Fertility and Sterility On Air - TOC: April 2025

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

01:47 Puberty progression in girls with Turner syndrome after ovarian tissue cryopreservation

14:55 Optimal Restoration of Spermatogenesis following Testosterone Therapy using hCG and FSH

27:58 Human embryos with segmental aneuploidies display delayed early development: a multi-centre morphokinetic analysis

39:56 Neurodevelopmental or behavioural disorders in children conceived after assisted reproductive technologies: A nationwide cohort study

45:23 Efficacy and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg combination in a cyclic regimen for the treatment of primary and secondary dysmenorrhea: A multicenter, placebo-controlled, double-blind, randomized study

51:13 Ovulation trigger versus spontaneous LH surge on live birth rate following frozen embryo transfer in a natural cycle: a randomized controlled trial

60:29 A Cost Analysis of Clomiphene Citrate, Letrozole and Gonadotropin with Intrauterine Insemination using Outcome Data from the AMIGOS Trial

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

Welcome, everyone, back to another episode of Fertility and Sterility On Air. We're in April 2025, volume 123, number 4, I'm Micah Hill, your Media Editor, and we've got our all-star team here today, minus our fearless leader, Kurt Barnhart, Eve, Pietro, Kate, great to see you all. Great to see you.

Good morning, everyone. We're going to jump right in. So, we've got a very nice views and reviews from Editorial Editor, Robert Norman, looking at clinical guidelines and sort of trying to tease out where clinical guidelines fit into evidence-based practice.

How do we follow them? How are they developed? I especially encourage you to read the one from Clarisa Gracia, who is the Practice Committee Chair for ASRM, who sort of talks through how they develop these guidelines. Really insightful read. Great views and reviews.

There's a fertile battle classic over ICSI from Peter Schlegel, so I encourage you to read that sort of classic debate over the use of ICSI for male factor infertility, and an inkling on climate change and health, and can we connect the dots. So, great front matter. Pietro, we're diving right into the seminal contribution next.

This is on Turner Syndrome. I think you had an article on Turner Syndrome a couple months ago that I listened to from January. What did we learn this month about Turner Syndrome and maybe doing no harm in these patients? Well, here we're doubling down on not only a rare pathology, but a rare intervention within a rare pathology.

So these articles always are kind of cool because it's really hard to study, and when you kind of amass a critical body of data, you publish what you got, because it's going to be helpful to whoever, since it's the first time that we're reporting on it. This is a great study published from the Netherlands. It's entitled, Puberty Progression in Girls with Turner Syndrome After Ovarian Tissue Cryopreservation by Sanne van der Coelen in the Netherlands, and I likely butchered that.

Apologies to my Dutch colleagues. So we all know that ovarian tissue cryo is typically offered to women who are at high risk for premature ovarian sufficiency, girls receiving gonadotoxic treatment being the primary example. This technique's been offered over the last decade or so, and has led to over 200 live births after transplantation of cryopreserved tissue.

More recently, this has really been extended to people who have a genetic predisposition for POI, so Turner's Syndrome patients. We know that about a third of girls with Turner Syndrome will experience spontaneous theallergy, and about 15-20% will have one or more spontaneous menstruations. But really what this means for them is that the likelihood of conceiving in an unassisted fashion is drastically reduced, giving rise to this urgent need for fertility preservation for them, with ovarian tissue cryo probably being the most aggressive and interventional of those options.

This technique really should be performed at an early age, before the ovarian reserve is exhausted. And kind of where that is and how to do it is up for much debate. One of the big questions that comes up when we're doing ovarian tissue cryo for this group is, what is the impact of the unilateral ovariectomy on the function of the remaining ovary? And more importantly, what this article really addresses is, what's the consequent impact on the puberty progression for these girls who are losing 50% of their ovarian reserve and stereogenic capability from that ovary? Some studies have reported that unilateral ovariectomy has no impact on fertility outcomes and leads to just one to three years earlier menopause.

But those studies are largely in women who are undergoing gonadotoxic treatment, not those with a genetic predisposition for POI. So the extent of ovarian tissue cryo and its effect on ovarian function in young girls with Turner syndrome undergoing ovariectomy is really up in the air. We don't know.

The purpose of this study was to try to add some data to this question and examine the impact of that unilateral ovariectomy on the function of that remaining ovary. So in total, the center had 93 girls with Turner syndrome, ages two to 18 years old. They had all undergone unilateral ovariectomy as part of the Turner Fertility Study.

And these girls were enrolled for a minimum of two years, maximum of six years. And they were followed prospectively. And the sample of women underwent the ovarian tissue cryopreservation procedure.

And they were only included if they had a successful ovarian tissue cryopreservation procedure, which was defined as having at least one follicle in the ovarian cortex fragment after re-implantation. So in total, they had 12 girls who are pre-pubertal who had undergone unilateral ovariectomy. One girl was treated to induce theelarches, which was discontinued one month after ovarian tissue cryo.

One girl was treated with gonadotropin-releasing hormone analogs to inhibit puberty and promote growth. Six girls had spontaneous theelarchy, and eight girls had spontaneous theelarchy and menarche. Now, of this group, they followed them in the following way.

They did blood analysis of follicle-stimulating hormone, LH, E2, AMH, and inhibin. They did this on the day of surgery, six months, one year, and annually after the ophrectomy. They also combined these blood sampling procedures with an outpatient pediatrician visit to assess for pubertal myoslomes.

So what did they find? Monitoring these patients for a meeting of three and a half years over five visits, they found that pubertal development was observed within the study cohort check, and it seemed to align with the expected pattern of pubertal development in girls who had not undergone unilateral ophrectomy. This is a big deal. This is the first time that this is reported in this cohort.

We assumed this to be true, and this, at least in this small cohort, seems to support that. But it's important to keep in mind that these are short-term findings. Long-term findings beyond kind of this three and a half median years of follow-up is not clear.

I suspect that they are also collecting this data, because where else do you have 93 patients with Turner syndrome being followed longitudinally but in the Scandinavian and Nordic countries, particularly Northern European, like the Netherlands? So kudos to them for amassing this group. One interesting finding from this data was predictors of girls who would undergo POI after ovarian tissue cryo. It seems to be that the kind of recurring theme for those patients who unfortunately just progressed no matter what was baseline AMH levels less than 0.5. These girls inevitably ended up with POI shortly after ovarian tissue cryo.

