Fertility and Sterility On Air - Unplugged: October 2025

In this month's Fertility & Sterility: Unplugged, we take a look at articles from F&S's sister journals! Topics this month include: circadian rhythm and reproductive health (04:34), fertility treatment outcomes after bariatric surgery (13:49), interleukin-22 balance and pregnancy (26:35), and mTOR inhibitors for fertility preservation in breast cancer (39:45).

Consider This: https://www.fertstert.org/news-do/chronofertility-integrating-multi-timescale-chronobiology-into-fertility-research-and
F&S Reports: https://www.fertstertreports.org/article/S2666-3341(25)00097-2/fulltext
F&S Science: https://www.fertstertscience.org/article/S2666-335X(25)00065-5/fulltext
F&S Reviews: https://www.fertstertreviews.org/article/S2666-5719(25)00011-8/abstract

View the sister journals at:

• https://www.fertstertreviews.org
• https://www.fertstertreports.org
• https://www.fertstertscience.org

Welcome to Fertility and Sterility Unplugged, 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. Fertility and Sterility Unplugged 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. Molly Kornfield, Dr. Blake Evans, Dr. Daylon James, and Dr. Pietro Bortoletto.

Greetings sports fans, and welcome back to another episode of FNS Unplugged, your favorite of the three Fertility and Sterility family podcasts. And I say third, because as I've reminded you in our last two recordings, we are getting ready to launch FNS Roundtable. Our third episode in the monthly installment of FNS Podcasts, hosted by Dr. Emily Barnard and produced by Dr. Benjamin Peipert.

It's a deep dive into the Fertility and Sterility Views and Reviews section when published in the journal, but also the Fertile Battle section when they alternate in the print journal. We're really excited to bring you this podcast. It's much more interview style with the authors and you'll get kind of the behind the scenes, how the battle came about or how the view came about.

But we're excited to bring it to you guys and you should be seeing that drop right here where you get your normal podcasts, hopefully in the next month. Now back to the show. Hi, Molly.

Hi, Blake. Hi, Daylon. Hey, how are you all? We're the Living Large.

We're in charge and we're bringing the hot science per usual. I want to give a special shout out. We have a very dedicated group of Australian listeners.

Eve was just down there at a meeting. I guess they say when they come to see us that we were just up there, but she was just down there to speak at their annual REI conference and was just very enamored with how much people listen to the podcast, enjoy the podcast. So a special shout out to all of our Australian fans down under and another big shout out to our fans in Brazil.

Very loyal listening base, people who really love the podcast. Unfortunately, they listen to it while they're working out. I don't know that I'd recommend that.

Your workouts must be low energy, but they say you should get into level two for your workouts. They're probably barely scratching level one, but whatever rocks your boat. So big shout out to our Brazilian listeners.

Yeah, that's awesome. I don't know. Daylon's voice just really pumps me up.

So I could see that. I bet it does, Blake. I bet it does.

Well, on a side note, we didn't think about am I going to have to record an intro song for this new podcast because we got it for Unplugged on air. Just go ahead and hum it for us. I can run the bass line.

I could do a little beatbox. You know that's mine. I'm bass.

I'm bass man. Someone drop a beat. Let's do it.

Molly, stay tuned. That's decent. That's like an acapella thing.

The new on air song is like an earworm, Blake. I love that one. It's so catchy.

I'm glad you say that. I felt like it was a little too rocky, a little like, you know, kind of hard, kind of heavy, but I'm glad you say that. Maybe the Brazilians are just listening to that intro song over and over again.

Yeah, it's actually so one of my friends from high school, he and I are doing all the music on Unplugged and on air. A little fun fact for you guys listening today. You probably didn't even know that.

That was me playing the bass on there. So there you go. Listen, enough of Blake's bass playing.

I think we should get into the science. We're packing the heat today. We have a pretty wide variety of articles, topics that you may not think are traditional fodder for fertility and sterility, but interesting nonetheless and applicable to kind of our worldview of how to best take care of patients.

