Fertility and Sterility On Air - Live from ESHRE 2024: Part 2

Fertility and Sterility On Air brings you the best of ESHRE 2024! In Part 2, hosts Micah Hill, Paul Pirtea, and Kate Devine bring you: progesterone levels in a randomized controlled trial with long-acting FSH with Annalisa Racca (01:19), live birth of day 7 embryo transfers with Marcela Colonge and Nicolas Garrido (10:57), an ICSI vs conventional IVF randomized controlled trial with Sine Berntsen and Nina la Cour Freiesleben (17:17), limitations of reporting mosaicism in PGT-A with Dhruti Barbariya and Antonio Capalbo (27:15), interview with ASRM president Paula Amato and president-elect Elizabeth Ginsburg (32:41), and ovarian aging with Kutluk Oktay (45:17).

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.

Hello and welcome to episode two of Fertility and Sterility On Air podcast, live from ESHRE 2024 in Amsterdam. Again I'm Micah Hill, the Media Editor of F&S. I'm joined in this episode by my co-host on the podcast, Dr. Kate Devine, and by Interactive Associate from Europe, Paul Pirtea.

We conduct a series of interviews going over the best of the science and the most interesting things we saw at ESHRE 2024. We hope you enjoyed episode one and we hope you enjoy learning and listening from episode two. We are back now on Fertility and Sterility On Air, live from the ESHRE meeting in Amsterdam.

We have the pleasure of having Annalisa Racca with us. She has presented an interim analysis on an RCT, looking at different doses of FSH after colifetropin alpha, and then looking at the effects of progesterone elevation. Tell me why did you do this study in the first place, what are you trying to answer? Thank you for your question.

When I was in Brussels, the theme of my PhD thesis was the progesterone elevation at the end of the follicular phase. And at that point, we knew and we discovered that the only solution was the freeze all of the embryos because the elevation of progesterone would cause a desynchronization with the endometrium. And we started to think a strategy to try to perform a flesh embryo transfer because all those freezals were giving a lot of workload for the lab and delay for the patient.

And so two parties were unhappy, patients on one end and the lab from the other end. So at that point, we said, why don't we think a strategy that can lead to a flesh embryo transfer? And because the progesterone rise due to the FSH that we're giving during ovarian stimulation, we thought about different dosages of FSH. And we wanted to discover whether a lower dose after colifetropin alpha, it's able to give us a good number of oversights, which of course is the action, but on the other end, lead to a lower progesterone value at the end of the follicular phase, therefore allowing a flesh embryo transfer.

Yeah. Excellent. And so these were antagonist or agonist cycles as far as the downregulation? The downregulation was done with fixed antagonist that was started on day six of the simulation.

And so the long acting FSH lasts for eight days? Yes. And then if patients needed more time, they were randomized? In three groups. Yeah.

We started stimulation on day two of bleeding with colifetropin alpha, 150 micrograms. And on day eight, we randomized the patients in three groups. Group A got 50 international units of REC FSH per day, group B, 150 international units, and group C, 250 international units.

And these cycles were done FSH only, right? There was no LH activity, no LNH, no NG or anything. Great. Pure FSH and colifetropin alpha.

Very interesting. So tell me what you found. I'm curious to know what you found.

I can predict what it was. Yeah. Basically, actually, we were a little bit impressed because we also thought in the hypothesis that we will find what we found.

But once you see it, it's always striking. It's pretty profound. Yeah, yeah, yeah.

It's true. So we basically found that the group that received 50 international units had comparable number of macular oocytes with the group that were given 250 units, but the progesterone value on the day of ovulation trigger was much, much lower. So in group A, with 50 international units, we had a mean of 0.4 nanograms per milliliter progesterone, while in group C, so 250 international units like FSH, the progesterone was 1, 1.4. So we had a difference of 1 nanograms in between group A and group C. It's a huge difference.

Of course, in our study, we wanted to find a strategy for the fresh embryo transfer. And because we are used to use a threshold of 1.5 nanograms to decide for a result in normal responders, we still are below the threshold because 1.4 basically was the limit. That's the average though.

So some of them are going to be... Yes, higher and other. So the average was 1.4. And therefore, we could still go for a good amount of fresh transfers, but a difference of 1 nanograms, it's huge. So it's really promising.

Yeah. Well, so did you find that you got more eggs though? So maybe their progesterone is higher, but is it balanced by getting more eggs or no? Well, in terms of mature eggs, no difference. In terms of oversight retrieved, there was one more oversight in the group of 250.

But at the end of the day, if the mature is the same, it's not, yes, it's not that relevant. So I guess the majority of the stimulation is done the same because the first eight days, these patients all have the same protocol. So it's really only the last three to four days, two to four days, it's different.

Just that short amount of difference in FSH exposure with the same amount of mature eggs is enough to drive this huge difference in progesterone. Absolutely, absolutely. And also on the basis, on the theory where we based ourselves, which is basically saying that colifluorotopin alpha, it's doing a strong recruitment at the beginning because it goes above the FSH threshold in the first 24 hours.

