Fertility and Sterility On Air - TOC: January 2026

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

Articles
01:51 Outcomes after frozen embryo transfer failure: changing the protocol does not improve live birth

14:23 Ovarian stimulation with follitropin delta is safe and effective: Results from the RITA randomized, double-blind, placebo-controlled trials

27:52 Donor Identity in Aotearoa New Zealand: a survey of parents regarding disclosure of donor conception to their donor-conceived children

36:55 The association of infertility, miscarriage, stillbirth, and parity with osteoporosis: a pooled analysis of five cohort studies

47:28 Extended Ovarian Transport for Centralized Tissue Cryobanking: Impact on Primordial Follicle Integrity

56:42 Temsirolimus and antimüllerian hormone protect fertility and the ovarian reserve against chemotherapy-induced damage in a murine model

01:04:09 Cost-Effectiveness of Single versus Double Embryo Transfer to Gestational Carriers for Male Same-Sex Intended Parents

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

Good morning, listeners. Welcome back to Fertility and Sterility On Air. For those of you keeping track, this is January 2026, volume 125, number one.

And I'm joined today by Kurt Barnhart and Kate Devine. Good morning. Good morning.

Looking forward to a pre-holiday discussion and then a post-holiday listen. Good morning, Eve. I've got my warm lemon tea.

I hear your voice is a little bit down, Kate. We're going to bear with you. And we are not joined by Micah today, who's at home and probably out for the next one or two episodes, but hoping that you're listening and doing well.

And Pietro's off this month. So we have an excellent episode with lots of juicy content that I'm looking forward to discussing with both of you. We are going to dive into the seminal contribution.

Kurt, you're doing this one, and the title is Outcome After Frozen Embryo Transfer Failure, Changing the Protocol Does Not Improve Live Birth. I have a privilege of presenting what I think is a terrific article. It's a privilege to present it in front of one of the authors as well.

So this is a very pragmatic, but well-done study. And congratulations to Jennifer J. Kim as the first author, and Benjamin Harris as a senior author, but it also includes our beloved Kate Devine and Micah Hill in the article as well. So I want to start by, I think this is a timely article because if you go back a little bit, freezing embryos is probably the biggest change in our field for the better in the history of probably ART.

The fact that we can successfully freeze embryos and then throw them to put back later with outstanding pregnancy rates has just changed the way we practice, reducing ovarian simulation, allowing us to get much higher cumulative pregnancy rates and the convenience of a frozen embryo transfer. So it begs the question then is what's the best way to put back an embryo no longer frozen, frozen than thought. That's one of those few acronyms that I think we get wrong here.

We're not putting back a frozen embryo. The question remains, you know, we started with program cycles. Many programs are comfortable with it, they're convenient, but there's a shift towards the possibility of a natural cycle, and we'll get into the definitions of that in a second, and which is better.

Although we might start with that they're both successful, one of the biggest problems we have in our field is when somebody says, look, IBF success rates are so terrific, how come my embryo didn't implant? What should I do with my next embryo? The question is, well, do we stay with the same cycle that looked fine to me? Or do we make a change for the sake of change? Or do we actually think the other cycle might have been the wrong choice in the first place? So that's what this question addresses. And I'm jealous with the amount of data and the comprehensiveness of this study. That was a long introduction to say the study is to assess whether changing from one protocol to another actually enhances or detracts from your success rates.

And I alluded a little bit to the fact that I'm jealous with the numbers that we're talking about. With this practice, almost 18,000 frozen embryo cycles that we can analyze. And the primary outcome for this was live birth.

And I'll just dive right into it. In essence, the study is clean and really logical. Basically, you start with somebody that has what looked like a very good frozen embryo cycle, either programmed or natural, that didn't work.

And then a couple comes back for another single embryo transfer and divide it into four groups, basically the factorial design. You could start with a program cycle and get another program cycle, start with a program cycle and get a natural cycle. Or alternatively, you could have started with a natural and stayed with a natural, or you could have started with a natural and gone to the program cycle.

Interestingly, and I'll ask Kate shortly, it's pretty much divided in the groups. I was kind of amazed on how random is the wrong word, because that's a statistical word. But how, you know, equal that these changes were, as opposed to, they didn't seem to be a bias in one direction or the other.

People are going to want to know upfront, so we can trust the data, which I'll get to in a second, that the inclusion and exclusion criteria are well done. It's all single embryo transfers. And the people that are excluded are people that you would want to exclude because they might have other reasons, such as three failed transfers or recurrent pregnancy loss or anovulation where they can't get a natural cycle.

And then the study, when you look at these two groups, compares not to the previous cycle, which would be perhaps a questionable statistical idea because you've got regression to the mean, but instead it's just saying, what's the pregnancy rate in that second cycle across the four groups? So the really top line function is, it didn't seem to matter. So if you started with a program cycle and then you have the two chances of staying with a program to go into natural, your pregnancy rates are 42 versus 40 percent, almost 41 percent, with a whopping relative risk of 1.02 and a very tight confidence interval around one. Interestingly, if you started with a natural cycle and then you compare the two groups, whether staying with a natural or going to a program, your pregnancy rates are about 39.9 percent versus 38 percent, again, with a very convincing non-significant relative risk of 1.06, with, again, a very small, tight confidence interval around one.

So we can get into the subtlety of the subgroups in just a second, but I was just, you know, that top level answer should be of interest to you all because I know it's a lot of consternation we have with our patients. And I actually have already used this paper in my consultation saying, look, I think everything went right with your frozen embryo transfer. We can change it if you want to, because it gives us some semblance of doing something differently or makes you feel better.

But I honestly don't think, because everything looked good, that we need to. And that is a really refreshing, you know, power, sense of power when I have that consultation to be really confident that we did it right the first time. And sometimes it's not going to work.

The success rates are under 50%, and trying again is fine. But at the same token, if you really feel strongly that we want to do things differently, let's go for it. You know, Eve, what did you think about that, just that top-line level in itself? Yeah, I couldn't agree more.

And I feel like, Kate, what I really loved about this was that you didn't compare to their previous failed cycle, that you used a group analysis and looked at it group over group instead of individual to individual, because ultimately, like, that's what we want to know. And I agree. Like, I think it's actually a really powerful, I always say, a counseling nugget.

I think it's a really powerful counseling nugget to say, look, this has been studied, and the data really support the protocol doesn't matter. And we can change you from a program to a natural or vice versa. But that's probably not what's going to account for your difference.