I'm going to start by telling you a little bit about a kind of a very different article in Consider This this month. It's a group of Chinese authors that are submitting a paper talking about chrono fertility. So when we think about fertility, fertility is not just biology.

The authors posit they say it's biology and time. We know that our bodies run on clocks. Some of them are daily sleep-wake cycles.

Some of them are monthly, the menstrual cycle, and some of them are seasonal. And when those clocks are in sync, we know that hormones communicate smoothly. Reproduction works better.

But when they're off, be it from irregular sleep cycles, late meals, shift work, mismatched schedule with your partner, reproduction, amongst many other things can also suffer. The way that the authors kind of help us think about this is think of the brain as a master clock that's setting the rhythm for many other smaller clocks in the body. And one of those clocks being the ovaries, the other one being the testes.

There are timekeepers for these clocks. Melatonin, for example, the authors highlight, rises at night, helps protect eggs and sperm. Cortisol peaks in the morning, influences signaling in the ovaries.

Things like disruptions to light at night, short sleep patterns, chronic stress are all things that could potentially scramble those signals and disrupt that master clock. There's a good amount of research that links poor sleep, irregular sleep to longer time to conceive and lower success with fertility treatments. And then there's a big body of literature talking about very short or very long sleep durations, men being night owls, being associated with lower testosterone levels and poor semen quality.

And if we think about fertility on a seasonal perspective, we see seasonal patterns in conception and sperm quality. Daylight temperature, routine shifts, all of these things absolutely have an impact. One of the things that I think we overlook in fertility is that fertility is a team sport, and it's two people's schedules often that we're trying to make sure are in good working order.

If you have an intimate partner who's a man who's producing sperm, their schedule, their sleep pattern, their meals, their energy peaks, all of those things need to line up for well-timed intimacy during the fertile window. Then there's some interesting data that couples who sleep and wake on similar schedules report better sleep, but also better relationship satisfaction. And that may be kind of the gateway to more successful reproduction.

The authors do not have a big sweeping statement for do this, do that, but they do have some kind of general good habits that may help with this chrono part of our biology. One, aim for a consistent sleep window, plus or minus 30 minutes, kind of having a time that I usually go to sleep at this time can be easier said than done. Second, bright light in the morning.

I'm coming to you from Boston, Massachusetts, but bright light in the morning is a laughable concept in about a month, month and a half. I have a happy light that I love, and I do my early morning work with, and it feels like a second cup of coffee. And then finally, on the way out, when you're trying to go to bed, try to minimize those blue lights using dimmer switches, get rid of the overhead lights, and use a nightstand to just make sure that the light patterns are syncing up with your sleep windows.

Second, they talk about shifting calories earlier in the day and avoiding very large meals at night. Those are all things that are associated with sleep disruption. And finally, if you believe in this exercise, it says that there are times that exercise is actually best for us, particularly later in the day or in the evenings.

If I exercise, I do it in the morning because that's the only time I have for myself in the evening. Sounds like a laughable goal, but listen, whatever floats your Finally, they talk about the partner. So look at your weekly routine as a couple.

They talk about planning intimacy around fertile days, not just around your busiest nights, which I think is a concept that I think a lot of our patients struggle with. Overall, none of these things are replacements for routine ART care. But if we can get a little help from just some lifestyle things that have other ancillary benefits, maybe we can better align our clocks and give biology a better chance to work.

Molly, Blake, Daylon, how do you all sleep? How many calories do you eat at night? Daylon, tell us about your workouts in the evenings. I, like you, Pietro, do a little calisthenics every morning just to keep my core strong. And I don't eat until mid to late afternoon on most days.

Oh, and intermittent faster? Not deliberately. I'm just, you know, just ramming out there, trying to get it done, get the grind on. With this article, I got to say, I was really enamored with the first word of the title, chronofertility.