So the recruitment was done the same for all of them. And we only needed to push the growth of the follicle once they were already recruited. Yeah.

So in the US, we don't have a lot of experience with corticotropin alpha. Do you have to monitor at all for those first eight days or do you see them on day eight? Because that's when the medicine is wearing off and we can make adjustments. So it simplifies the monitoring.

I think it simplifies by far the ovarian stimulation because we saw them on day two to decide the start and we saw them the second time on day eight when we randomized. Right. Above of the 160 patients that were recruited, 12 had finished their stimulation on day eight.

So a small percentage of patients are already in eight days, they are done, which is also proven by previous studies from Woman Fatima and Barbara Lawrence that also are showing that those patients that are already in eight days with colifluorotopin alpha had a statistically significantly lower incidence of progesterone elevation due to probably the simulation of a step down protocol because you start very high with the FSH, but during the days you go down because your body is doing the clearance of the medication. Okay. Yeah.

Yeah. That's really interesting. What I love about your data is I've always thought that premature progesterone elevation has multiple factors that can make it happen.

One is the extrinsic, which your study shows beautifully, giving the higher doses of FSH and that's been consistent with our research, FSH dosing is always associated, always correlated with the progesterone levels, the more you get. Then a pure, some sort of LH activity can help lower it, probably because you're increasing enzymatic expression to pull that progesterone over to estradiol. But there's also some intrinsic patient factors, how many follicles do they have, and maybe patients that have polymorphisms in the steroid pathway genes, they're going to have different effects of pulling that progesterone through.

But this is one of the most beautiful, elegant things I've seen that shows how the extrinsic, what we're doing as the doctors can affect that progesterone growth. Absolutely. Absolutely.

I think it's very interesting to see the effect of what we are doing and we are really used to one size fits all. I give high dose because at the end I want the other size, but this doesn't work. I mean, you can have the same number of all sides by giving a little less.

And you also keep in mind that on day eight, coliferatopin alpha is not disappearing from your body. It's just behind, below the FSH threshold. So the minimum you give will put you above the FSH threshold and you will still get the chance for a fresh transfer.

Yeah, that's fantastic. I think as a field, we may be going too far towards the freeze all, especially in the U.S. and there are a lot of patients that benefit from a fresh transfer. So anything we can learn from this that gives them the best opportunity to get a fresh transfer? Absolutely.

Absolutely. It's less workload, it's less time to the pregnancy. It's the chance of a fresh transfer with all the risks that are linked to a freeze all and the preparation of the endometrium with artificial cycle.

So we know a lot now to understand that some part of our patient population could benefit from a fresh transfer. And in the design of the study, we really choose normal responders because this is where we can do a fresh transfer. I mean, in a poor responder, we try to do a fresh transfer and we know that if progesterone is rising, even with a threshold of one nanograms, we already have impaired outcomes.

But in the normal responder population, we are not really risking OHSS unless they have an hyper response, which is good for them at the end. Right. But in terms of population selection, we said, why not normal responder? Because this is the population who will gain the maximum of the benefit of a fresh transfer.

I 100% agree. Yeah, it's great. Well, I thought this was a wonderful study for our listeners.

When can we expect to see this in a full paper in press so we can read about it? Well, our idea is to submit to the company because it was founded by Organon by the end of October. Wonderful. So probably beginning 2025, hopefully.

Well, I look forward to reading the full paper and learning even more. I think this was a very elegant study and it taught us a lot. It confirmed what I think we all thought, but it very well demonstrated it's been fantastically done.

Congratulations. Thank you. Thank you so much.

It's very nice. This is Micah Hill. We're back on Fertility and Sterility On Air live from ESHRE 2024 in Amsterdam.

And we have two more researchers here that have a very interesting project. So I'm going to let them introduce themselves and then we'll start talking about the project. Hi, thank you.

I am Marcela Colonge. I work for RMA Northern California and I am the first author of this study. And my name is Nicolás Garrido.

I'm the director of the EV Foundation in Valencia in Spain. Excellent. Welcome.

Thank you both. So I saw this abstract and it sort of caught my attention. There's been more data coming out about the utility or the clinical efficacy of transferring day seven embryos, embryos that don't blastulate until day seven.

So that was your research. Tell me sort of what was your question and why did you think it was important and ask it? So how, like, I think it's an important question because I used to work for EV Chile and in EV Chile, we used to discard all the embryos in day six and when I moved to the U.S., they had a different policy for embryos. So they don't, we now, finish the embryo before day seven.

So all the outside that are fertilized, we keep it in culture until day seven. And I thought that some of the embryos that we've frozen were like, in my opinion, where they didn't have the quality load. So I wonder if there could be a cutoff point where you can say, okay, these day seven embryos are good to go or whatever.

So I wonder if they had like a, how bad or how good was the life rate for those embryos? So I did that study because the numbers are huge for the company. And so there was another study that had like very similar result that was published for Hernandez in 2019. And they had big numbers, also more than 5,000 embryos, the cycle, sorry, included and also asked, but we did it in only one year.