The AMH number is actually quite interesting. So we know that after you undergo unilateral liferectomy, half of the growing follicular pool is removed. With it, the AMH level is typically halved, because that's the predominant producer of the AMH, that growing pre-entral pool.

Interestingly, after decline in AMH concentration, there is an unexpected increase in AMH concentration in most girls in the study. That happens kind of at that first six-month follow-up period. There's a couple of potential explanations for it.

Some say that there's this now activation of this primordial follicular pool into this AMH-producing secondary and small entral pool. And they think that this new growing pool of follicles is responsible for this temporary increase in AMH production. There are other studies that have kind of supported this.

There's an increased responsiveness per follicle to FSH in women with a single ovary compared to women with both ovaries. So that kind of checks out. But that's an interesting pattern that we typically see, even in patients receiving gonadotoxic therapy.

You kind of knock out the existing pool of AMH-producing follicles, and then this other wave is kind of overactivated initially. So you do see this transient rise and then fall in AMH. So at a high level, what does the study add to us? I think in the event that you have a Turner syndrome patient in front of you, and you are one of those tertiary referral centers who's having to undergo some of this shared decision-making with the patient and their mother, the parents, we have a little bit of data now to suggest that undergoing the oophorectomy does not slow down the pubertal milestones, at least in this three and a half median years of follow-up.

And patients who have very low AMHs prior to ovarian tissue cryo are very likely to experience POI after the oophorectomy, but this was probably true independent of having to have the oophorectomy or not. So I'll stop for a second. This is cool data in that it's the first, and it's nice to have for counseling.

Eve, Kate, Micah, any experienced counseling Turner syndrome patients with ovarian tissue cryo, that's not something that I personally have done. It's not something that our center does, but there are certainly reference centers along the East Coast that we've collaborated with before to refer these patients to. Yeah, I will say my experience is limited in that we have a separate team at Lurie Children's who sees the Turner patients and does that counseling.

Our fellows do rotate in the Turner Clinic, but when they come to see me, it's typically for, oh, say, cryopreservation. The one thing, if you get in the weeds of the numbers from this cohort, this cohort is only a fraction of the entire cohort. The majority of patients in the cohort actually didn't have follicles that were seen at the time of OTC.

So what they're saying is in this cohort of patients, if they had follicles seen, then if they had a low AMH, pubertal progression was delayed or not present. And then if they had follicles, it wasn't. But what about the majority of patients who underwent OTC who didn't have follicles? And so I don't know.

I agree it's novel. It's super cool. But I still feel like, oh, say, cryopreservation, if and when possible for these patients, is going to serve them better from a fertility standpoint, whereas OTC may potentially serve them better from a long term, actually short term, because the longevity of these graphs is not very long, but from a hormone and menopausal status.

But I still feel like we're not quite there yet in terms of best treatment for these patients. I think that's a very good summary, Eve. We don't do it at our program either, but our PAGS unit does at Children's DC and at the NIH, and they do a lot of these.

So I do think this data, I think you summarize it well, Pietro, it's not huge, but it's the best data set we have. And it's not really looking at is there benefit for these patients in doing this, but is there potential short term harm? And at least for the power that they had, they weren't able to see that there was harm. So I think that's encouraging in the short term.

It's another small piece that they can use when counseling these patients. But I agree with Eve. I still think long term, we don't know exactly what the best management for these young women is.

To Eve's point about ovarian stimulation and oocyte cryopreservation, any of you have experience doing prepubertal or peripubertal stimulation and retrieval? I know there's a growing body of literature to suggest that it's feasible, that it works. You can get eggs out. I personally haven't done it.

Yeah, we've done it and we've done it. I'm hesitant to say successfully because I haven't had any of these patients return. We do have an IRB and we are following these patients longitudinally, but they've gotten 18, 19, 20 eggs retrieved and gone through more than one cycle in these patients who have reasonable AMH levels.

I think the youngest that I've taken through a cycle is 12. So that patient actually recently came back to see me. She's now 21 and wanted to know whether or not she needed to freeze more eggs and just had questions about timing of ovarian failure, which is very variable in the mosaic Turner patients.

But at 21, her AMH was 0.7. So I think it's probably imminent that she's heading towards ovarian failure. But we had a good number of eggs and I think it's hard. And the discussions about future PGT are also important where if you do OTC, you may not have that opportunity to prevent subsequent Turner syndrome in their offspring.

So I think these are really complicated discussions. And I think especially when you have a pediatric or adolescent patient, it's assent. It's not really informed consent for the patient.

But these are complicated conversations with the parents who I think everybody just wants to do what's best for these young girls. And it's hard when we don't really know the answer. 100%.

I'm so happy that you are looking at this cohort longitudinally, even and I can't wait to see those data. And I really hope that this group will do the same because it's true. It's such an important outcome in a population that really is not able to give informed consent and we would be so much better served to serve them if we knew the long term outcomes and really the utility of these eggs and what kind of success they have is really worth it for them.

The part that keeps me scratching my head about doing ovarian tissue and even just ovarian oocyte cryo in these young patients is what's that age related rate of aneuploidy look like when you go to actually turn these eggs into embryos? If microtubular instability really is as high in the teens and early 20s as it is in the late 40s, late 30s, early 40s. And I'm thinking about that beautiful frenzy at curve that we all kind of have in the back of our mind. Do we have enough data to tell these patients that, yeah, 20 eggs at 14 years old is just as good as 20 eggs at 24 years old.

They may need more because of that very high rate of microtubular instability, but we don't know. I think there's such little data out there on it. So kudos to this group.

Kudos to Eve's group and the folks at Larry Children's for all studying this intently and coming up with data that we hopefully will publish in fertility and sterility in the coming years. Great, thank you, Pietro. Kate, we're going to jump to andrology now, and you have a article looking at recovery of spermatogenesis following testosterone therapy.

Really interesting article about male endocrinology. Tell us about this. I agree.

Super interesting study from first author Dr. Blair Stocks and senior author Dr. Larry Lipschultz at Baylor. And so this was a retrospective cohort analysis of 77 men. All of whom had low sperm concentration defined as less than 15 million who had a history of exogenous testosterone use and presented there from 2020 to 2024 desiring to conceive.