That's where they got me. And then after that, I feel like we were trying to shoehorn everything into that title because I feel like there's two competing ideas here, which is like circadian rhythms and the impact on health, like sleep, really. And then alignment of your schedule, you know, and like avoiding normal marital hatred.

Apart from that, I don't know about putting a clock on so many elements with fertility other than, you know, synchronizing the fertile window. So I love the term, but I think it's a little bit of an overreach and not as a negative necessarily. I think that's what's about to consider this format.

It's like throwing an idea out there. And I think this is an idea that will stick, but I think we've got to be careful about maybe applying it a little bit too extensively. I think this is a really interesting concept.

I agree with everything that you guys have said, but I think the current climate right now is one in which we're a little bit, there have been some statements just in, you know, in general that were a little more anti-ART, anti-using the treatments that are available and putting more personal blame on individuals, and blame isn't the right word, but saying, you know, we should use all these lifestyle things to get pregnant. But we all know that our patients may have the healthiest lifestyle and for whatever reason, whatever it may be, they need the technology. And so I think this is an interesting concept, but just as Pietra said, does not replace appropriate use of induction, IUIs, IVF.

And I do see people that really are delaying their care, either because they themselves found online that they have to do all these lifestyle things first, or they even have a physician telling them these are the lifestyle changes you have to make before you access fertility care. And so I think great discussion, really interesting physiology to think about, but also I'm really aware of the context in which we're talking about this article and the current climate that we're in. I was waiting for someone to say RRM, but no one did.

So it's one of a buzzword, if you will, for RAIs now across the country. But yeah, I kind of got vibes of restorative reproductive medicine reading this. Of course, you know, this is something you can mention to patients.

They're always asking what's something else I can do? Is there anything else I can do? And of course, it'd be ideal to have good sleep hygiene and mention a lot of these things in there too. Of course, there's only so much this can do until we really are utilizing our treatments for whether it be IUI or IVF. But helpful nonetheless to still counsel patients, say it's important to keep these things in mind.

But don't stress over having this particular light in your room at this time of day type of deal, although PHR does that type of stuff. So whatever. It's for the vibes.

It's just like, just like the scooter behind you. Our listeners cannot see your scooter behind you, but I really want to see you ride it. Yeah, for the listeners, I do have a adult-sized scooter, not electric, just real horsepower with the foot.

Yeah, not a razor. Or is it a razor? No, they don't make razors for adults. Oh, that's a good question.

Yeah. But you do tricks on that thing though, right? You do tricks for sure. I can see you doing the 360, 440s, 780s, all that stuff.

You're an animal. Backflip. Probably my best trick is that I get seven and a half hours of sleep every night.

That's my superpower. Wow. That's impressive.

Yeah, I think the real insight from that conversation, Molly, was that you called it avinduction, shortened it up. I've read abbreviations of ovulation induction. Avindy.

Band name. Avindy. I just made that all up in real time, but maybe it will catch on.

We'll see. That'll be our band name. That'll be our band name.

I hate that so much. I'm so glad Trump sent in the troops to Portland. Wow.

Avindy. Yeah, you guys are out of control. Yeah, you deserved it.

Too much artisan matcha. We totally deserved it. All right.

Enough politics. Molly, tell us what you got from FNS Reports, my old home. So, FNS Reports this month.

The article I selected is called Outcomes of Ovulation Induction in Obese Women with Infertility After Bariatric Surgery by first author, Miranda Blanco-Brendel and last author, Harry Leeman. So, in our field, I think we're all really aware of the increasing prevalence and the unique challenges of caring for individuals with a higher BMI in the fertility treatment context. Obesity has an impact not only on general health, but also fertility and response to and success with fertility treatments and then, of course, obstetric outcomes.

And I think many of us often ask if someone undergoes weight loss, substantial weight loss, either through traditional diet and exercise, which we know, unfortunately, has a pretty low success rate, but is always worth trying, or with the much more successful alternatives of either doing bariatric surgery or using GLP-1 agonists. How does this potentially augment their risk profile in terms of how they'll respond to fertility treatments and then how they'll do during pregnancy with their obstetric outcomes? And so, this article really just looks at those fertility treatments and kind of the outcomes with the first trimester pregnancy. When I am counseling a patient on options for weight loss, something we probably all do every day in our clinic, I think we're really balancing the potential risks of these interventions or the potential benefits.