So one year. Yeah. Okay.

So your question was, how good do these day seven transfers do? And this was a cohort study looking at the historical data from your practice? Yeah. And multi-center. And did these include PGT? Yeah.

This is all PGT? Okay. So this is euploid PGT, day seven success. Got you.

And before we get to the results, does your lab typically, so if they have a day five, day six, day seven euploid, and the embryo grade is all the same, do they transfer preferentially based upon day? So the day sevens would be if that's the only embryo they have, most likely. Yeah. Okay.

And it's an important thing to remind, if you permit to comment on that, because I think the usefulness of this study that came from Marcella's thoughts and experience in two different laboratories, because at the end, the reason why she tried to address this question was the differential experience. Probably we cannot take this as a pure comparison day five versus day six versus day seven, because as you said, it's kind of biased because the worst cases are those where only day seven embryos are available. But on the other side, I think this is still very useful information because success rates are kind of reasonable.

And otherwise you are discarding additional probabilities of patients coming from the same stimulation cycle. This is, in our opinion, and we've been discussing about this, the proper way to interpret the context and the results. Yeah.

So we are not doing a fair comparison between day five and day seven because you pick the day seven as the last. So they've either failed everything or that's all they had in the first place. So how well did the day sevens do? We don't have to compare them, I guess, then to day five and six, but how well did they do? How often do these embryos make pregnancies? The main objective was measuring life birth.

So 21.6% of the transfer made a life birth. So one in five, if you're discarding those embryos. Yeah.

Compared to zero. Right. If you discard them.

Yeah. That's a big difference. Okay.

So as an embryologist, you're an embryologist, correct? So as an embryologist, what do you think of these data? Should the practice or should the field move towards more places growing to day seven? Yeah. But that is the main point. But also, I think this, no, I think it's actually a study that is ongoing, a study where they are collecting more data to answer other questions.

So this is the beginning of a bigger study. Yeah. Yeah.

That's great. Yeah. Because I would say that most of the labs, they end the culture in day six.

So these are- That's what my lab has historically done for the last couple of, last decade. Yes. Okay.

What's your final take home point? Well, I think no further take home points, but the last message delivered from her. So it seems from the data that we obtained that employee rates are not as good as. Yep.

Life birth rates are not as good as, but the overall message is if this is your last and the only chance you have, then you probably should go for it. And for those laboratories not practicing this, probably a change in their approach because they are getting more life births and healthy life births. This is not something we have explored yet in detail, but data seems to point to nothing is happening with them, but we need to get in that deep detail on this, but probably to let people think about adapting their policy if they are not using them till now.

Yeah. Outstanding. Well, congratulations on your wonderful research and thank you for coming by to share it with us today.

Thank you. Thank you. My pleasure.

All right. This is Micah Hill, the media editor, again, back here live on Fertility and Sterility On Air podcast from ESHRE 2024 in Amsterdam. And we're joined by two more researchers who have a very interesting clinical trial that we're going to talk about.

Please introduce yourselves for our listeners. Yes. Thank you, Micah.

I'm Sine Berntsen and I am a doctor and a PhD student at the Fertility Clinic at the Copenhagen University Hospital, Hvidovre in Denmark. I'm Nina la Cour Freiesleben and I'm a medical senior doctor, head of the Fertility Clinic at the Copenhagen University Hospital, Hvidovre, and the senior author of this study. Wonderful.

Thank you for joining us. So let's dive right in. Tell our audience, what was the hypothesis? What was the question that you asked for this study? So the reason why we did this study was that the indications for ICSI have widened.

And previously, ICSI was used for poor sperm quality, of course, for which it was developed. But in later years, it's also being used for advanced maternal age, poor responders, unexplained infertility, among others. So what we really wanted to examine was, is there any benefit in using ICSI over conventional IVF if there is no severe male factor? Okay.

And so there's obviously some pretty large cohort data sets from Australia, some from SART in the U.S. that don't show any benefit in non-male factor. But you didn't do a cohort study, right? No, no. What kind of study did you do to address this question? No, this is not a cohort study.

We did a randomized controlled trial. So this was a prospective study, and we included a little more than 800 patients, women. Yeah.

And also data on their men, of course, and the children. So quite a lot of participants, actually. And so the exclusion criteria were severe male factor, I assume? Yes.

We had patients with partners with normal or non-severely decreased sperm quality. This meant that on the day of oocyte retrieval, they had to have a minimum of 2 million progressive motile sperm in their sperm sample. But actually, we also included patients using donor sperm, because then we know that the sperm quality is good.

Yeah, exactly. Yeah. Yeah, and of course, it's also first cycle patients.

First cycle. So, yeah. So no previous... Really good prognosis.

Yeah. No reason to think they're going to have fertilization failure, maybe? No risk of inclusion bias. Right.

Including second or third cycle patients. Yeah. Gotcha.

That makes a lot of sense. Okay. So you randomized almost 800 patients.