There was one subgroup, and I do want to talk a little bit about this, Kate, where when you did a programmed initially, then you had a higher success in one specific subgroup on a natural cycle and not a modified natural. But, Kurt, I don't know if you're going to go back. Yeah, we're going to go into that.

So, that was the top line to say that at the very beginning that there doesn't seem to be a difference. And there were a couple of, and again, this is for those listening closely to my methodologic evaluations paper, this is the right way to do it. There were some planned subgroup analyses, not just let's see what we find and publish the results.

Let me take the easy one first. By the way, I didn't say it, but the results were controlled for things like fertility diagnosis and age and all the appropriate variables. The one thing that is controversial is whether you control for the use of PGTA or not.

And they did in their primary analysis, but they also satisfied my question, which they knew was coming, which is in a sense, when you have a yes or no variable, like the use of PGTA or not, you really can't control for it because controlling is kind of put them back in the middle and see the overlap, but there is no overlap. You either used PGTA or you didn't. So, the right thing to do was what's called the stratified analysis, which they looked with and without PGTA and the same analyses and basically found the same answer, which is very, very reassuring and adds robustness to the analysis.

I'm also pleased that it was only about 45 to 50 percent that used PGTA. So, it wasn't a program that used 100 percent PGTA, which as a side note, I'm comfortable with. And then the other aspect was it's both a vocabulary problem and also a scientific problem, like what is natural, right? So, the definition of this paper was programmed was if you use estrogen and progesterone and there was no corpus luteum, however you did that, that's a program cycle.

But the natural cycle is everything from you didn't do anything other than monitor their ovulation to you triggered their ovulation or you actually gave them stimulation to get them to ovulate. And we're still in the weeds of trying to figure out which one of those is actually better. And in one of the planned subgroup analysis, I'm sure Kate can describe better than I, but when you actually change to a pure natural cycle, it appeared that that was statistically significantly higher than changing to other types of natural cycles.

Now, that begs the obvious question, is that a true finding or is that just a hypothesis to go look at that in another RCT? Is that a statistical, you know, freak? But it does kind of add to our armamentarium and lingo that we think that if you're really trying to do a natural cycle, it might be the true natural cycle is the better of the group. I'm saying that only from teleology, like if you're trying to replicate what happens in nature, then replicate what happens in nature and the least intervention possibly could be better. Kate, did you have a lot of feeling on that, you know, statistically and biologically that that was a true finding or are you still kind of thinking that it's one of those things that just kind of piqued your curiosity and needs further study? The latter.

I mean, I do think that we can overanalyze any data set. And I know that we certainly were not powered to look at subgroups of changing over to different types of natural cycle, quote unquote, frozen embryo transfers. We did a lot of comparisons in this study.

And of course, we can have a positive finding that's due to chance. And then one variable I think that is hard to control for in this analysis is the long study period from 2012 to 2022. And the rate at which we were doing modified natural cycles and which types of natural cycles we were doing over which time period as we've, as a field, learned more about these protocols, I think may also have some impact on the results as a somewhat unmeasured confounding variable.

So I agree with you, Kate. I think that it's an intriguing finding and I and saying that the natural is better because there are always limitations of cohort study. Again, you hear my enthusiasm for this study, but let me just tell everybody when you're planning to do a study like this using SART data, your own data, there's some things you can't control for.

For example, some of the minor limitations of the study is you still, even as big as this study is and well done, you can't control for why somebody changed or didn't change. That's called confounding by indication again, and you cannot control that out. No matter whether you use propensity score or Bayesian analysis or something like that, that really can only be covered by randomization.

The other thing that, it's a minor, but there also is a small issue with the study was that the second embryo transferred could be from a second cohort and not necessarily the same cohort. And even if it was, well, it could be cleaner obviously if it was all of the same cohort or a different cohort. But again, that adds some unmeasured confounding, but it's the size, the rigor, the sensitivity analysis that make this finding robust and convincing.

If you really wanted to geek out, this would be an excellent opportunity to, as I described in a previous podcast for what's called a simulated RCT, where you could actually select people by the criteria of an RCT, use controlling before and after, really limit the population to those that could have been randomized. And there's a big push and you'll see it in our journal that a lot of people now are doing these things called again, simulated RCTs. There's instructions on how to do it on our journal.

And that can even give you more convincing and robustness to say that I'm not fooled by the data of a cohort. Yes, it is a lovely counseling nugget to be able to tell our patients to select the frozen embryo transfer protocol that works best for them based on convenience. And really the main thing we're changing when we go to the next transfer is the embryo.

So keep calm and transfer another embryo. Yeah, I love that. My patients always ask, well, what are we doing different? It's a different embryo.

And that is the biggest take home from this is that the protocol is just not as important. So I think, again, I want to echo that. Kudos, great paper.

I love papers that are well done and that answer a very pertinent clinical question that we struggle with every day. And I think that this paper absolutely meets both of those. Moving on, we're going to talk about the RETA trials.

So the next paper, Kate, that you're going to tell us all about is ovarian stimulation with phallotropin delta is safe and effective. Results from the RETA randomized double-blind placebo-controlled trials. So take it away.

Yeah, I'm excited to talk about this one. The results are long awaited and I think largely unsurprising, but I'm excited to talk about it in the context of the process of drug approval in the US and really what should be the appropriate study design to ensure safety and efficacy, which is really the goal of a phase three trial. So this one's called ovarian stimulation with phallotropin delta is safe and effective.

Results from the RETA randomized double-blind placebo-controlled trials. First author is my US fertility colleague, Dr. Michael Scheiber. And the studies, it's two studies in one paper, technically, details the results of US multicenter double-blind RCTs that evaluated as their primary endpoint, the cumulative probability of achieving an ongoing pregnancy per IVF-XC cycle start.

And they, the patients were randomized, participants are randomized in a 10 to one ratio to phallotropin delta, which the, with the brand name Recavel and one 11th of the population were randomized to believe it or not, placebo. And again, with looking at the outcome of ongoing pregnancy. So we kind of know how this one's going to go.

And of course, this was with the purpose of obtaining FDA approval for this drug, which is approved already in much of the world, including throughout Europe. So importantly, the assignment to the placebo arm was justified ethically by the authors, the IRB, et cetera, because those that were randomized to placebo and then not surprisingly didn't respond to treatment were subsequently provided with an IVF cycle free of charge using an FDA approved gonadotropin protocol. So to get into the methods a little bit more, 578 patients were randomized in RETA-1 and 587 in RETA-2.