So, there are obstetric risks to undergoing bariatric surgery, a higher risk for a small, for gestational age infants, as well as more nutritional deficiencies in pregnancy. So, it's not only a win-win to have bariatric surgery. And it also will delay pregnancy because there's variation, but most physicians recommend at least like a year or even 18 months after bariatric surgery before trying to conceive.

And I think most of us are still recommending stopping GLP-1 agonists prior to conception, all of us, I believe, currently, with the potential risk of regaining that weight. And furthermore, this is really balanced with the age-related decline of fertility that we're all super aware of, and in patients who advance maternal age, can you really wait a few months for GLP-1 agonists to work and then to take them off it, or wait for the bariatric surgery waiting period? The authors in this article cite that the ASRM Committee Opinion on Obesity and Reproduction specifically states the need to understand, quote, the specific impact of bariatric surgery on the responsiveness to subsequent fertility treatments for infertility. So, this article is definitely highlighting a need, and the research is pretty limited, partially because the end is just limited for this.

And the authors hypothesize that undergoing bariatric surgery would improve the efficacy of ovulation induction, or ov-induction, or ov-ND, in individuals with obesity. I hate it. I hate it so much.

I love it. Ov-ND. Ov-ND.

So, this study was retrospective. They identified three groups. It was kind of an interesting study design.

So, group one was 27 individuals who had infertility and a history of surgical weight loss. Group two was 27 individuals with obesity and infertility, and their BMI was matched to the pre-op BMI of group one. So, their BMIs before bariatric surgery.

Group three was 28 with infertility and a BMI matched to the post-op BMI of group one. And then they also matched on age and infertility diagnosis. So, you're looking at your post-surgical group and then comparing it to what they would have had pre-surgery at the higher BMI, and then a group that is at the lower BMI they're at now, but that has not undergone bariatric surgery.

So, kind of an interesting design there. There were some differences between the groups despite this matching. So, more did use IUI in the bariatric surgery group than in other groups, although it was not statistically significant.

And more patients did use Clomid in group two. Do you mean that they used IUI in vitamin C? Yep. Yep.

IUI is definitely IUI. And if it's partner IUI, it's PUI. And if it's donor IUI, it's DEWY.

And I don't know about vitamin C for that one. Oh, no. Are you serious? You really say those? You say that? Okay.

Yeah. That's how we talk in Portland. So, there are these differences between which groups are using more Clomid, more IUIs, but the infertility diagnosis seemed to be pretty similar between the groups.

For the ob-induction cycle outcomes, they looked at pregnancy rate, clinical pregnancy rate, biochemical pregnancy, and clinical pregnancy loss rate. They found that clinical pregnancy rate, probably as expected, was higher in the group that had the lower BMI, but that had not undergone bariatric surgery. So, that was the best prognostic group.

And then it wasn't as significantly different, but the next best was the bariatric surgery group. And then the lowest was a group that had not had bariatric surgery and had similar to the pre-op BMIs. They also, although not statistically significant, did find substantially more clinical pregnancy losses in the group that had the post-op BMI.

So, that had the lower BMI in the controls that were matched by post-op BMI. So, the lower BMI that had actually not undergone bariatric surgery, which was kind of an interesting finding. The authors hypothesized that the higher clinical pregnancy and potentially lower clinical pregnancy loss rates were related to more robust alluvial phase in patients with lower BMI.

But I think a significant limitation of this study, as it may be with all retrospective studies, is that they had different types of infertility, which in the demographics table didn't look enough statistically significant enough, but I think could be impacting the outcomes here. And we also have differences in terms of what medication they're getting. So, Clomid, you might get an extra egg over Letrosol, higher multiples rate, which could impact their outcomes.