I think you were powered to detect a 10% difference? Yeah. Yeah, exactly. We estimated that it would... We looked at our own numbers from our patients and estimated that the cumulative life birth rate... So the cumulative life birth rate means that we have the fresh transfer and any subsequent frozen-thaw transfers.

So we estimated that this was around 45%, and then we wanted to show a clinically relevant difference of 10% points, so 55%. Yeah. Yeah.

What I liked about the cumulative design is if there is a decrease in fertilization, but both groups get one good blast and you just go through the first transfer, you're not going to see the difference, but you're letting transfers play out over a year. Exactly. So if there is a difference, you have a better chance of detecting it.

Yeah. And actually, it's more than a year because our follow-up period was minimum one year after inclusion. Yeah.

So that was the last patient we included had a minimum of one year. Gotcha. So they pretty much got all their embryos transferred or had a baby.

We still have some who had, but most of them, yes. Okay. All right.

So we know what you did. We know why you did it. What did you find? What were the results of your study? We can't disclose this now because it's only sent later, you told me.

So what we found was that there was no superiority of ICSI over IVF when there is no severe male factor. Okay. Were the numbers close, the rates close to each other? Actually, the live birth rate in the conventional IVF group was higher than in the ICSI group, but it was non-significant.

Yeah. Non-significant. So within a few, within four percentage points of each other, something like that? It was around 42% in the ICSI group and around 46.6% in the conventional IVF group.

So maybe they're live. So some of the studies, at least when they do sibling oocyte splits, this is different. This is unexplained infertility, but total fertilization failure is higher with conventional than with ICSI.

Did you find any difference in fertilization failure, total fertilization failure in your patients? Yeah. But in our case, we did not find any difference in fertilization failure. Right.

So, yeah. They didn't see a benefit. Now, I guess the one caveat is those studies were specifically unexplained, and you probably have some patients with unexplained, but some with other diagnoses.

Exactly. And it's also different when it's sibling oocyte than when it's different patients. Exactly.

Yeah. There's a lot of problems with sibling oocyte studies, and you can't actually look at live birth as an outcome because you can't transfer embryos from both cohorts into the same patient. Exactly.

Yeah. Well, that's fantastic. So do you think there's any need for more research on this, or do you think that with your clinical trial and with the very large cohort data sets that are out there that show no benefit to ICSI and non-severe male factor, do you think we need more studies, or do you feel like we kind of have this question answered? I think that concurrent with our study, there was also two studies going on in Vietnam, one in Vietnam and one in Asia, also looking at this with patients with normal and also non-severely decreased sperm quality respectively, and they pretty much found the same thing we found, no superiority of ICSI.

So I think that we can ... And the important thing is to say that our study differed a bit from theirs in cases of we had blastocyst transfers, almost only blastocyst transfers. Yeah. They do a lot of day two, day three.

That was day two, day three. They also had double embryo transfer. We only have elective single embryo transfers.

Yeah. So this is two important ways that our study is ... This probably makes it more generalizable to European ... Yeah. That's the gold standard, right? ... US IVF standards.

Yeah. Yeah. I lost the thread.

Yeah. But I think we can say now that we have these three studies, large randomized control studies, also from different parts of the world now, different patients, and this also has an influence on ... Right. ... on live birth rates.

So it's important that we have studies from different areas of the world and different patient groups. So I think that there's no reason to use ICSI over conventional IVF if there's no severe malefactor. So you're obviously a clinical expert.

You're the senior author. Do you agree with what your first author just said? I agree. Yeah.

Yeah. Yeah. And also in the study for the generalizability, we included all patients fulfilling the inclusion criteria, even if they had only one mature follicle and if they had advanced maternal age.

Right. Female age could be up to before 41 ... Okay. ... at inclusion.

So these groups were included in our trial, and we didn't find any difference or advantage even ... Yeah. ... even there. Yeah.

So, yeah. But ... I agree. It's also worth mentioning that what we found was also that not only is ICSI not superior, there might actually also be a reason that ICSI could maybe be helpful.

But today, we're going to disclose that we also did a meta-analysis where we actually pulled the data from our study and also the two studies ... The other two. ... in Indonesia, and we actually show that ICSI is inferior to conventional IVF. Yeah.

The raw numbers in all those trials, ICSI is lower. It just wasn't statistically significant. Mm-hmm.

So I can imagine as you combine them, you get more power. Yeah. So this is really interesting, and ... Yeah.

I think by combining, we get a better risk estimate. Right. Yeah.

And the effect ... Exactly. It's not too big of a power, but ... Yeah. ... to get a more precise impact.

Yeah. Yeah. A better quality of the evidence.

Right. Yeah. Yeah.

Well, that's fantastic. Congratulations. I know that clinical trials are very hard to do, especially once it's big.

So as an MD and working on your PhD, this is amazing. Thank you. This is your thesis? Yes.

This is my thesis. I think you should pass your thesis. But I'm not the one that determines that.

But congratulations, and thank you for sharing this incredible data. Yes, of course. Of course.

Thanks for having us. I hope we will see clinical practice change. I know in the U.S., ICSI is like 70, 80%.