And the reason they were two different trials was certainly based on the FDA requirement that they look at patients responding both in a younger cohort and an older cohort as these patients are different. So RETA-1 was patients aged 18 to 34 and RETA-2 aged 35 to 42 years. The authors state that those sample sizes, again, 578 and 587 were determined to provide adequate safety data based on the observed frequencies of adverse events, but that the sample concomitantly provided 99% power to assess superiority in terms of that primary outcome of ongoing pregnancy.

And again, just don't need that many patients to achieve adequate power relative to placebo. Ongoing pregnancy was defined as a viable intrauterine pregnancy at eight to nine weeks post-transfer. So RETA-1 participants being younger had to have 12 or more months of unsuccessful pregnancy attempts prior to randomization, whereas RETA-2 patients, the older patients had to have six or more months.

So other notable exclusion criteria were ovulatory dysfunction, unmitigated uterine factor, including fibroids that are three centimeters or greater, surgical or donor sperm, more than one prior IVF cycle, and extremes of BMI or extremes of diminished ovarian reserve, specifically FSH greater than 15, and those with severe endometriosis. And adverse events that they looked at included OHSS and injection site reactions, pretty typical pharma trial stuff. The starting recovil dose was fixed based on age with a higher dose in the older cohort, and all were antagonist protocols and triggered with agonist or HCG based on their response.

PGT was not performed and fresh transfer was performed so long as they weren't concerned about OHSS. So if they got an HCG trigger, unless 20 or more eggs were retrieved, they got a fresh transfer. Frozen embryo transfer protocols could be a programmed cycle with progesterone and oil or a true natural cycle with urinary LH monitoring and supplemental vaginal endometrium or micronized progesterone.

And every transfer was a single embryo transfer. So spoiler alert, not surprisingly, recovil was found to be superior in terms of attainment of ongoing pregnancy within 12 months of stem start, and was also superior for the secondary outcomes of live birth, number of eggs retrieved, number of 2PNs, number of blastocysts. OHSS occurred in about 3% in Rita 1 and about 1.5% in Rita 2. And unsurprisingly, nobody that got placebo got OHSS.

So, you know, the FDA's current approach to approval for fertility drugs is kind of a moving target. But the authors state that their rationale for designing this study against placebo is that the FDA would require them to do a double blind comparison. And then they state that the existing comparators of effective medications are currently marketed and sold in pre-filled devices such that to do an actual placebo controlled trial would be quote unquote impossible.

I would push back on that a little bit insofar as Gonal F is available in vials of medication, not only in pens. And there have been other studies of new gonadotropins coming to market relative to a comparator. One that comes to mind was a FINIX study.

I don't know if you guys remember that one, but it was back, you know, somewhere around 2015, 16. There was a folatropin alpha that's available in Europe that was brought to market and compared in an older cohort to Gonal F in a double-blinded trial. And unfortunately, that drug was not approved in the U.S. because they did not achieve their non-inferiority margin, their pre-determined non-inferiority margin.

So, I'll stop there and just kind of hear what you guys think about this, because I do think it's a fascinating topic. I'm kind of like in the weeds on it myself for a couple of different projects that I'm working on. But at the end of the day, I don't think that Faring would have said, oh no, we have to compare it to placebo.

Because at the end of the day, it's so much less expensive to do a study with a much smaller cohort, and also one in which there's essentially no risk of not finding efficacy. So, you know, of course, then as providers, we have to decide, okay, what do we need in terms of a phase four study potentially to determine whether this is actually the right thing to do for our patients, because we don't know based on these data. And I don't blame Faring.

Again, this is, you know, they are accommodating what they know the FDA will want and and they need to get their drug through the market with as little risk and cost as possible. But I don't think this study design serves patients very well, either the participants of the study or the general population. Yeah, I agree.

And I think it borders on unethical. You're randomizing patients to a placebo group that you know, has zero efficacy. These are patients who have been trying to conceive on average in this study, I think for like three and a half years.

And so I it's actually somewhat unethical to take those patients and put them into an arm that has zero percent likelihood of achieving success. And I feel like while yes, it's going to prove efficacy, the drug works over placebo, those poor patients who had to go through the motions of an IVF cycle had to inject themselves, go in for monitoring, endure a cycle cancellation, have further delays in their treatment, granted, their subsequent cycle was funded. But I think that the FDA needs to perhaps loosen their requirements to allow drug trials to not harm patients.

And I think that there is harm in the placebo group. While there's not medical harm, I do think that there's potential for profound psychological harm. And again, I don't blame Faring, I blame the FDA for some of their rigors and standards.

And I've certainly worked with clinical trials that have had FDA requirements. But I would not say that that is no harm. It is an interesting topic.

And I think you're right, Kate, it's kind of a loophole that, you know, drugs, especially new drugs, need to be tested against placebo. It's kind of an odd aspect here. But the alternative would be a non-inferiority trial, which would be, you know, really expensive.

And in other industries, there's something called non-inferiority drift, which really is a big issue here where, you know, drug A shows it works with placebo, drug B is non-inferior, but it really is non-inferior by like 5% or 10%. Then drug C comes in and it's non-inferior to the second one by 5% or 10%. And by the time you've got the fourth one, you've got a drug that's, you know, 30% or 40% less efficacious than the original.

And you're just getting new drugs and extending patents and it's all business decisions. So I agree with you, the problem is the way we approve drugs, not the companies trying to get the drugs. But, you know, an expensive trial to actually compare the two head to head is tough.

I have a feeling you're going to need to do that anyway as part of the package, but it is interesting. But I'm glad we could publish something like that at FNS because it does show not only the rigors or the non-rigorous aspects of FDA approval, but also shows, you know, what it is to get a trial and how drugs work. So there is value in that, but I agree it's a special patient that needs to be in it.

Well, it's also a, it's super risky for these companies to go against a comparator with a really narrow non-inferiority margin. You know, going back again to Phenox that was looking at a foliar benfol, that's phalotropin alpha. It's used in huge numbers in Europe and is, it would be very, very surprising to me if it is truly inferior.

Maybe it is, but that company spent tens of millions of dollars on that study, not to bring it to market. So I think there's got to be a more logical way for the FDA to approve some of these drugs that are already at market, including using some of the post-marketing data from, you know, the global utilization of these medications that could serve the patients, get us the information that we need as practitioners. But I mean, again, not to beat this one to death, but it's also the outcome that they choose to, right? So I believe that gonolaph was approved based on the number of follicles that grew and follistim based on the number of eggs.