And then IUI in an unexplained infertility patient, mild male factor, may have a higher success rate there. So, we have some confounders coming up. I would think that PCOS or obesity-induced anodulation is of course going to be really affected by weight loss, but I think infertility due to a tubal or a sperm issue is probably going to be less impacted, but I might be sort of understating or underestimating the impact there.

And I think we've all had those ovulatory patients who have had years and years of infertility and then they lose weight and suddenly have an unplanned pregnancy. So, I think those other impacts of obesity on fertility, even in an ovulatory patient, like endometrial receptivity, oxidative stress, aneuploidy, possibly aneuploidy are coming into play as well. So, I think, you know, overall, I think this gives us some preliminary data about impacts of fertility treatment, bariatric surgery.

They seem to do as well as people with high BMIs who had not had bariatric surgery and may even do a little bit better. And so, not doing worse, which is good, but still may not be doing quite as well as patients who have those lower BMIs to start without having had bariatric surgery, which I think makes sense to me. I think this opens a door where we need a lot more data on this.

And I think as more people are accessing bariatric surgery, we're getting more coverage for it. You will have more potential data to learn about these outcomes and maybe multicenter study, get a lot more data there. Are more people seeking bariatric surgery? I mean, I feel like if I had had bariatric surgery in the last 10 years, I'd be pissed because of GLP-1.

So, I feel like there's going to be a bit of a handoff here in terms of the science, but wouldn't you imagine that all the same conclusions here would apply? I know you said maybe do even better, but when it all comes out in the wash, you think that the same findings here could be extended to all the people who are losing weight more dramatically, you could argue with the GLP-1 inhibitor? Yeah, I think they won't be comparable because the GLP-1s, I don't know that they don't have lasting impacts, but I think that you come off them and it seems like you start to gain the weight back. And there will be some nutritional deficiencies from that rapid weight loss, but probably not to the extent of a bariatric surgery where you still have the surgical change. So, there's no removing it before trying to conceive.

And so, I think we can't extrapolate to GLP-1 agonists. I think we don't have the data. We have decent data on obstetric outcomes after bariatric surgery.

I think we don't have that data with GLP-1 agonists just yet, but probably we'll have a more significant body of it soon. I also wonder if there will be some future research on keeping people on it in pregnancy. I wouldn't do it right now.

I don't think that there's been, we haven't proven the safety of that, but I don't know if that's a direction we're heading. But I think you may be right, Dale, on fewer people getting bariatric surgery overall because there's the GLP-1 agonists, but I think there's still a lot of people who don't want to be on a medication for the rest of their life and so are still choosing the surgery. I don't know.

What do you guys think about that? I'll let Blake chime in because you probably have more experience with just by nature of where you live in the country, but I see very, very, very few people who have a history of bariatric surgery in the Northeast. They have a lot of thin patients on GLP-1s, in fact, which comes to no surprise to people who follow the news. But what's that like in Oklahoma, Blake? I wouldn't say we have a very large population of bariatric surgery patients, and we certainly have them, but absolutely GLP-1s, and I feel like everyone is on that.

Every female is on GLP-1, every male is on testosterone here, and so that's another story. But I do feel like, as you were saying, Dale, that we're just going to be seeing more and more GLP-1s, and maybe we won't be having this conversation here in 10 years about morbidly obese patients and fertility treatments, but I feel like the biggest challenge for us, because Oklahoma is certainly an obese state, we have a lot of obese patients, our BMI cutoffs for IVF would make a lot of people cry to hear the number that we go with for egg retrievals, and so... Go ahead, what are they? 50. My center's BMI cutoff is 45.

I mean, don't get me wrong, a BMI of someone that's less than 50, so if it's like 48, that doesn't make me feel great by any stretch of the imagination. But if we limit our cutoff to 40 or 45, like a lot of places do, we're going to have a lot of patients that don't do IVF. So these retrievals certainly are very challenging, but I think with GLP-1s becoming more and more common, I do agree, I think bariatric surgery is probably going to go by the wayside.