Yeah. I think in a lot of places in Europe, it's the same. It is.

I think we way overuse it. Yeah. Yeah.

We think so too. Thanks. And maybe patients would even benefit ... Yeah.

... from an extra cycle, fresh cycle, instead of ICSI as an add-on. Yeah. Yeah.

Well said. With that, we'll leave that as the final word. Yeah.

That was very well said. Congratulations. Thank you.

All right. This is Micah Hill, the media editor, back. We're here live, Fertility and Sterility On Air at ESHRE 2024 in Amsterdam.

We have a very exciting abstract about mosaicism. I know this is a hot topic and one that we're all dealing with clinically. So I'm going to let our two authors introduce themselves and where they're from, and we'll dive right in.

Great. Thanks for having us. My name is Dhruti, Dhruti Barbariya, and I'm the clinical lab director at Juno Genetics UK.

Hello, everybody. This is Antonio Capalbo from Italy, chief scientific officer of Juno Genetics. Thanks for having us.

I'm happy to keep going with the discussion on this new data. Yeah. So tell me, what was the specific question about mosaicism that you were addressing with this study that you did? So the study which we presented in this year's ESHRE, we are trying to look at the reproductive potential of mosaic embryo transfer outcomes, and specifically looking at the ongoing pregnancy rates and the clinical miscarriage rates in comparison to the euploid embryo transfers.

And so that was the objective of the study. How did you go about doing it? What was the design of the study? Right. So this is a very key feature of the study.

This basically is a non-selection study. It is a prospective-minded study wherein we looked at around 5,500 single embryo transfers in a European setting. Previously, we have done a similar sort of study on a big U.S. data set where we had U.S. clinics and it was approximately 10,000 single embryo transfers.

And so for a non-selection study, we're essentially talking about like a predictive value study, right? An ability to not have the result of the test influence the transfer, and that way we can measure positive, negative predictive values, sensitivity, specificity, all those sorts of things, right? Okay. Fantastic. So a great study on a design on an important topic.

What did you find in this? Right. So right now, the biggest topic of contention in the field is whether the mosaic embryo transfer outcomes, they perform poorly compared to the euploid embryo transfers. And there have been various different studies showing different outcomes.

So because our study is a non-selection prospective-minded study, it basically does not have the biases of retrospective study like selection bias on patient population. And what we found with this particular study was that if you take into account all the different clinical and embryological parameters, along with the chromosomal status of the embryo, meaning mosaicism or euploidy, the mosaicism has a very limited impact on the ongoing pregnancy rates compared to, let's say, the embryo morphology or the day of biopsy of the embryos. And when you say mosaicism, were these all low mosaics? Were they high? Were they a mixture? What was the sort of the range of mosaic embryos that you had that would be transferred here? So we had a spectrum of mosaic embryos.

We also did basically look at the different stratification of the mosaicism levels. So it had 20 to 30, 30 to 40 percent, and so on and so forth. And what we saw that if you had a high-level mosaicism, let's say 50 percent or above, it does have slightly significant impact on your ongoing pregnancy rate.

However, this data, this sort of population of the high-level mosaic in our data set was only 1.5 percent. Okay. So the clinical effect size is very small, and also that the proportion of those embryos were very small as well.

So overall, it does not have a major effect on the overall findings of the study. Okay. So as a senior author who's done a lot of research in this area in general, what do you think the take-home point is for the clinicians seeing those patients in the clinic? Well, the take-home for the clinician in general, I think, for our scientific community is that once again, I think we need to be very careful when we start reporting new findings in clinical genetics, in PGT.

This is very well established in the general broad field of clinical genetics, but it's been many times forgotten in the field of PGTA. So I think, as we have shown here, where we have properly validated these new findings in prospective randomized trials and prospective blended studies, now we know how to cancer patients on these findings. We know that these embryos are almost showing similar live birth rates and reproductive competence as compared to embryos without this intermediate copy number.

So I think, going forward, we really need to be careful when we implement new things and technologies and new reporting criteria, as we have done in this study. I think, also, if we want to extend this concept to the general field of PGTA today, and we want, also, to incorporate new data that have been presented at this ESHRE meeting, the concept now that is emerging, and it has been also well… I mean, getting consensus among all the experts now is that PGTA should really be designed to deselect uniform meiotic kinopoies, and that the one that are really associated with negative outcomes and clear diagnostic values, and anything that we add on top of this should be thoroughly validated. Yeah.

I actually think that's the perfect ending point, because that's very well said, and a very good take-home point. I wish we had seen all platforms, as they've emerged over the last 20 years, be validated in non-selection studies or predictive value studies first. I really appreciate you all doing this work, sharing it here in ESHRE, and sharing it with our listeners on the facilities group.

Congratulations, and thank you. Thank you. Thank you.

Thank you for everything. Thank you, Chris. Thank you.

Live at the Fertility and Sterility on-air podcast from ESHRE 2024, and I'm very fortunate to have our president of ASRM, Paula Amato, and our president-elect, Liz Ginsburg, here with us. Welcome, Madam Presidents. Thank you, Micah.