And so they were all placed. And this is one of the strengths of the study on a fairly standardized regimen of compounded HCG and follicle stimulating hormones. So 3000 units of HCG and 75 units of recombinant HCG were administered subcutaneously three times per week with the goal of improving spermatogenesis.

And the primary outcome assessed was sperm concentration. So semen analyses were performed every three months from initiation of gonadotropin therapy and the duration of time that was considered what the authors referred to. And I really like this term HCG FSH reboot was defined as the duration to achieve recovery.

And so the authors found that 74 percent of patients had improved sperm concentrations with gonadotropin therapy. The true novelty of this study derived from the fact that 27 of the men, which was approximately a third of their cohort, continued their exogenous testosterone injections during gonadotropin therapy. So testosterone doses ranged from 100 to 400 milligrams weekly so that the dose was not standardized.

And the decision to continue testosterone was made in those men who wanted to do so to avoid hypogonadal symptoms. That was done with patient counseling by the physician in a shared decision making model. In terms of results comparing the group that continued versus discontinued the exogenous testosterone, there was also no difference either in the ultimate semen analysis or sperm concentration achieved, nor in the percent of the group that improved, who basically changed their category, whether it was severely oligospermic, mildly oligospermic or asospermic.

So really the other thing that the authors were able to contribute was that they found that there were no difference in the baseline characteristics between the two groups. And they were also able to identify just using simple logistic regression, which of the baseline characteristics were predictive of a response to the gonadotropin therapy. So they found that age, BMI, duration of gonadotropin therapy, duration of testosterone prior to the gonadotropin therapy and starting serum testosterone and luteinizing hormone concentrations were not associated with whether they responded.

But a larger starting testicular size, higher starting sperm concentration and lower starting serum FSH were associated with improvement. So I think this is a fascinating study for a number of reasons. We all take care of these men.

It's a challenging population to treat. They do not all respond to discontinuation of testosterone alone. And there are a variety of regimens out there to help them recover the spermatogenesis up to levels that are sufficient for them to be able to conceive, whether that be with low tech treatment or naturally or with ART.

A couple of really important points that the authors made and what I found to be a very helpful discussion was that while this was a feasible regimen for them in Texas, where these medicines are available from compounding pharmacies at a relatively modest cost, brand name medications, which is what patients in 46 of 50 states are left with, costs around $4,000 a month. So really kind of cost prohibitive for most patients. You know, there are limitations to the study, without a doubt.

It's, in my opinion, a small sample still, though it is the largest sample to date, as the authors note, that's been published on treating these patients who have low sperm count following testosterone treatment with gonadotropins to improve their spermatogenesis. Again, it's helpful for counseling so we can counsel them about what's their chances of responding since they were able to look at a number of baseline characteristics and associate that with their response. And it's important to note that similar to prior studies, including studies we've reviewed recently in this podcast, of the men that were azoospermic at the start, 30% did not recover any sperm in the ejaculate.

So same limitations that we talked about last time we addressed this, which is to say we don't know what their starting spermatogenesis was prior to initiating testosterone therapy, and that may very well be a very significant confounding variable there. So I personally find this helpful. Many men just absolutely can't tolerate going off of their testosterone.

And so this gives some hope there. Given the small sample, I'm not sure that we can say, you know, close the book on this topic. That said, numerically, actually, while there was no statistically significant difference, the men who continued their testosterone even had slightly higher semen analysis, sperm concentration.

So opening this up to the group, would you guys feel comfortable letting men who say that they don't want to go off their testosterone based on this study, continuing it and supplementing with gonadotropins? I spoke and pulled the four urologists that I work with, and they all said no. They all said that they would not let the men go off or would not advise them to stay on the testosterone, even if they had the money to go on four months or so of this expensive gonadotropin therapy. But the thought being that they're concerned about the quality of the sperm that's chronically exposed to exogenous testosterone or what was there? What held them back from recommending it? So the predominating thought was that they didn't believe that that there would actually be no difference.

So I think they were fascinated by this study as well. But with their healthy skepticism, they were wanting to see more data and particularly in men who come to us saying that they want to be able to conceive naturally or with low tech treatment, they felt that if they could tolerate being off the testosterone for long enough to get to conception, that was probably going to be in their best interest. You know, I have not had the same quantity of experience in administering this therapy as they have.

So I have to certainly defer to their expertise on some level. That said, I actually find this study to be fairly convincing. Yeah, I think it depends on what the end goal is.

And I don't necessarily think that if the end goal is ART that you need to be on four months of testosterone therapy. And in fact, if you do the math, if you are on one month of and it's not testosterone therapy, it's the reboot with HCG and FSH. But if you're on one month of it and you're able to get some degree, if you're able to go from esospermia to some degree of spermatogenesis, then you may be able to pursue ART.

And then your other three months, that would be twelve thousand dollars. You could then apply towards the cost of ART. And so I think it's just, again, the devil is in the details on how you counsel these patients in terms of what are your end goals and at what cost and what time.

And so I think we do see a different population because we're seeing the couples who maybe are more willing to pursue ART as opposed to the urologists who may be just seeing the male partners saying that they want to conceive without medical assistance. And so I think the most worrisome point, and Kate, you touched upon this, was that a third still didn't have sperm. There were a third of asospermic men despite being on this reboot therapy.

And I think the point is well taken. And we don't know what the starting point is. But to me, that's really concerning.

And I actually felt like they wrote the article in terms of, wow, this is really successful. And I read the article from the opposite vantage point of, wow, this is really scary. I think that when males initiate testosterone therapy, a large percentage of them either don't think that it's going to damage their fertility or they assume that it's completely reversible.

And we don't really know because we're not getting analyses on these men a priori. But to me, that was really concerning. And I wouldn't say it's a marked success if 30 percent of the males remain asospermic after four months of treatment.

$12,000 later. Exactly. I would love to see a study where they do something similar.

And I think the jury is out on what is the best gonadotropin and or selective estrogen receptor modulator plus HCG protocol for these patients. That said, I think in terms of the question about can they continue their testosterone, it would be a great topic for a randomized control trial because obviously there's going to be some differences in the men who do or do not choose to proceed. And then beyond that, I'd love for that trial to have fertility outcomes reported upon as well, not just the return of spermatogenesis.