And so this transition over to clinical pregnancy, while obviously we want more distal outcomes in general in our studies, is that really oppressive of new drug development in our country as well. So a lot to think about here from this study. And I think, you know, we're all aware of the presidential announcement of Pertuveris.

It'll be interesting to see when, and if that's approved, how, on what grounds FDA approves it in this expedited process. But this kind of provides a nice framework for us to think about that and other new medications as they come to market. And really, when do we need to insist upon phase four data to change our prescribing patterns? Right.

And then how much does it have to differ to change your prescribing patterns? I mean, just because a company has a new drug, is it actually better? And even if it's only incrementally better, is the cost and the patents worth it? These are really philosophical questions that aren't an answer. And it goes back to the paper we just talked about before. There may be really subtle differences in simulation drugs, but ultimately the goal of IVF is to get multiple eggs, and you can achieve that in lots of ways.

We just have to be careful what incremental difference we're looking for and what we're expecting. Yeah. I mean, it has to be either cheaper, more patient-friendly, or work better without compromising the other two too much.

Right? Right. Exactly. But this can't answer that for us, unfortunately.

Yeah. I think it's a great discussion. And I agree.

I think it's going to be really interesting to see with Percovirus what actually the FDA requires. And is it fair? Is it fair for the government to align with one drug company and lower the standards for approval and not align with another drug company and hold them to a different standard? And so I think that there just needs to be uniformity in how we approve drugs and not have special dispensation for certain drugs based on politics. I think that the science has to prevail.

So moving on to the next article, I'm going to take this one. It's shifting gears to donor gametes, and this is Donor Identity in New Zealand, a survey of parents regarding disclosure of donor conception and their donor-conceived children. And I thought this was a really interesting article as well by Karen Anderson with senior author Cindy Farquhar from New Zealand.

The laws in New Zealand are different than the laws in the US. So in 2004, New Zealand's Human Assisted Reproductive Technology, or HEART Act, established a central registry, and they mandated that all donors be identified in, I think I'm going to mispronounce this, in New Zealand, aiming to promote openness and access to genetic information for donor-conceived persons when they reach the age of 18. And there are some cultural differences between New Zealand and us, and factors influencing the shift to open identity in New Zealand were increased recognition of the negative consequences arising from closed identity adoption.

And I think we all know this, prior research has shown that disclosure of donor conception is considered beneficial for an individual's identity formation, especially when it's done early in their life. So despite legislation that's been enacted in New Zealand, disclosure is not mandatory, and previous research focused mainly on donor-conceived people born before the HEART Act. And so what this study does is they explore whether parents disclose donor conception and their experiences after this legislation went into place.

It was a cross-sectional survey, it was conducted in June of 2024, and parents of donor-conceived children ages 7 to 18, who were born between 2006 and 2016 after a clinic-based sperm, egg, or embryo donation. Invitations were sent by the fertility clinics, and again, they have a registry, so they're able to identify all of the patients who have donor-conceived children. Was sent to 1,317 eligible parents, and they completed this online, anonymous Qualtrics survey.

They had a response rate of only 28.4%, so 374 valid responses, and I'm going to circle back to that point later. Of these 28% who responded to this survey, 86% of those had already disclosed donor conception to their child, whereas 11.5% planned to disclose, and less than 1% planned not to disclose. And the median age of disclosure was 8 years.

Of the parents who disclosed, 85% told their child that the donor was identifiable, and 94% told them this, especially if the donor was a family member or a friend. I did not find this next point that surprising. The highest disclosure was among two-parent gay and lesbian families, so 96.3% of those families disclosed that they used donor gametes, followed by single parents, and then heterosexual couples at 82% had the lowest rates of disclosure.

When they surveyed the reasons for disclosure, the majority felt like it was the child's right to know, 93%, followed by trying to be open and honest, importance for identity, and only 7% admitted to choosing to disclose for fear that one day their child would take a DNA test and discover this on their own. Most parents disclosed with a conversation, and about a third also used a book to help them disclose. I thought the next point was a little bit concerning.

23% of these parents had concerns about disclosure, and 18% reported negative child reactions, and this was not associated with age of disclosure. And this is a higher number than I've come across in my own reading. 71% of parents who disclosed had no professional support, and of those, the majority, 83%, felt that they didn't need professional support.

Most of the professional support occurred in the fertility clinics before treatment and not at disclosure. And so I think we can, they identified several themes. So, disclosure was a right and an identity need.

There were stigma and relationship concerns. They feared social stigma with the children, and they feared impact on the parent-child bond. And there was this theme of need for ongoing support, not just support in the fertility clinic.

And so overall, I think we can say that disclosure in this population was common but not universal, with some parents remaining uncertain or planning delayed disclosure. And the one thing I want to circle back on, as I alluded to earlier, is the 28% response rate. And I really worry that this introduces a very high level of bias towards disclosing parents.

It makes me wonder that those who are choosing not to respond may also be choosing non-disclosure. And so the rates of disclosure may actually be far lower than what this survey leads us to believe. And so I think that that's, I don't know how we get to studying those parents, but I do think that it does open the door for the idea of some ongoing support that should be available for parents who choose to use donor gametes and for the donor-conceived children.

So Kate, Kurt, what do you both think about this? The reason this gets published is because it brings it to the forefront and at the discussion that's really, really needed. But my personal belief is I really think the options need to be discussed with a parent, and that's our job. And then really what they want to do is what they want to do, and that's the best solution for them.

They shouldn't be changing their mind based on a survey from somewhere else. It's just cross-sectional data as you've described. But the point is all of the stuff that was in there about here are the ramifications and here are the options, people should know.

And I think sometimes we're just silent about it. So that's what I think the power of this paper is. I totally agree with that.

I don't think you can really get at what is the true rate of disclosure in the population of donor recipients based on this study, but it is an important item of discussion. I also got PTSD a little bit as former SREI research chair as to how hard it is to get people to respond to surveys no matter what you do. So feel for these authors there.

I also thought some of the qualitative comments from recipient respondents that they put into the paper were really prescient. So like specifically this idea that, you know, a lot of these patients felt that they were kind of on their own as soon as they became pregnant and while they wanted to do the right thing by their donor conceived children, that they really didn't feel that they had the resources. So you touched on that really well, Eve.

