1 and 2, these are women over the 18 years of age who had ultrasound confirm at least one fibroid greater than 2 centimeters or multiple small fibroids leading to a uterus volume of greater than 200 centimeters cubed. No fibroids greater than 12 centimeters were accepted. The big crux of the paper is this really nifty statistical method called the Kaplan-Meier survival analysis, which was used to evaluate the time to achieve and maintain a heavy menstrual bleeding reduction, and they adjusted for both race and the study site.

Here's a fun statistical fact. I got a one-up, Micah. He's trying to teach you guys a little stats.

I'm going to teach a little history. So Edward Kaplan and Paul Meier were two statisticians who submitted two competing papers to the Journal of the American Statistical Association at the very kind of same quarter of the year, and the journal editor one John Tukey. And if you're a statistician, you know of the Tukey test, also the creator of the box plot.

If you've ever seen a box plot, he's the one who first described it. He convinced both of them to combine their work into one paper, which is no easy feat for two academics, and that one paper has been cited more than 34,000 times since it's published in the 50s. So kudos to the authors for collaborating and kudos to the journal editor for having the prescient idea to combine two cool thoughts into one good paper.

All right, back to the paper. What did they find? They found that Linzagolix significantly and rapidly reduced heavy menstrual bleeding, and the fastest response was seen in those taking the 200 milligram dose both with or without advect therapy, and they achieved clinically meaningful reduction within as many as three days. By week four, 68% of women had a maintained response, which was amazing compared to the placebo group.

So why does this matter? I think first, patients always ask, what's the most effective thing to help me feel better? And then second is, how quickly will I get there? If this is going to take me six months to do it, I may change my decision-making. I think this tells us that Linzagolix is rapid, reversible, it's non-surgical, and for people with heavy menstrual bleeding, maybe a really helpful tool for quick improvement in quality of life, sometimes as a bridge into menopause, sometimes as a bridge into surgery. I think rarely we're seeing it used as a bridge into fertility because generally, if you have fibroids that are this symptomatic, we're often recommending surgical removal for them.

So I think this paper is great. I'm glad to see it in Fertility and Sterility. And as a reminder, if you have something that's in the gynecology realm that you think should be in Fertility and Sterility, we would love to see it.

I will echo that. Fertility and Sterility is more than just an IVF journal or an infertility journal. It's reproductive medicine in its general form.

Hopefully as we get more of these oral antagonists out there, we'll see the price start to drop. Although in our field, I'm not always knowing that that's what's going to happen. That's wishful thinking, Micah.

Yeah, I was going to say there's just going to be another form of the same drug. Yeah. Unfortunately, these drugs are expensive.

They seem to be highly effective and rapid, but they're more expensive than some of the other options. All right. As always, we have a bunch of other good stuff to read in the journal.

So I encourage you to read all of the papers. And my final shout out, Pietro, you gave my number two shout out to our Brazilian friends. My final shout out is from Max Azadi, who posted a post last week on LinkedIn saying, Doctors, Barnhart, Hill, Feinberg, Bortoletto, Devine, it's hands down the best way to keep up on new studies, especially when so much of what gets published these days is low quality or even misleading.

Huge respect to Kurt Barnhart for calling this out. It's refreshing to have such a, quote unquote, fearless editor-in-chief for F&S. So thank you, Max Azadi, for essentially giving us a great advertisement in LinkedIn.

We appreciate all of our listeners. You can see us next week in Chicago for a journal club at MRSI, and next month in Paris for ESHRE for F&S On Air live podcast from that meeting. So we look forward to seeing you all there.

Please swing by our booth. Come by and chat with us. And maybe we can even interview you to be on the podcast at one of these meetings.

We would love to see you there. Thank you to all of our listeners. Thank you, Eve, Pietro, and Kurt.

This was great, as always. It was great to see you guys. I hope I get to see you in Chicago, and if not Chicago, then Paris.

The labor of love. Let's keep it up. This is a lot of fun.

I'm glad people are listening. Hey, we miss you. We'll see you at the next recording.

Until next time. Bye, everybody. 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.