For sure. But why not in the interim for those patients who are really hesitant to come off testosterone, why not have a month or so where they're on T, recheck a semen analysis. And if it's not different or there's no improvement at that point, then you say, OK, get off your T. But I think it's these data to me are very convincing that it's reasonable in the extremely hesitant male.

It's very reasonable to continue the T in the short term and maybe as treatment evolves to have further discussions about discontinuation. But I think they can continue in the short term. I'm kind of convinced I'm not a urologist.

I mean, this this data is so incredibly helpful right now. And I don't know what your guys' local environment looks like, but there is an epidemic of firefighters, police officers who are being prescribed injectable testosterone. They show up to the firehouse or the police station.

They slap a flyer on the wall saying, did you know that police officers have lower testosterone levels due to our work life balance issues? Have your testosterone level check that comes back at 350 and they say, well, we can sell you this 500 dollar prescription a month. It will show up to your house. You'll have better libido, better gains at the gym.

Your energy levels will improve. They're all on it. No one is told about the reproductive impact of it.

And then they show up with their wives to consultation with me and they're dumb founded that their testosterone tanked their sperm. It's an epidemic in Massachusetts. We see so much of it.

And this data is the kind of data that I'm going to forward to my local urologist and be like, hey, did you see this? Because right now our standard of care locally is either cold turkey stoppage, which, as you can imagine, does not go well, or bridging them with clomid. I think this is a step above and a step better that may kind of facilitate them feeling OK and us getting the sperm back for us to be able to do ART with. So I love this paper.

I thought this was a awesome thing to see in FNS. I really enjoyed it, too. Thanks, everybody, for your comments.

I mean, to your point, Pietro, they cite a study that 25 percent of urologists believe that testosterone improves fertility. So, you know, always good to get the word out to our communities about the harm that this can do. Fantastic.

Thank you, Kate. So I'm going to take the next one. We're moving on to the ART section, and this one is titled Human Embryos with Segmental Aneuploidies Display a Delayed Early Development, a multicenter morphokinetic analysis.

So essentially looking at time lapse and segmental aneuploidy. This was by a group of a bunch of great authors out of Europe. First author Figliuzzi and senior authors Laura Rienzi, Marcos Meseguer, and Antonio Capalbo.

So a great group of authors. And this is looking at three different studies across Europe, one in England, one in IVI, Valencia and one in Israel. And they were trying to assess if we can detect the chances of an embryo being segmental aneuploidy versus whole chromosome aneuploidy versus euploid using morphokinetic patterns.

And this is essentially unique in that it's looking specifically at segmental versus these other types of aneuploidy, because this has been looked at before with just whole chromosome aneuploidy. So retrospective cohort study over 7000 embryos between these sites over a five year period using PCR to amplify. And then NGS, as far as looking at the euploidy status out of these 7000 embryos, six hundred and ninety seven.

So about 700 of these had segmental aneuploidies. They did a lot of pretty nice statistics. So these times at which embryos make these different checkpoints, as far as from a developmental standpoint, aren't standard, standardly distributed.

And so they did some normalization of their data to try to normalize it. And then they did multiple logistic regression to try to look at what factors were associated with the chances of an embryo being a segmentally aneuploid embryo. One comment, I think, is that we all understand that with logistic regression, the assumption is that each individual embryo is unique and not related to the others.

And in a case like this, obviously, each patient will have multiple embryos. So that's not from a statistical standpoint, correct? You should do something like GE or generalized linear models where you can sort of cluster embryos per patient. But my only comment on that, having run a bunch of these analysis, is that usually doesn't move the needle as far as the outcome very much.

So it's maybe not statistically the most rigorous approach, but typically doesn't change your outcomes. And then finally, what I liked is they looked at receiver operating curves to try to actually see if they could predict what would be associated with an embryo being diagnosed with segmental aneuploidy. And then the other thing which we'll see, which is very good that they did, is they did a training set and then a validation set.

And that's important because if you just look at your data, your model is going to fit what your data says, and you may come up with conclusions that don't hold when you apply it to a new data set. So 70 percent of their data trained their model, and then 30 percent was used to validate it. So what did they actually find? Well, first of all, what they found is that segmental aneuploid embryos develop slower, especially through the first three checkpoints.

So if you sort of think about it developing through the cleavage stage, they develop slower through the first checkpoint of dividing into two blastomeres. That was about half an hour delayed. Getting up to the cleavage stage embryo was about two hours delayed.

But then these embryos caught up. So the segmental aneuploid embryos caught up in developmental blastocysts. They were still a little bit slow by 1.7 hours, but they caught up over where they were at at the cleavage stage.

So how did this differ? This was slower than euploid embryos. I think we would maybe expect that. It was actually slower than whole chromosome aneuploidies, which surprised me through that first divisions up to the cleavage stage.

But then they got faster than whole chromosome aneuploidies by the time they got to the blastocysts. Okay, so they're a little bit slower. How much slower is half an hour, two hours? When we think about this from the time it takes an embryo to develop, 120 hours roughly, let's say, to the blastocyst stage, we're talking about 1 percent slower to 2 percent slower.

So it's relatively small amounts of time, even though these are statistically significant, which I think is worth noting. So what we've talked about so far, if you think about it from a statistical standpoint, is just association. Relative risks, odds ratio, is it associated? Yes, it's associated with slower development.

What does it actually mean for our ability to predict these embryos? What these authors really want to get to is, can we predict based upon time-lapse imaging whether an embryo is aneuploid or segmental aneuploid or euploid? And so they used AUCs. And just a reminder, an AUC of 0.5 is a coin flip. It means Pietro flips a coin and says, this embryo's heads, I'm going to transfer that one.

0.6 is barely better than a coin flip. When you get up to 0.8, 0.9, you're talking about a test that is helpful from a prediction standpoint. So what did they find? Between these three centers in their training set, their areas under the curve were 0.6, 0.56, and 0.74. So not great to okay.

But then what's really interesting across the board, every time they applied their training model to a validation model, it did worse. And it did substantively worse by about 10%. So all of those AUCs dropped by 10%.