Glad to be here. Me too. Thanks for having us.

So, Paula, I know I've heard just through the grapevine that there have been some questions about the ASRM abstract submission process for 2024. And actually, we've recently got some emails and stuff that we didn't think was accepted get posters, which was nice. But just tell us, our members, our listeners, sort of what's going on with the abstract process for 2024.

What should we know about that? Yeah. Thank you for asking. I, myself, have gotten a few emails wondering why someone's abstract was either rejected or not accepted as an oral when the person thought it was a good study.

And there are things about the process that I wasn't familiar with that I think would be valuable for all the members to understand. So, I'm just going to go through a few of those. Thank you.

So, there's various categories where you could submit your abstract for. And because we want the meeting to be somewhat diverse, and obviously we get the most abstract submitted for ART-IVF topics, but we don't want the whole meeting to be ART-IVF. So, there are only a certain number of slots for each category.

So, what that means, unfortunately, is that, you know, your abstract could score quite highly, but if it's in a very popular category, then it might not get accepted as an oral, for example. But in another category where there are fewer submissions, a lower scoring abstract might get accepted. Is that fair? Maybe not.

On the other hand, I think there's some value in having some diversity of topics. So, that's one issue. The other issue is, you know, the space limitations.

And since we went from paper posters to digital, and then of course we moved the meeting to different cities, the poster hall actually, or rooms that were allotted, you know, vary in size. So, we can only accept a certain number of posters. And that's too bad as well because we, you know, this year I think we got something like 1900 abstract submissions.

And most of them were all very good, but we couldn't accept them all because there are space limitations. So, what happened this year, last year we were in New Orleans and the space was actually smaller. So, when we made the initial cutoff this year, we were going by those numbers.

And actually in Denver, we have more space. So, some people might have noticed, got in that communication that their abstract was rejected, but then a few weeks later, oh, by the way, it's accepted. And that's because we realized we had space for 200 more abstracts.

Another thing is the review process is, you know, it's challenging. We try and make sure that each abstract is reviewed by three different reviewers. And we have the rubric that we use.

We try and standardize as much as possible. But obviously, everybody reviews a little bit differently. And the reviews aren't standardized to any particular standard.

So, you might get three reviewers, two people might think your abstract's fantastic. There might be one outlier that scores the abstract a little lower, brings the whole score down, and that impacts you negatively. I don't know how to fix that.

You know, maybe there's some way to statistically, you know, whatever that's called, where you standardize to the mean or something. But that's a problem. The other problem is, you know, people agree to review, and then they, you know, they get busy because everybody's busy, and this is a volunteer thing.

And not all the reviewers are able to review. So, in the end, we're having to ask the same, you know, the same reviewers to review even more abstracts. So, that's not ideal.

Another issue is, we'd love to accept, you know, a lot more abstracts. So, one of the ideas is maybe we can have a supplement publication, maybe in F&S, like the old days, or maybe online, where we do accept, you know, the majority of abstracts, because the majority are really good abstracts, but they don't all get presented at the meeting. That way, you know, people can still say, you know, my abstract was accepted at ASRM, but maybe you didn't get the oral opportunity to present your poster, but I think that's better than not getting accepted at all, right? So, anyway, these are some of the things that are, you know, nuanced that I think if people understood, they wouldn't feel as bad if their abstract wasn't accepted for an oral or accepted at all.

I'm also open to feedback. I think we're all open to feedback. So, if anybody has ideas to improve the process, please email ASRM or me personally or Dr. Ginsberg, and we're looking for better ideas, because, of course, we want the best science to be presented and as many people to come to the meeting as possible.

Thank you. That's very helpful to know. I certainly had a couple fellows and residents get that nice surprise email that their rejected abstract is now a poster, and they're very excited about that.

Yeah, and thanks for bringing up the trainees. I think all trainee abstracts should get accepted. So, you know, whether you're a resident or a fellow, usually you're working with a faculty, and maybe one other idea was to have a separate session for training abstracts.

Yeah, those are all great ideas. Thank you for sharing that. That's great.

I learned all that as you were saying it, so that was all live information for you as well, so that's very helpful. Thank you. Liz, what do you want to share with our membership? Well, I did have an abstract comment, and I want to make sure people are aware that there isn't any favoritism involved.

I certainly have had. I'm the program director at Brigham and Women's Hospital. We have had abstracts rejected too, so I think that obviously the science was good, but it's partly what reviews you get, and it's the same thing as when you submit a paper.

It may not get into the journal that you think it's the best fit for. So you have to just sort of chalk it up to luck and not think any, you know, don't let yourself, you know, get too upset by it. There's always another meeting if you want to present the paper to your peers.

One other thing I want to say, the staff at ASRM, especially Chevis Shannon and Callie Armstead, they spend a lot of time trying to get that program together, and the abstracts accepted in the process, and they put a lot of work. So please don't take it out on them personally, because it's not what they are up to. That's great.

They are amazing staff that you have. Great. So I thought I would talk to people about the Embryo Transfer Simulator course that we did.