Also, too, when you keep in mind that these patients shouldn't be conceiving for about a year after doing their surgery, it's just not an appealing option to a lot of patients. So while I do certainly have a decent amount of patients that have had it, I'm seeing less and less of it, I feel. I have thought about with bariatric surgery, referring someone for bariatric surgery, they get the surgery, six months out, they're going to meet my BMI cutoff, they can proceed with IVF, and then six or 12 months later, okay, now we can transfer the embryo.

So is there kind of a role, let's say she's 38, is there a role for fertility preservation there? But then you are, of course, balancing it with, will I have... Should I just wait the whole year when the BMI will be much lower? We're going to get a better outcome. How much am I really gaining by going six months earlier? But that is, I don't think I've actually done it, but I played around with that idea with some of my patients. I don't know if you guys have tried that.

I think that's the premise of the GLP-1s, right? The weight loss is profound and fast, and you don't have to make that trade-off of six to 12 months of achieving a target weight before you can conceive. Three to four months on a GLP-1, the results are pretty dramatic, pretty quick, and they can get right back into reproduction after a short washout period. I'm excited to see how we build a body of data to suggest that it's safe in first trimester, early pregnancy and beyond.

I think that's going to open up a lot of doors, and it's a bad time to be in the clomid and letrozole business, is all I'll say. The avian business. The avian business, as they say.

I hate that so much. I think I just, I enjoy it because I know that you hate it so much, and it just brings me joy for some reason. I don't know.

Yeah. I'm sorry. Daylon, I never thought I'd say this, but please tell me something about FNS science so we can stop talking about clinical medicine for a second before I lose my mind.

I'm going to rescue you, partner. Rescue from all of these delicious acronyms. Anything you're doing to mice that we should know about? You know it is.

I try and stay away from the mice stories because you guys are haters, but this one is the real deal, and I'm going to come back around to my rationalization for how this mouse study is a little extra in terms of its application to human health. But first, by way of review, I mean we talked about the timing, right? The chronofertility. We talked about obesity here just now.

This story, it's more about inflammation, right? Stress maybe, but all kinds of environmental insult and how that manifests as inflammation to undermine fertility. And really it's about, if you want to go even more basic and fundamental, it's about barrier function, right? A key to our survival is the barrier function of our mucosal tissue, which balances the protection of our body, right, from the environmental, that harsh environment out there. But also balancing that with nutrient absorption, excretion, also reproduction, and even the host-microbe interactions.

In the reproductive tract, the endometrium is the main barrier organ or cell, plays a pivotal role in all different aspects of a successful pregnancy. And of course, even in the absence of pregnancy, it's subject to cyclic hormonal changes and mobilization of all these different cell types to prepare the uterus for implantation. But if there's an inflammatory insult, like those resulting from infection or immune dysregulation or endometriosis even, you can disrupt the barrier function, which can lead to implantation failure or later on in pregnancy, pregnancy loss, other complications around conception, like preterm birth and or preeclampsia.

So, this is a story about inflammation, right, which is a very hot topic generally in disease. Everyone's talking about inflammation, perhaps even more so late as pregnant women are being instructed to avoid acetaminophen. In terms of preconception, do you guys ever talk about inflammation with patients in terms of like their struggles with infertility or treatment for that infertility? Does inflammation ever come in as a counsel point? I bring it up often when I'm talking about the impact of endometriosis on the uterus.

The analogy that I use is the volcano analogy. You don't need to be dipping your toes in the magma to feel hot and burned from that heat. You just need to be near it or even on the volcano to feel that discomfort.

And part of what we do with endometriosis is we try to move you off the mountain and further away from that hot lava, the heat, the magma. That is kind of a good analogy for inflammation in the pelvis through excision surgery, through suppression, through you name it. But for me, it's actually a big part of what I talk about for patients with endometriosis is how to manage inflammation.