One of them at one of the centers dropped actually worse than a coin flip. In other words, Pietro flipping a coin is better than this model predicting whether these embryos had segmental aneuploid. So ultimately, the title of this article is what they looked for.

They did identify some unique morphologic features by time-lapse imaging. These embryos grow slower through those initial checkpoints. And they give some nice hypotheses for why that might be.

And then they sort of catch up at the end. They hope, and their conclusion in their abstract is that this can then be applied to help us good predictive models to say, these are the embryos that will develop this. And maybe we should transfer these ones and not transfer those.

I don't think this data gets anywhere close to that. Again, these AUCs are basically coin flips. Yes, they're statistically significant.

And they sort of focus on that. But I think from a practical standpoint of applying it, it's not that helpful. So this is just, in my mind, another time-lapse imaging that fits into generally what I learned from these studies.

We learn something new and unique about how embryos develop. And that's very helpful from a research standpoint. I still just don't see these studies telling me something that I can clinically apply that's going to help me make a decision to the patient that's sitting in front of me.

That's my take home from this article. What did you guys think? I think that's exactly right. I think with time-lapse, we're in that stage where we're learning cool stuff that we otherwise would never have seen before.

But none of it has risen to the level of, it is changing our clinical practice and improving patient outcomes, comma, yet. I am not personally ready to put the nail in the coffin in time-lapse imaging. Because I think with any technology, there is the stage where you're learning, you're figuring out.

And as the machine learning improves, the vision learning improves in these units, I think we'll get close. I don't think it's going to be the silver bullet that these authors expect it to be. But if it at least allows us to rank or prioritize embryos for transfer without PGT, and that moves the needle for us, that in and of itself would be really cool.

But that's not what this data tells us. Yeah, I agree. I also thought it was really interesting that there were center to center differences.

And so when they looked across the board, each center did worse with the training model. But then when they separated it out, like center A versus center B versus center C, like within the centers, they were better able to have their own predictions. And to me, that's actually more worrisome to say that if you put all of this R&D into developing these algorithms for time-lapse, that they're not generalizable to the center where your embryos are growing.

And I don't know exactly what to make of that, except to say that there's a lot more work that needs to be done on this before it's ready for prime time. And I think intellectually, you know, the idea that aneuploid embryos do implant and aneuploid embryos do lead to live birth, especially like segmental aneuploidies like Cri-du-chat or a 22P deletion, those lead to live births. And so is it realistic to think that we actually can predict how these embryos are growing and developing? And that would translate to a reduction in implantation rate when we know that some of these embryos will go to term.

And so intellectually, I have a little bit of trouble, a lot of trouble. As you guys have heard over the years, I have a lot of trouble wrapping my head around trying to predict implantation potential of embryos that we know in nature will actually implant and grow and develop. And so what are we really trying to do here? Right.

Until it can replace PGT in the patients that we otherwise would think would be appropriate candidates, it is not helpful and certainly not cost effective. And, you know, we have an executive order now. The onus is on us more than ever to practice in a way that we are employing technology that we know will benefit our patients in terms of their outcome.

So we've got to keep doing the research on this. I hope that most of us are pretty cautious about using it clinically still at this point. I have to imagine some of the center to center differences are differences in media, time-lapse machines, mixed gas versus non-mixed gas incubators.

There's so many individual small variables that go into this. So to say time-lapse broadly is probably not fair. You probably do need to drill down to the details.

Yeah. I mean, they also use different PGT reference laboratories. And so what is the inter-laboratory consistency of calling something a segmental aneuploid embryo? And I think that that's concerning as well.

And that I think laboratory to laboratory, you're going to see differences in those bioinformatics and in the algorithms that the re-biopsies for some of these embryos with segmental aneuploidy is not consistent. I think that the rates of consistency are only like 30%. And so there's just, to me, and I say this a lot, there's more questions than answers.

I agree. I think a lot more data are needed on time-lapse. But we've also been looking at this for a decade without, in my opinion, without making tangible and significant progress yet.

They said the same thing about the space program, Eve, going to the moon. That was crazy. That was silly.

I'm not saying it's crazy and silly. I'm just saying, like, I don't, I have not yet to be convinced that we have tangible progress yet. I think we'll never get there.

You bring up such an interesting point, and I'll leave this as the last philosophical thought on this article. So as you mentioned, 30% of segmental aneuploids, when they then re-biopsy or take apart those embryos and biopsy the whole embryo, only 30% confirm that that's segmental. So theoretically, you have to explain that one of two ways.

And the way these authors explain that is those embryos were mosaic. In other words, you biopsied the cells that had the segmental chromosome. And so it's true mosaicism, and you caught it.

My way of thinking about it, which I think is more likely, is it's bioinformatics. Your test was wrong. The thing that said it was segmental aneuploidy is wrong most of the time.

You only confirm it. So intellectually, you have to approach if it is wrong 70% of the time, why is it wrong? And there's two different explanations for that. I just think philosophically, that's an interesting approach to how you think about this misdiagnosis from some of these tests.

All right, we're going to move on to epidemiology. And Eve, we're jumping into you. I really enjoyed how this epi study approached this question of neurodevelopmental disorders with ART.

Tell us about this. I agree. So the title of this is Neurodevelopmental or Behavioral Disorders in Children Conceived After Assisted Reproductive Technologies, a Nationwide Cohort Study.

And this is by Patricia Angel and others from Denmark. The objective of this study was to evaluate differences in risks for drug-treated neurodevelopmental or behavioral disorders in children conceived through ART in comparison with children conceived without ART and to examine if different treatments alter these risks. So the study used data from the Danish Medical Birth Register, DMBR, and cross-linked information from both the Danish Civil Registration System as well as the Danish National Register of Assisted Reproductive Technologies.

And that registry provides data on method of conception, including IUI and IVF and ICSI. These are all robust registries. We've talked about them before on the podcast.

They contain multiple data fields and a wealth of information ranging from everything from socioeconomics to smoking. The exposure group were those children who were conceived through IUI, IVF, or ICSI. And they call that group the ART group.

And technically, I would argue that IUI is not really ART, but they lump them together. The outcome of interest that was studied was neurodevelopmental or behavioral disorders in children from birth to age 7 who required medications and any medications in the following categories, antipsychotics, anxiolytics, antidepressants, antiepileptics, ADHD, or hypnotics slash sedatives. And they were also able to ascertain, and this is key, whether the parents of those children were on similar medications prior to pregnancy.