That said, I think we could really think a little bit more about how do we better support these patients beyond, you know, yeah, you're pregnant, graduate to your OBGYN. I don't have the answer, but this paper certainly highlights that there's a need. Yeah, I totally agree.

And I think it's interesting that perhaps that link or that health psychologists that are practicing, that many of them are independent of the clinics, freestanding, and have more potential to develop longitudinal relationships with patients and may be able to support both the patients and their donor conceived children. And so I think perhaps one take-home point that we can do as physicians is counsel our patients exactly that, that we're gonna start the conversation about donor conception with the psychologist, but that it's not a one-time conversation that we're mandating that they do before donor conception. This is the beginning of that conversation.

And I think perhaps reframing it in that way and encouraging long-term relationships with their health psychologist or a health psychologist who has keen understanding of donor conception is the way to go and starting that relationship that starts with us. Yeah, that's a really important point, Eve, that the receptivity of medical information is gonna change by huge life events. And telling somebody before they start the process is very, very different of telling them after they've succeeded in the process.

And they may have very different beliefs and understanding and may hear you differently. So I think the conversation needs to happen both before and after. So we're gonna, again, switch to a more epidemiologic paper.

This next topic is on osteoporosis. And Kurt, I'm gonna send this over to you. The Association of Infertility, Miscarriage, Stillbirth, and Parity with Osteoporosis, a Pooled Analysis of Five Cohort Studies.

Yeah, this is a paper by Chen Liang, is the first author, and Geeta, I'm gonna mispronounce her name, Mershra, it looks like. It's a wonderful collaboration between a couple of Australian groups, a group in the Netherlands, and a couple of statistical and epidemiologic groups in the United States, North Carolina and Ann Arbor, Michigan. So this is kind of a high-level question, and I'll stay high-level with the presentation because the paper can't get too granular.

But the question is basically, what are the consequences of our patients in later in life? If you have a patient that doesn't get pregnant or has fewer children or has infertility or has miscarriage, do those reproductive events link or change the course of later events in life? And in this particular case, they're looking at osteoporosis. The reason that I think many authors and epidemiologists looking at osteoporosis is the perceived link between estrogen and its metabolisms and bone density and bone remodeling. You're going to hear me say this probably throughout the paper.

I think our understanding of the mechanism is kind of rudimentary, and some of the times it's explained very maybe not in the best terms during the paper of what they're looking for in terms of a true mechanism. But let's skip that for a second. The goal is to say if you have a large number of menopausal women, in this case 140,000 women, can you go back and look at their history, and it is a self-reported history of things like infertility, stillbirth, and parity, and then look to see if any of those are associated with the development of osteoporosis later in life.

Now, maybe not in our clinics, but in worldwide health, osteoporosis is a big actor here. I mean, it is a strong burden. It's a chronic disease.

It affects people's quality of life. So, osteoporosis is, I think, an important question. And the answer they come up with is that a history of infertility is associated with a greater risk of osteoporosis with a hazard ratio of about 1.16, or about a 16% increased risk of having osteoporosis if you have infertility.

Also, if you have recurrent miscarriage greater than 3, you've got about a 17% elevated risk of osteoporosis. It continues to say if you had a risk of a stillbirth, 1.4, 1.1.4, or 14%, as well as low parity at 1.20. Now, this is a nice study in that it takes five different cohort studies and combines them together. They do a nice job of it.

And I'm not going to bore you with how they do that and the statistical difficulties they had and the way they controlled for it. Please read that on your own. But I just want to stay high level with this because I did some research with Natalie Stentz about 15 years ago, where I'm really curious about what the underlying disease, if you will, of nulla parity or infertility, does it really have consequences? And I was convinced with Natalie's work that it does.

And we found that an all-cause mortality was around 20% higher in women that had infertility. We also found out it had a higher incidence of some cancers. And there was another node of risk in things like diabetes and endocrine disorders.

Now, the argument is that it's kind of a canary in the coal mine, that if something is wrong with your endocrine systems in general, not allowing you to get pregnant, that might result in problems later in life. And this paper is taking that one step further with the specific disease of osteoporosis. I like, and I'm most comfortable talking about, the idea of nulla parity.

And they find association, which is characterized in many conditions, even in male infertility in health and female infertility in health, it has this kind of you idea that there's a higher risk if you're nulla parit, the risk is lower if you have one or two children, and then it increases again for some reason if you have multiple children. But it's the same idea that if you don't have a child, and you're missing that nine months of the pregnancy state, or in some cases, multiple years of pregnancy states, if you have multiple children, that you could really have a very different endocrine environment, which might lead to differences in health. Now, the paper talks about estrogen deficiency, which I think is really a result of what we understand in menopause, that if you have lower estrogen, you've got, you know, lower bone remodeling and things like that.

But I think premenopause, it's something different. And it's not as simple as you have low estrogen. But it is the pregnancy state, I think, that is what matters.

So if you believe that this association exists for nulla parit, you could also believe it exists for infertility. And it looks like it does in this study. What it doesn't answer is if what we do actually reduces those risks.

Because every time I talk about this, it says, well, what if I am infertile, but I then get pregnant with donor egg? Does that change everything in my life? I don't know the answer to that. Or, you know, if you're having trouble getting pregnant, and you conceive with IVF, does that make me now a fertile person? Again, I don't know that these kinds of studies can't answer that. But it's an intriguing question.

So this study, the reason it's an FNS, again, just is it extends this belief that fertility is a disease. And sometimes, although we can't identify the specific reason that someone is infertile, that the body is just not as perfect as it could be. And that can have consequences later in life.

I don't, again, I don't believe it's estrogen levels. I think it's just the whole metabolism of, again, the menstrual cycle, the presence of a corpus luteum, the presence of a pregnancy. Remember, pregnancy is a high estrogen state as well as a high progesterone state.

So those are the kind of things that really do contribute in one way or another to health, and in this case, osteoporosis. So congratulations on these authors for extending this conversation. I'm not really sure there's anything that affects our clinical practice based on this paper, but it should intrigue us all because these are patients that we're dealing with when they're healthy.

And we don't often see them when they're not 20 or 30 years later. But we probably should understand that it's an opportunity to talk about ways of improving your health. Again, I don't know if the answer is further exercise or if the answer is regulating your menstrual cycle.