That was a good analogy, Pietro. Yeah, I gotta say, you may hate the acronyms, but I'm starting to hate your analogies. I mean, why do you gotta be so dramatic? It seems like Pompeii and Vesuvius, you're making these people out to be like they gotta be running for their lives.

I'm not playing the Jurassic Park theme park song in the background. Like I'm just talking about magma as an analogy for inflammation, but fine. I think you should play that song in the background.

Pietro's laparoscopies, he just thinks he's in Jurassic World. Just plays that song on repeat in every single surgery. Yeah, the drama.

You know, if there's one thing I don't want from my doctor and my surgeon is someone who thinks they're in an action movie. All right, partner, but I love your analogies. Keep coming with it.

Getting back to the story, this is not really geared towards preconceptions, but I think there's some ideas that we might transpose. And as we alluded to earlier, while it's a mouse model, stop hating, I think there are many facets of the inflammatory signaling apparatus and paradigm vis-a-vis disease and reproduction that are fundamentally conserved, right? I could make my case, but that's for maybe another conversation. So for myself, at least, and I can try to convince you guys as well, I found the data compelling.

So let's get to the data. The word comes from the group of Svetlana Dembaeva, sorry about the mispronunciation. I think it's Rosalind Franklin University of Medicine and Science in Chicago.

And her group was investigating the potential application of recombinant interleukin 22 to preventing abortions that are triggered by inflammation. That's like a model of abortion in mice. And the design was pretty solid.

They used wild type mice, but they also had these mice that had a knockout of the gene for IL-22, right? So these mice didn't make their own IL-22. And in those knockout mice, when you treated them with the recombinant IL-22, so restoring the IL-22 that they were missing, you were able to salvage the barrier function of the endometrial mucosa to the level that was observed in wild type mice. They use this electrical resistance model to show the barrier function.

So for me, that was solid because it established like a mechanistic means of the IL-22 function in the context of normal fertility. And next, they combined the IL-22 treatment with this induced abortion model where they inject the mice with this lipopolysaccharide, which is highly pro-inflammatory compound, about a third away through gestation. So that's day eight and a half of 20 days, a typical mouse pregnancy is 20 days.

And they tried three doses, five, 10, and 20 total micrograms. And what they found is that the recombinant IL-22 rescued these IL-22 knockout mice in the context of this LPS injection. So they saved the mouse from losing the pregnancy.

But what was more interesting to me was that when they administered the same treatment to wild type mice, the lower doses, so five and 10 micrograms rescued the pregnancy, but the high dose not only didn't rescue the pregnancy, it was actually worse than the treatment alone. And in both the wild type and those IL-22 knockout mice, if you just injected that high dose of the IL-22, so no pretreatment with that lipopolysaccharide, no inflammatory induced abortion, so just a healthy mouse, you blast it with a high dose IL-22, and it's not good for pregnancy. The increase of the risk of loss.

So two things. One, there's this clinical idea that you might be able to use IL-22, recombinant IL-22 treatment to mitigate risk of pregnancy loss in the context of like normal pregnancy or tenuous, whatever, at risk pregnancy. But conceptually for me, there was a more interesting for me angle here related to this overall balance of inflammatory versus anti-inflammatory signals that are critical, the balance being critical to mediating the complex and dynamic changes that accompany implantation and all the other aspects of gestation.

And, you know, the catch here is that given the array of inflammatory signaling modulators that are out there, I mean, we're talking about interleukin number 22 here of more than 40 that have been identified to date and described, and that's not even to mention the TNF family and all the other, I mean, there's literally hundreds of these inflammatory secretive modulators. So we're at the tip of the iceberg here and may never be able to effectively control the balance. But I think it's important that we're appreciating the relevance and the importance of this inflammatory access more and more, particularly in the context of pregnancy loss.

So yes, it's in mice, but I think, you know, broadly speaking, this builds the case for minimizing inflammatory insult in pregnancy, and maybe we'll draw attention to patients who have inflammatory or autoimmune conditions and the risk of pregnancy loss in those specific patients. So I don't know, guys, not like we're going to be out there dosing our patients with IL-22 if they're at risk, but maybe something here. What do you think? There's so many markers for inflammation, and so I think, well, I mean, this is very interesting.