They did several sensitivity analyses to examine the effects of potential confounders on the association between ART and prescription of any of these medications. And that's also key. So in total, there were almost 58,000 children from ART compared to nearly 1.2 million conceived without ART during the study period.

46% of these patients were IVF, 26% IUI, and 24% were ICSI with 4% other. 17.5% of ART babies had low birth weight. That's also pretty key, and I'm going to circle back to that.

Maternal and paternal age were higher for ART conceptions as well as education and income level, and these patients were less likely to smoke. ART patients were more likely to be on neurodevelopmental or behavioral medications. So the unadjusted and adjusted analyses showed a very minor increase in the odds of prescribing neurodevelopmental or behavioral medication to ART offspring.

Prescription of antipsychotics was most commonly associated with IUI conception, while sedatives were most common with IVF and ICSI. The overall odds of needing medication was highest for ICSI with an odds ratio of 1.18, and the confidence interval was 1.07 to 1.29, followed by IVF and IUI. But the sensitivity analyses here were critical, and I really commend the authors.

I think they sliced and diced and looked at these data in a multitude of ways to better understand whether or not this is a true finding and a true risk or whether or not this is an association. And so when they included birth weight or preterm birth, it made the effect of ART not significant. They also did a sibling analysis, and this is fascinating, and I have not seen sibling analyses in many studies.

But what they looked at is if the firstborn child was ART-conceived and on medications, there was an increased likelihood that the secondborn, even if not on ART, even if not ART-conceived, would be on meds and vice versa. And so what this suggests is a carryover effect where the parents are more aware of neurodevelopmental or behavioral issues in the second child, regardless of mode of conception. And so the authors conclude that though there were slightly higher odds of medication use in children conceived through ART, when they considered birth weight, gestational age, and birth order, the effect of ART became non-significant.

So I want to open this up for discussion. I think it was really beautifully done, and I think unlike a lot of other registry studies where they see these small associations and claim large impacts, I think these authors were very responsible in the way that they looked at these data and the way that they thought about it holistically in terms of the parental and the sibling risks. What do you guys think? Super well said, Eve.

I loved exactly what you said, that they did the sensitivity analysis to try to drill down deeper. And most of these studies we read would just stop at that initial finding and say there's an association and not talk about how big the association is and then not look at whether it's maybe explained by the very effects that you said. So I thought this was exceptionally well done.

All right, Pietro, I want to talk briefly about an article that's in the gynecology section. And the reason I selected this one this month was specifically just to highlight to our readers that we do take gynecology articles in FNS, especially good ones, as a reproductive journal. And so this one was an RCT.

So give us the high-level quick overview of this RCT in the gynecology section this month. I have a cool gynecology article all the way from Tokyo, Japan, entitled Efficacy and Safety of Estetrol Slash Trisperinone Combo in a Cyclic Regimen for the Treatment of Primary and Secondary Dysmenorrhea, a multicenter placebo-controlled double-blinded randomized study. This is like Kurt's dream.

All the buzzwords that Kurt loves, all in one title. And it's a gynecology article. So my one regret is that Kurt is not here to listen.

If you're a fellow and you're paying attention, yes, I said the word estetrol. And if you're preparing for your boards, you should know what estetrol is and where it's from. And I had already forgotten it.

So allow this to serve as a refresher for all of us. Estetrol, or E4, is a native estrogen that's synthesized exclusively in the fetal liver and reaches the maternal circulation through the placenta. It's a really special estrogen in that it interacts with nuclear and membrane estrogen receptors, as well as membrane estrogen receptor alpha.

It acts as an agonist of nuclear estrogen receptor alpha and an antagonist of the estrogen receptor alpha-dependent membrane-initiated steroid signaling pathway. This makes it pretty unique in that it's the first native estrogen with selective action in tissues that differs based on the selective estrogen receptor modulators. And if you're still paying attention, and I haven't lost you yet, the big difference between E2 and E4, just the number of hydroxyl groups.

So estradiol, two hydroxyl groups at position 3 and 17. Estetrol, or E4, four hydroxyl groups, 3 and 17, plus 15, plus 16. Now, if you're still paying attention, let me tell you why this study was important.

So this study was important that estetrol and drosperinone have been shown to be very efficacious contraceptives. Good for bleeding control, very minimal safety concerns. So these authors decided, you know what, let's do a small four-month double-blinded placebo controlled trial and follow patients for 36 weeks and see in this Japanese cohort of women, what does it do for dysmenorrhea, which has not previously been studied.

The endpoints being dysmenorrhea score, as well as kind of the usual visual analog scale scores. All of this was recorded at baseline and during specified treatment periods via an electronic diary. So in total, they had 81 participants in the E4 drosperinone group and 79 in the placebo group.

The average age was 33, BMI was 21, and about a third had primary dysmenorrhea, whereas two-thirds had secondary dysmenorrhea. At a high level, what they found was that this combination of estetrol and drosperinone compared to placebo showed superior efficacy for total dysmenorrhea scores after four months of treatment, and it also improved average pelvic pain scores via the visual analog score. And importantly, during the study period, there were no VTE incidents that were recorded.

Estetrol has been available in the United States since the late 2000s and teens. I think it's a medication that's underutilized, and I think this study adds to the growing body of literature that it appears to be safe, good for bleeding, good for pain, and no big safety signal. So I think something for the gynecologists in the room to keep in the back of our armamentarium.

And if you're a fellow who's still listening, remember, estetrol produced in the fetal liver or hydroxyl groups compared to estradiol, two hydroxyl groups produced mainly in the ovaries. I don't think I'm surprised that an estrogen and a progestin would help with dysmenorrhea. Better than placebo.

Right. Better than placebo. So I guess one question is, do you think this is the best study design? Should this have been compared against a standard already treatment and done a non-inferiority trial? And then the second follow-up, is there any advantage to this formulation over a combined OCP or any of the other combinations of estrogens and progestins that we can get? I think you'd have a hard time getting this through an American IRB.

Withholding known to be efficacious first and second line treatments from patients with dysmenorrhea feels a little funny to me. They weren't even offered NSAIDs. They weren't offered an alternative estradiol-containing combined contraceptive.