I'm recommending that you get pregnant to reduce your risk of osteoporosis, but it is an intriguing association. What do you guys think of this paper? I feel like I'm getting mixed messages on pregnancy and osteoporosis. So on one hand, we know that pregnancy leaches the bones of calcium, right? And so it is this U-shaped, the more pregnancies you have, the worse over time, but yet the high estrogen and progesterone levels in pregnancy are somewhat protective.

And so I don't know quite how to wrap my head around it, and I struggle with it. I also somewhat struggle with lumping all of infertility into one category, that infertility has a higher risk of disease in the future. Well, sometimes it's male factor infertility and the impact on the female is negligent, and we're not teasing that out.

And I think that there's a big difference in long-term risk between somebody who has polycystic ovarian syndrome or diminished ovarian reserve or primary ovarian insufficiency. And so I think that the risks are just very different or two-fold factor due to a previous history of an STI is going to have a markedly different impact. And so while I commend the large data, combined data, five studies, I think in doing that, you're really losing the granularity of being able to tease out what is the risk factor at play here.

I suspect that that risk factor really has to do with low estrogen, that it's primarily in a diminished ovarian reserve population. Women who have DOR probably have more miscarriages because of poor egg quality. They probably have lower estrogen over a more prolonged period of time, therefore leading to more osteoporosis in the future.

Combine that with some body mass index issues, race, other risk factors, and it's the perfect storm for osteoporosis. But I don't think that this study is poised to adequately address that question. I'm comfortable with that, Eve.

I agree with you that when you put infertility, especially as self-reported without specificity, you can't get the granularity of what the risk factor is. But at the same token, when you do that and you see that there's a risk, there's something there. You believe that there is an association, although you don't know specifically for what patient.

But I also agree with you and have talked about this and written about this, that each different definition of infertility might have its own risk factors for subsequent disease. You know, the decreased ovarian reserve and the unexplained are the most obvious. There's questions about telomere length and aging and stroke risk, whereas the PCL women has very different risks and endometrial cancer and things.

But the point I'm making, again, to quote Michael, who likes what I said, this is let this data flow over you and recognize that there really is an interrelationship between your reproductive life and the rest of your life. And, you know, this is just one way of saying, let's start by teasing this out. Yeah, I could not.

That people have alluded to are being in a privileged position to be to be able to use to help patients understand that they need to look after their their total health, but just hard data to apply. Doesn't mean we shouldn't look and keep doing these. But but how do you specifically counsel one patient based on on this study? It is a harder question.

Yep. That's the problem. Biologic research.

I agree. Agree. We're going to talk about extended ovarian transport.

Kate, this one's yours. Extended ovarian transport for centralized tissue cryobanking impact on primordial follicle integrity. Thanks, Eve.

Another great paper. Love this month's edition. So this is a really highly practical study for those in this really still niche field of ovarian tissue cryopreservation, about which we really know so little in terms of how to do it best.

So these authors tried to answer the question of what accounts for the tissue damage that occurs in transport of recently resected ovarian tissue? And what is sort of the upper limit of time in terms of how long can this tissue be in transport? And the reason why this is such a practical question is, again, because this is a relatively new field that requires a really high level of expertise and very specific conditions and equipment in order to cryopreserve the tissue. And so while it is relatively feasible in most settings for a gynecologic surgeon, for example, to obtain ovarian tissue, unfortunately, in many settings, it can't be appropriately cryopreserved and needs to be moved over potentially a pretty wide geographic distance. And so what these authors did to try to answer these questions was that they evaluated markers of apoptosis and DNA damage in ovarian tissue that had not been exposed to chemotherapy.

So we wanted to control for that variable, that damage may have been already induced by chemotherapy, which is a real concern for a lot of these patients. And understandably, small sample size, there were six patients who were undergoing clinical ovarian tissue harvest, and there were 10 organ donors, so recently deceased patients that had agreed to donate tissue. The tissue was transported in standard conditions, which was four degrees Celsius in organ transplant media, or hep B's buffered media for cadaveric and clinical tissue, respectively.

And, you know, from an ethical perspective, and I think the authors did this well in their study design, there was a cortical section that comprised of less than 5% of the total sample, since again, these were samples that were going to be used clinically, was sectioned. So a less than 5% section was then immunostained as well for markers of apoptosis and DNA damage. So specifically they were stained for anti-active caspase 3, so we'll call that AAC3 going forward, which is a marker of apoptosis, gamma H2AX, which is a marker of DNA double-stranded breaks, and hypoxia inducible factor 1 alpha, which is a marker of hypoxia.

And they stained these sections for these markers in a blinded fashion, so the investigator who was handling and staining and evaluating the samples was not aware of the clinical characteristics of the donor, nor were they aware of the transport time. And the expression pattern as assessed by the intensity of the staining was then analyzed relative to the time spent in transport after resection. So the primary to primordial follicle ratio was also assessed, and that was assessed as a marker of follicle activation, and again, relative to transport time.

And so what did they find? So what they found was that AC3, which is the apoptotic marker, and H2AX, gamma H2AX, which is the DNA double-stranded break marker, were elevated in terms of their immunostaining and significantly associated with transport time, whereas the other markers, so again, the hypoxia marker and the follicle activation marker, were not. They were not elevated, and they were not associated with time in transport. Their analyses were adjusted for age and BMI, and based on the data that the apoptotic marker and the DNA double-stranded break marker were elevated, the authors concluded that the increase that's observed, and this is well known and understood in prior research, much of which has been done by these very prolific authors, it was already known that there was increased follicle apoptosis, and so here they felt that they were able to narrow in a bit on the mechanism, that it does not seem that the increase in apoptosis is due to hypoxia or stromal damage or increased follicle activation, but rather increased DNA damage associated with this prolonged transport time.

They then went one step further in terms of their analysis and looked to see whether they could identify a time threshold so as to better guide protocols, really, in terms of how long can this tissue really be in transport without losing its benefit to, you know, the recipient with oftentimes self-donation, but again, some of these are cadveric samples. What they found was that AC3 staining rose markedly at 21 hours for both primordial and early-stage growing follicles, and that gamma H2AX seemed to have an increase, suggest an increase, in the loss of DNA integrity at about three hours, and so they concluded from this that about 21 hours is sort of the upper limit of what this tissue can stand in terms of otherwise kind of reaching a critical point of apoptosis, and they have a pretty elegant discussion that draws upon some of their prior research as well, suggesting that, you know, even though there was also a threshold in terms of DNA integrity at three hours, we know that those, that double-stranded DNA breaks can be repaired up to a certain point, and they also noted that the overall intensity of the DNA double-stranded break marker, that gamma H2AX, was pretty low, and they took that to mean that probably ongoing repair of those breaks was happening in real time in these tissue samples, and that really, from a practical perspective, they think that you have that full 21 hours as much as obviously sooner is better. So, I'll stop there.