For the last, I guess, six years, ASRM has put on an Embryo Transfer Simulator course. ASRM has five, six Embryo Transfer Simulators, and these are sort of lower half of the body plastic models with five different uteruses and with ultrasound guidance. So you can walk people through the process of doing an embryo transfer from how to hold the catheter, making sure that people know how to hold the catheter, hand it back to an embryologist to press the plunger, afterload technique, direct technique, trial transfer, followed by embryo transfer.

So it's really nice for us as teachers to hear how it's done internationally when we go to this meeting. And these simulators are available in the U.S. as well. Some, I know, fellowships have sent fellows to simulator courses as well.

So that's something I don't know if our membership is really aware of, that this is available in the U.S. as well. Yeah. There's also didactic content.

There is really kind of an expert opinion that was published in Fertility and Sterility some years ago. And unfortunately, there's not as much randomized data on embryo transfers as there are on other topics in the field of ART. But it was really, I think, partly a consensus-based paper talking about how important standardization of embryo transfer technique is within programs in order to do good QAQI of embryo transfer outcomes, pregnancy rates per position especially, you need everybody practicing within a particular standard.

And so the didactic piece of it talks about the different steps of the embryo transfer from the surgical timeout, making sure the embryo is identified by two different people. There should be two identifiers on the dish, making sure you have the correct patient in the room, the correct embryo has been selected for transfer, from speculum placement, cleaning the cervix, aspiration or removal of cervical mucus. And then I think nobody really knows whether an afterload technique or a direct transfer technique or a trial followed by afterload, which of those techniques is best.

But I think the consensus is pretty good in the literature that standardization is important. And so that's something that we try to focus on in the course. And it's also very interesting that people have different sensitivity of their hands.

I think one of the things that I learned teaching a course is that having sensitive, delicate touch is really important. When you have a plastic model, obviously an embryo transfer catheter is going to buckle if you push too hard. And in a patient, it probably is going to cause uterine contractions and some discomfort if you're shoving a catheter against the inner part of the cervix.

So I think the model is actually really helpful for helping people realize how much pressure they should be putting on a catheter if the embryo transfer is difficult. And there are five different simulator models. So one is a direct transfer where the uterus is straight.

The next one is an antiverted uterus where you may have to extend the sheath, even if you're somebody who does a direct transfer, you might need to put the external catheter in in a curved, antiverted way and then thread the internal catheter in. The next one is, I'm going to skip to the next one because number C is actually extremely difficult. D should be C. So D is an anterior niche or ridge in the cervix, the posterior ridge where you have to hug the posterior canal.

The last one, the E is a retroverted retroflexed uterus. And then C, which is really the hardest one is a very tortuous cervical canal with anterior and lateral manipulation needed. So I think it's a really good way to get a sense for how to manipulate a catheter during an embryo transfer.

You said that very well. The model for the people who are harsh and abrupt with it gets stuck. They bend the catheter and it just won't go.

So it really does teach you to be gentle and manipulate the angle and use touch rather than brute force to get it. I just want to congratulate you as ASRM presidents on the model. To me, it's impressive that all the fellows in the U.S. get this, that you bring it to the fellowship symposium, to PCRS, to ASRM.

It's come to my fellowship at the NIH a couple of times. I know you do regional ones. The fact that all the presidents of ASRM are here at ASHRA teaching international people every day how to do it just shows that ASRM really values this as a tool, that you're willing to spend presidential time to do it, I think, to me, is impressive.

It's an incredible effort. Thank you. We have to give credit to Dr. Richard Reindoller, who actually, during his term, was when it was originally conceived and developed.

And Keith Ray, who does all the work behind the scenes, the man behind it. Thank you very much, Madam President of the Spark Committee. We really appreciate your time and talking to our members.

Thank you. Thank you, Micah. Dr. Oktay, so pleased to have you here and to have you give us a little bit of an update as to what you conveyed to your attendees of your graduate course, postgraduate course, pre-Congress course yesterday in advance of the main ESHRE meeting.

My understanding is that you had some insights into ovarian aging and potentially aspects of non-nuclear DNA and how that might be contributing to ovarian aging. Tell me a little bit about what you conveyed to your audience. Thanks.

Thanks a lot. Thanks for covering the topic. So ovarian aging is, you know, dear to all of us as clinicians.

We're dealing with the consequences of that. So we've discussed one aspect of that, oocyte aging, and whether there are any cytoplasmic mitochondrial treatments that can improve that. And so in my part, I went over that topic and primarily in the history, there were attempts to do cytoplasmic transfer.

Thinking that mitochondria were being replaced to, so to speak, rejuvenate oocytes. So I've discussed with them what the problems with that is, but at the same time, what cytoplasm might have to offer. So I'd be happy to share further details with you.

Yes, I'm really interested to learn. And obviously this is, you know, a really important clinical topic that all of us deal with on a daily basis, literally. So first, though, I mean, I think mitochondrial contribution was front and center, at least in terms of the title and agenda for your talk.