So my gut is, yes, they probably should have compared it to not placebo. But this is the first study ever of this combination looking at dysmenorrhea. So it's a reasonable first place to start.

But I have to imagine this author group is looking at that next wave of studies. Thank you. Yeah, sorry.

I was just going to say, when they do that next wave of studies, just to give some kudos where they're due to this group, I hope that they take the same rigorous approach in terms of examining so many different valid outcomes for this dysmenorrhea score. I mean, they really looked at it both in terms of validated questionnaire and like four other different objective ways of assessing. So I do think that there's a lot to be said for, especially when we're talking about dysmenorrhea, which is so often subjective to look at it objectively as these authors did.

Well said. So just a reminder to all our listeners, we are the premier journal for good gynecology and reproductive medicine. So submit your RCTs to Fertility and Sterility.

All right, we're going to move finally into my favorite section of the journal, the research letters. We have one from Kate and one from Eve. Kate, we're going to start with you.

You are my world expert on all things luteal phase and frozen embryo transfer. So tell us about this small RCT that's in the research letter. Yeah, so I did think that this lent itself perfectly to a research letter.

It was an RCT where these French investigators randomized 108 patients younger than 39 years old who were undergoing natural cycle frozen embryo transfer of an untested blastocyst. Patients were randomized to having a natural LH surge, so truly a true natural cycle versus a modified natural cycle using subcutaneous recombinant HCG trigger. Patients were randomized in a one-to-one ratio from 2018 to 2021.

The mean age at time of FET was 31 years old in the true natural cycle group versus 32 in the modified group. So this was a very good prognosis group of patients overall. You know, I would have liked to see also what their age was at the time of embryo creation.

Those data were not provided. There was no blinding and there was no dummy injections. So this was an unblinded RCT.

Or open label. So no exogenous progesterone was given to anyone in this study. So that's an important really kind of deviation from I think the way most of us are doing natural cycle or modified natural cycle FETs in the U.S. at this point.

They also had an interesting twist to their protocol in the true natural cycle arm, which was that they measured serum progesterone three days after the LH surge was noted. And if the serum progesterone concentration was less than three nanograms per ml, they delayed the transfer by a day. So it was six days post-surge if the progesterone was greater than three, three days post-surge.

And it was seven days post-surge if it was less than that. Positive pregnancy test was the primary outcome. And the authors acknowledged that the study was powered to detect only a 25% difference even in its initial recruitment goals.

And we'll talk a little bit about, you know, how that changed over the course of the study period. So they found no differences in the primary outcome of a positive pregnancy test per transfer, nor in any of the secondary outcomes of cancellation, miscarriage, ongoing pregnancy, or live birth between the true natural cycle group or versus the modified natural cycle group. And the true natural cycle group was actually numerically favorable both in the intention to treat analysis as well as in the per protocol analysis.

They found a 35% positive pregnancy and 31%, 35% positive pregnancy in the true natural cycle group versus 31% in the modified natural cycle group with the trigger. Unfortunately, this study comes on the heels of several others now that have looked at this question. So while I do think it adds to the literature, we know a lot more now than we did when these investigators first started looking.

I think they are certainly to be commended to taking this on as a randomized controlled trial, but it is hard for me anyway to draw firm conclusions from this study. So, you know, one place where they did struggle was that a pretty large proportion, in fact, 16 out of the total 54 patients who had been randomized to have a modified natural cycle, so to receive an HCG trigger, actually surged in advance of getting the HCG trigger and then did not get the trigger, but rather were treated exactly per protocol as their true natural cycles were. So that really did skew the sample sizes, leaving them even more underpowered than they were previously.

So while I think overall, it's reassuring that either one of these probably would achieve similarly good outcomes, you know, from a practical perspective, rather, I'm always left scratching my head as to kind of what is the true downside of doing an HCG trigger. Now, I know there's biologic plausibility to a more natural trajectory of hormones as we see, and a progesterone rise as we see with an LH surge. That said, now we have so many studies showing very similar outcomes, and as these authors astutely note, it's just so much cheaper and easier to get the timing right with fewer monitoring visits, and they show that statistically here, that for me, I think that to give these patients an HCG trigger and the merciful intervention of not having to come in every single day just seems well worth it.

For me, I think the remaining questions about how and in whom, and I think that's an important one, we perform natural cycle or modified natural cycle frozen embryo transfers is where we need to turn our attention. These authors limited their enrollment to patients who were younger than 39 years old. And so, you know, I think that that is prudent to do.

I think we all wonder about the health of the corporeal luteum or corpus luteum among older patients. That said, I have a lot of older patients that really want, who are ovulatory and really want to do natural cycles, and I think that still remains very much, you know, an unanswered question. So, I'd love to see us turn our attention to who are the best candidates and are there differences in older patients.

For me, I think let's just trigger these patients and save the center's money, save the patient's money, and save everybody time. The gut check I always have with some of these studies is what does the implantation rate look like? In a really good prognosis group of patients, average maternal age was 31 at the time of FET. Pregnancy rates in the low 30s at baseline is always like, okay, that's a little different than for what we would expect in an American setting.

But I think beyond that, I really drilled down on the method section here, how they define the LH surge. I feel like if you asked four reproductive endocrinologists how they define the LH surge, you'll get five different answers. How do you guys feel about using the three time above the basal LH value as being kind of the quick and dirty, like, yes, this is an LH surge? I'm putting my Zev Rosenwax hat on and having served my time as a Cornell fellow.

We're looking for the E2 drop. We're looking for the P4 rise. It's a much more head-scratching, chin-scratching dynamic.

It is here and it happened at midnight rather than today at 7 a.m. No, I mean, Curt's group last month, and we talked about this on the podcast, Curt's group last month defined the preovulatory, periovulatory, and luteal phases based on cutoff levels with pretty good sensitivity and specificities. They used an LH above 24, I believe is where it was. If you have a baseline LH of 4 and all of a sudden you have an LH of 12, I'm not impressed that that's a surge.

And so I think that that's really the crux of where I think their timing was off for transfer. We do it a little bit differently, and we have moved to almost universally triggering starting progesterone three days later and then transferring a week post-trigger, and it seems to be working really well. Our pregnancy rates are well above the 50% in a good prognosis population.