I mean, it's a really clinically relevant, but also, I think, mechanistically elegant study. Obviously, we would love to see even more basic science assays done beyond immunostaining to get further into the details of these mechanisms, but respecting the really sacred nature of these tissues, they had 5% to work with. These were clinical samples, and, you know, there's a nice, actually, commentary as well from a German group that does this routinely, and these data can be used from a totally practical perspective as to where do we place these reference centers relative to where tissue are collected so that when patients who, you know, kind of hang their hopes on this tissue for potential future childbearing or endocrine function, these are patients that are facing really kind of crushing diseases for not just their health, but their fertility, how far can their tissues travel and still be useful to them? So, I will, I'll stop there and kind of hear what you guys thought.

Yeah, I think it provides more of a framework for how long is too long and what's a reasonable transport time, and I think that as someone who works in a center that does take tissue, I think it's a very valuable guidepost to say where we can and should accept tissue from. Yeah, it also adds standards. You know, people that are thinking of doing this, you can add, I don't know, parentheses on how far you can go or what you should target or things like that.

So, this is nice work, and it really does add to those who are trying to implement or better their programs. Yeah, agreed. Totally agree, and Eva, I don't want to cut you off.

I want to hear more about your experiences as somebody who does this on a regular basis, but, you know, we had our Pediatrics and Adolescent Gynecology Journal Club with our colleagues from the NIH last week, and this is kind of a timely review relative to that, and that Dr. Veronica Gomez-Lobo, shout out to her, was really highlighting how this is still such a very small community of folks that are doing this work and have expertise in it. So, you know, kudos to these authors for expanding our knowledge base. It's really still a field very much in its infancy.

200 babies born, right? That's not a lot. Yeah, I agree, and actually, I want to talk about the next paper because my hope is that we're not going to need to do OTC in the future, that we are going to have better gonadoprotectants, and this next paper is really one of the first that I've seen that moves the needle significantly in that direction, and granted, it's a mouse study, but there's a lot of work being done on mTOR inhibitors along with AMH, and this study combines both of those. The title of this paper is Temsoralemus and AMH Protect Fertility and the Ovarian Reserve Agonist Chemotherapy-Induced Damage in a Murine Model, and this was a study with senior author Marie Madeline Dolmans from Brussels, Belgium.

So the five-year survival rate for childhood cancer, as we all know, has gotten better and better. It's about 85%, but the pregnancy rates among cancer survivors are 40% lower than the general population, and this is something that we see every day in our practice, and it may be more secondary and fertility as well because of reductions in ovarian reserve. Chemotherapy and especially alkylating agents like cyclophosphamide and busulfan are highly gonadotoxic.

They lead to ovarian reserve depletion and reduced fertility in cancer survivors. The mechanism by which chemotherapy depletes the ovarian reserve and impairs fertility are well established, and there are different pathways through which these agents act. So one pathway is direct via oocyte apoptosis.

Another way is indirect, and that may be destruction of rapidly dividing cells like granulosa cells, and then apoptosis in granulosa cells leads to a decrease in AMH. AMH inhibits primordial follicle recruitment, and therefore you have the reduction in AMH causes activation and burnout and depletion of these follicles. And chemotherapy can also trigger activation of quiescent follicles by upregulation of the PI3K mTOR signaling pathway, and again, that leads to follicle activation and then burnout of primordial follicles.

Current fertility preservation methods such as oocyte vitrification or OTC are not feasible for all patients, and especially if you live far from an OTC center and you don't have time to undergo oocyte vitrification or you're premenarchal and can't undergo oocyte vitrification. So what this study looks at is the use of both AMH and an mTOR inhibitor combined that protects ovarian reserve. So combined use has shown promise in some short-term studies, but long-term fertility outcomes are still largely unknown.

This study looks at this in a mouse model. So they had an experimental murine study with 37 female mice that were randomly assigned into one of three treatment groups. There was a control group.

This group got PBS only, and then they underwent ovarian stimulation and mating. There was a chemotherapy group with a combination of busulfan and cyclophosphamide, 13 mice in this group. They got their chemotherapy on day zero, and then there was a gonadal protection group, which was a temsoralemus five doses beginning a week prior to chemo, then chemotherapy on day seven, followed by five doses of recombinant AMH over the next 24 hours.

They examined the mice five weeks after treatment. All mice underwent ovarian stimulation. They were mated with fertile males to assess fertility.

They assessed fertility by vaginal plug, and if no plug was observed, then a second round of stimulation was performed three weeks later. Then after mating, all animals were euthanized for embryo collection and ovarian analysis to evaluate follicle reserve, apoptosis, and primordial follicle activation and proliferation. From a fertility standpoint, not surprisingly, the chemotherapy alone group did the worst, and there were no statistically significant differences between the control and the gonadal protection group, which I think is actually great news.

So the control group had 41.4 embryos, and the gonadal protection group had 36.3, and the confidence intervals overlapped, and so there were no statistically significant differences between these two groups. In the chemotherapy group, there was a significant reduction. There was on average 20.6 embryos that were recovered.

So they saw the same findings in the group when they looked at ovarian reserve. The chemotherapy group did the worst, and then the control and the gonadal protection group were not statistically significantly different. They also looked specifically at apoptosis, activation, and proliferation, and saw the same thing, that the chemotherapy group overall did worse, and the gonadal protection and the control groups did not have a statistically significant difference.

And so I think from this study, the conclusions are really that combined administration of both temsoralemus and AMH during chemotherapy effectively protected ovarian reserve and fertility in mice. And if this could be done in humans, this approach could offer a new method for fertility preservation for patients who are unable to use current techniques. But further research is obviously needed to confirm long-term efficacy and applicability to human tissue.

But I do think that it's a large step forward. I think it's very exciting. I think the idea of developing better gonadal protection is so needed in our field, and I think that if we can offer patients both fertility preservation through classical methods, such as vitrification, as well as gonadal protection, we're going to do a much better job protecting fertility of cancer patients.

Kurt, Kate, what do you think? Yeah, this is our future. I think we're nascent in the future, and understanding all this, and this kind of research is elucidating it. But this is the game changer, if we can ever get to it.