So what did you tell your attendees about the contribution of the mitochondria to ovarian aging and to what extent that could potentially be a therapeutic target in the future? Obviously, this is something that has been long discussed and unfortunately has not yet borne fruit. Yes, sure. Yeah.

So starting with mitochondria. So mitochondrial theory of aging is an established theory for somatic cells, and it certainly plays a role in somatic cell aging. When you apply it to oocytes, it's not as universally true.

It is true. It's untrue. By that, what I mean is only a limited number of genes that control the function of mitochondria are encoded in the mitochondrial DNA.

A majority of the function of the mitochondria is controlled by nuclear DNA. So in all likelihood, age-related decline in mitochondrial function in oocytes, if there is one, is more controlled by the genomic DNA. So that means that we cannot simply replace mitochondria to treat that problem.

And also, mitochondria has a lot of plasticity. It tends to repair itself by fusion and fusion, and you really need to reduce mitochondrial numbers to something like 10% before you can affect reproduction. So for these reasons, mitochondrial treatments alone would not be a solution.

The initial treatments where they thought they were replacing mitochondria were involving cytoplasmic transfer. And in cytoplasmic transfer, you only replace 10% to 15% of the cytoplasm, and there were no controlled studies, and there were some concerns whether there were significant mitochondria coming from the donor cytoplasm. Many children born didn't carry the mitochondria from donor oocytes.

However, we are learning now that cytoplasm has a very important role in regulating genome function in the oocyte because it brings a lot of transcripts from the mother before the DNA is completely transcribed. And some of these transcripts and many unknown factors may help with the early function and even mitotic function. So I'd be happy to expand on that if you want.

Yeah, I mean, that's fascinating. I was going to say when you first started talking about the history of, you know, quote, unquote, mitochondrial transfer, that it's, you know, both disappointing and maybe to some extent a relief because on the one hand, of course, we're all looking for something that can help our patients. On the other hand, there's also this whole can of worms that is associated with the concept of, you know, three-parent contributions.

And so to take genetic material and cellular material from a third party is something that obviously we've all had apprehensions about as well. And so, yes, of course, I'm very interested to learn more about how cytoplasmic transfer and or, you know, some of the more current technologies where maybe just those transcripts that are thought to be relevant could be conveyed and how might that work? Yes. So there's actually quite a bit of animal study experience now that, for example, you know, if you take nucleus or spindle from aged oocytes and transfer it into a young cytoplasm, it improves mitotic function.

And they kind of call this, you know, the sea of life or fountain of youth, whatever you call it. Cytoplasm is rich with a lot of factors we don't know, but some of the factors we guess. For example, a lot of the DNA repair transcripts are in the oocyte passed on from the mother to help repair DNA damage and protect genome integrity.

And now, you know, we have data that shows that ATM-mediated DNA repair pathways also regulate mitotic function. But many other factors are not known. But there is animal data that suggests that cytoplasm alone can correct some of the meiotic dysfunction.

And what's currently believed to be, you know, with the cytoplasmic transfer improving function, which was not proving with that because it was only a small amount of cytoplasm, is more likely the cytoplasm and all the other regulatory factors in there. But this is not something you can achieve with 10 to 15 percent of the cytoplasm. And that's why there are now experiments to do a spindle transfer from age oocytes into enucleated donor oocytes, a nuclear spindle transfer, and even some clinical trials going on in Oregon, of course, the institution of our current president, Teo Serrano-Palomatos, to address that.

So I think the direction may be shifting towards moving the spindle into a better environment than, you know, trying to inject small amounts of cytoplasm into an aged oocyte. Wow. Well, that's fascinating and promising.

And we're all waiting with bated breath to see what those experiments yield. Obviously, that's proving the converse, right? Transferring the aged oocyte spindle into the youthful oocyte. What do you think are going to be the next steps in terms of translating all of this exciting research into clinical care? So, of course, the nuclear issues will persist, so we cannot correct everything.

But even when you select with PGTA, after a certain age, you don't get the same implantation rates. I think this would be an additional way other than selection. And there are some women, you cannot find normal embryos even with PGTA.

So it's going to help a significant number of women. And the next step is really the clinical trials. And, you know, first of these trials is taking place with Shoukhrat Mitalipov and Paula Amato at the University of Oregon.

And I think we're going to need to wait for the outcome of these trials and the safety data before we can pick and choose and apply these approaches to patients who failed otherwise, who can't have a euploid embryo or have very low euploid embryo rate and cannot succeed. Yeah. Well said.

And we're grateful to you for your time today, as well as for, you know, your excellent synopsis of the state of the art in terms of oocyte aging. We're also grateful, of course, to Dr. Amato, our ASRM president, for not only leading our ASRM, but also advancing and moving the needle on this extremely clinically relevant topic. So, Dr. Oktay, thank you again.

And I hope that you enjoy the meeting. Thank you so much. Thanks again for having me.

Enjoy the rest of the meeting. Thank you for listening to the FNS On Air Podcast Special Edition, The Best of ESHRE 2024. We hope you enjoyed this.

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