I just want to ask you guys a question if you put on your editor's caps for a second. Kate kind of mentioned that the study is relatively small, but it is an RCT on a question that's of huge clinical interest. From an editorial standpoint, how do you guys think of RCTs that you would say, okay, this is probably underpowered.

It's probably too small. It's probably destined to find a null finding, but yet it's a well done in general RCT. How do you think about those studies when you think about them in a journal like FNS? I think it's a hard question.

I don't think every FET gets published just because it's an FET. RCT, RCT. Oh, just because it's an RCT.

I think that at the end of the day, as much as I commend these authors for taking this on and putting their noses to the grindstone and getting this done over a three-year study period to get to their 108 patients recruited, we kind of moved on from here in the time that they did this study, unfortunately. I don't think it really moves the needle much, and maybe that's why it's a research letter. I think an interesting one and a good opportunity to discuss the methods and discuss from a practical perspective what treatment protocol is going to most benefit our patients.

I could have really seen this going either way as an editor, to be honest. Okay, Eve, we are coming to you to get us over the finish lines. We have a cost-effective analysis, a cost-effectiveness analysis on the Amigos trial.

Tell us about this one and what did we learn about this? Thanks. This is a cost analysis of Clomid versus latrizole versus gonadotropin with IUI for couples with unexplained infertility, so the Amigos trial. They used pregnancy outcomes and used cost data from publicly available sources, and they included associated maternal and neonatal care, as well as complications associated with singleton, twin, and eke, high-order multiple gestations, to calculate the cost of live birth for each of these treatments.

They created a decision tree using each of the treatment arms and each of the treatment outcomes, including pregnant, not pregnant, clinical pregnancy, ectopic, biochemical pregnancy. Each branch of the decision tree took the probability of outcome times and costs, and all costs were reflected as U.S. dollars and adjusted for inflation to the year of 2022. I don't think anyone is going to be surprised by the findings.

The cost of a singleton or twin gestation was more than $7,000 in a gonadotropin cycle compared to an oral medicated cycle, so $7,000 more expensive for a singleton or twin gestation. The estimated cost per singleton live birth for latrizole or clomid IUI was $41,000, and for twin gestation it was $156,000, and then if you add 7K to each of those numbers, you will get the cost per gonadotropin cycle. The cost per live birth in high order multiples, which was only seen in gonadotropin cycles, was $553,000, so, ouch, and 11 times more expensive.

So the authors conclude that given the additional costs and risks of gonadotropin IUI without benefit, it's difficult to justify its use in the setting of unexplained infertility. I want to steer our listeners towards a truly excellent reflections piece that was written accompanying this article by Jessie Walter from Northwestern to better understand some of the strengths and limitations of this paper, and I think a lot of really great points about cost analyses, and I just want to give Jessie a shout out. You are such a rock star.

As a limitation, Dr. Walter highlights the cost estimates were drawn from various sources ranging more than a decade, and the assumptions in the research letter were not explicitly spelled out. It's probably due in part to the research letter format. She also highlights that the robustness of any cost analysis is dependent on multiple sensitivity analyses where the inputs for outcomes and costs are varied to ascertain whether this changes the base case in question.

Additionally, she also discussed how cost analyses in this article were performed from the healthcare sector perspective, capturing costs borne by third-party payers, but they didn't capture the broader non-healthcare costs, which is really important, things like loss wages, transportation fees, and other things that factor into the cost of pursuing multiple treatment cycles. She highlights that consensus guidelines and health-related cost-effectiveness studies recommend that researchers conduct costing analysis from at least two different perspectives, and so I have to say I really agree with this point. I think especially as patients often think that twins are cost-effective, I think we need more robust cost-effectiveness analysis to demonstrate this, and I want to put this out there that I think it especially has to be done in a gestational carrier population where we are still seeing far too many double embryo transfers.

So, I think a really nice little nugget of a research letter, I think it really drives the point home about gonadotropins and the exorbitant cost associated with high-order multiples, and even though I think the cost-effectiveness analysis left a lot to be desired, I think that we can still learn from that reflections piece about what are the important points and how should we be designing these studies in a more holistic fashion. So, really nice, nice research letter. I think those points from your fellow and the reflections are really good.

Don't you think… Faculty, yeah, she's good. Faculty, sorry, faculty. Don't you think those would only make the cost differences even more disparate if you factor those things in? Like, it would only drive the difference even greater.

I do, I do, and I think like a really well-done cost-effectiveness analysis on singleton versus twin in gestational carrier, when you look at the healthcare sector and when you look at the other factors, I think that really needs to be done. It drives me crazy. We will not do a double MREO transfer in our center, but I can't tell you the number of patients who give us feedback that they had a happy twin delivery, their twins were only in the NICU for about eight weeks, but they wanted to circle back and let us know that they had a great outcome.

And I just, I think that that practice of arguing that it's more cost-effective to use two embryos in a gestational carrier, we need some good data to stop that practice. Yeah, and on the one side, I agree with you, Eve, that it's so important to consider the gestational carrier population. And on the other hand, kind of push back that I don't care whether it's more cost-effective, it's still just not the right thing to do, to be transferring two embryos to a gestational carrier who is acting altruistically.

And so I don't know what that cost-effectiveness would show. I think it would be very interesting. Obviously, gestational carrier journeys are very expensive.

So two versus one, we might find that in fact, it's more cost-effective. I don't think so. I think it's possible.

But even if we were to find that, I would say still don't do it because it's not the right thing to do and the health of the gestational carrier is paramount. Yeah. And I will say as somebody who has personally carried a twin pregnancy to term, oh my goodness, like, I just think that's the wrong thing to ask somebody else to do on your behalf.

Well said. Well, thank you, everyone. This was a fantastic discussion today.

There's a lot coming out from F&S media team in the next month. Pietro, you are doing a journal club in Portuguese coming up. Eve, you are going to the best of ASRM and ESHRE and giving a talk and we'll have a podcast from there.

Kate and I will be at PCRS doing a journal club live from there in a week as well as a podcast from there. So as always, look for all of the information that's coming out to learn about the science that's happening in Fertility and Sterility. Have a great April to all of our listeners and we'll see you back in May.

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

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