And when I read these papers, I wonder, are we going at breakneck speed or not fast enough? But it really is interesting to learn all these wonderful ways that we can change things in the pathway of preserving a woman's oocytes and why we're losing so many so quickly. So I'll just leave it at that fairly high level. I think this is really important work, but I think it's going to be a while before we actually have something in the clinic.

I'm sure these authors are already onto non-human primates. I hope so. So I hope it's closer to a breakneck speed than not fast enough, Kurt.

I agree. All right, last but certainly not least, I feel like I have been begging for somebody to do this cost-effectiveness analysis. So Kurt, I'm going to have you talk about the cost-effectiveness of single versus double embryo transfer to gestational carriers for male same-sex intended parents.

And I could not be happier to see this article in Fertility and Sterility because this is a daily conversation that I have with patients in my clinic. Yeah. Every once in a while, you get a really practical question.

It's not novel in the sense that we've been having this question for a long time and the methods are not earth-shatteringly pushing the envelope, but it's done really well and it has a very concise answer. And that's why this is a very good research letter and congratulations to the team out of Stanford for putting this together. And it's a very intuitive question, as you just said, Eve.

It's basically the cost-effectiveness of a single versus double embryo transfer in a gestational carrier. The two sides of this are obvious. We all agree that our field has moved towards single embryo transfer.

It works. Yet, when people have a lot of resources put into a program, they want to stack the deck in their favor and they want things to work faster and less expensively, which is why a lot of same-sex couples push to having, well, why don't we have two embryos put back? And I've heard the argument, well, I don't mind if I have twins, but it really is a double-edged sword about the consequences versus immediate gratification. So this study uses TreeAge, which is a very intuitive, simplistic way of putting a cost-effective analysis together.

The figure one in this paper shows the correct way of doing it, where you basically have a decision between a single embryo transfer to double embryo transfer, and then you follow the outcomes downstream, which is you're pregnant, you're pregnant with a twin, you're pregnant with a singleton, you have a live birth, you miscarry. Then it also looks at the children, the gestational delivery and neonatal health, and then it can run through the scenarios with appropriate assumptions put into it and come out with what is essentially cost-effective. Cost-effective is an interesting term, you know, it's because there's various ways of looking at from a health economy of how much is cost-effective, how much are you willing to spend for an outcome, and this study is using just to be complete cost to the healthcare system.

Again, well done, and the results are, you know, again, robust and straightforward, and I'm really pleased to have them. So when couples possess four euploid embryos, they made an assumption the embryos were tested and were euploid, but when you have four euploid embryos, single embryo transfers is cost-effective compared to double embryo transfer with an incremental cost ratio within what health and economics consider normal, basically saying you should do a single embryo transfer. Even when they change the model to having you have six euploid embryos, a greater amount, and it's still cost-effective to put a single embryo transfer in and you're still more likely to have children.

The actual results, the most intriguing one, so I just want to say them to you. So the results are driven by the child. The results are driven by the relative risk of preterm delivery, neonatal disability, and neonatal death.

So that's lesson number one. You can probably get to, you might get to a pregnancy faster with a double embryo transfer, but the health and consequences of the child are what are driving this, and I don't think sometimes our patients understand that, so that's lesson number one. And then when you're choosing a single embryo transfer, they do a nice job of putting in what about the bad consequences, and if you put a single embryo transfer, you're only about four percent chance of having no children.

You have a 21 percent chance of having one child and a 74 percent chance of having two child, where you, when you double embryo transfer, you actually have a greater chance, 11 percent chance, of not having a child, less of a chance of having two children. So both in cost, in healthier children, and in actual overall probabilities, this is dominated by doing, putting back a single embryo one at a time. So straightforward, intuitive, it answers the question, and now we have data you can show somebody to say this isn't just my opinion.

When you factor all these things in, we should be putting back a single embryo, and even though you get great pressure to put back two because it's a cash payment, or because I really want it to happen, or because I'm okay with twins, you can push back and say, I understand your point of view, but the data says you're not correct. We should, we should, we should be patient. So that's the value of a paper like this, and I'm glad it's published.

I'm glad someone did the study. Congratulations to the team. Not a lot of argument with this.

It's very convincing. Yeah, I think one other point that is worth highlighting is the likelihood of having two children was actually higher when you went single embryo transfer by single embryo transfer, and that's a point that I really try to drive home to my couples as well, because we're not getting a significantly higher likelihood of achieving a live birth by putting in two embryos, and so a while back, there was a paper that had a title like one by one or two by two, something along those lines, and showed the same thing, and I think that that's a really salient point, particularly for couples who want more than one child and who may have a limited supply of embryos, that your overall likelihood of two children is going to be higher with single embryo transfer because of that ceiling of maximal efficacy of a single transfer episode. So I think that's just another nail in the coffin for single embryo transfer, particularly for gestational carriers, and again, I think really intuitive, and we know the data, but there are lots of pressures when you have that couple in front of you who's looking at their spend, their personal spend, as opposed to healthcare spend, and many people view healthcare spend as not my problem, but I think you have to look at it systematically as well.

Yeah, but I think what convinces me is the health of the child afterwards that we often forget, but anyway, I wanted to end with this, is look at what's happened as our field, and we've gone through, or at least I know you guys too, about this idea about multiple births being the major issue of our field. It used to be like higher order multiples, we don't even use that word anymore, and now we even reduce twins, and it goes back to what I started with, that it's because of prior preservation and the success of transfers that we really should be putting back one at a time, and this is kind of like closing the door of that last bastion of, but what about this certain situation? So it really helps us go full circle to say we should be practicing good medicine to help our patients, and good medicine, even though it takes time and persistence and there's a lot of tears every once in a while, one at a time is the right thing to do. Agree, and I think that's a beautiful way to end this episode of Fertility and Sterility on Air.

Kurt, Kate, thank you for being with me on this very cold December morning, and to our listeners, we hope that you have a very happy New Year, happy and healthy New Year, and had a wonderful holiday season. As always, pleasure working with you. Thank you very much, Even and Kate, and we'll see you next year.

Happy New Year, Kurt and Even, to all of our listeners. This concludes our episode of Fertility and Sterility on Air, brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine. This podcast is produced by Dr. Molly Kornfield, Dr. Adriana Wong, Dr. Elena Huganesh, Dr. Selena Park, Dr. Carissa Pinkey, and Dr. Nicholas Raha.