I just, I always wonder how do we get to that next step? You know, there's so many different interleukins and cytokines and natural killer cells, so there's so many different things. How do you narrow it down to saying we're going to try this one and then see a proof of concept and then move forward clinical trials? It just seems like so many different trials that have to be done to move forward, but how do we get to that point? Yeah, I agree with you. I feel like the harsh reality here and maybe the less encouraging result here is that too much is bad.

So, like, are we really going to fine-tune the dose of all these things and tighter and do this massive combination? Not realistically, especially given that every patient is different and going to have a different, like, kind of inflammatory, anti-inflammatory balance as a background, but I do think that there may be some master regulators. You know, you look at, like, IL-1s, you look at, like, TNF-alpha that are really kind of at the top of the pyramid that maybe, and there are a lot of immunoregulatory, immunomodulatory therapies that are focused on dampening that in the context of, you know, rheumatic or autoimmune disease. So, I don't think that we're going to figure out the physiological levels, but that doesn't mean that we can't have some kind of sledgehammer treatment for a subset of patients.

But yes, I'm bullish, to say the least, on how refined these treatments are and how good we can even get them at any point. It's a little oversimplified, but what I really like about this paper is it just, it highlights that just in a very simple way. If you don't have it, then it's okay to give it, but if you already have it, it's actually harmful to give it.

And it makes you think about these kitchen sink approach embryo transfer protocols, where we just give them all the immunosuppressants or modulators. And that for some people, it might help, but some people, it actually could make things worse, could cause harm. And so, an oversimplified view of this paper, that's what I like.

It really supports that thinking, that it isn't a one size fits all approach. One of the things I'm most excited about that's coming down the pipeline is people are working on non-hormonal therapies for endometriosis that target inflammation. And one of the really cool developments, people are working on a NSAID eluding IUD.

So, instead of having progestin only, you can have a little bit of local ibuprofen delivered to the source of these inflammatory signals and this big muscle that can become crampy and aggravated that maybe coupled with the progestin may be really cool. I'm so excited to see how that plays out, but there's something there. Why couldn't we think of that? That's so simple yet so cool.

Yeah, I thought of it. It's under patent. I'm joking.

I wish. It's like, maybe, I don't know. Blake, why don't you take us home? I've heard that you have a real short two-page article this month in FNS Reviews.

Did I get that right? Yeah, Pietro, that's correct. I am certain that you all have read all 67 pages of this article, but I'm going to just do you a solid and condense it and give you the need to know details or deets, as Molly would probably say. I'm going to talk about a fascinating area of cancer research, a medication called mTOR, which stands for mechanistic target of rapamycin, how it might help women who have breast cancer undergoing treatment preserve their fertility while also undergoing chemotherapy.

The title of this paper is called Mechanistic Target of Rapamycin or mTOR Inhibitors for Fertility Preservation in Breast Cancer, a Narrative Review by first author Yuji Tanaka out of Japan. Why does this matter? Well, breast cancer is one of the most common cancer in young women. Annually, about 20,000 women under the age of 45 in the U.S. are diagnosed with breast cancer.

Nearly all survivors receive some sort of endocrine therapy and or cytotoxic chemotherapy, particularly cyclophosphamide, which we know is very gonadotoxic, which places these women at particularly high risk of infertility. And a lot of the survivors of breast cancer say that they want children, but the authors quote only a very small fraction, anywhere from 4 to 18 percent actually undergo fertility preservation. So what are current fertility options or preservations and what are their limitations? Well, oocyte cryovation, embryo cryopreservation, as we know, are going to be the most commonly utilized approaches.

Of course, success... And Molly, what do you guys call those in the PNW? Any funny names for those? No, I don't have one for this. I'm going to think about it. Thank goodness.

That is literally the best thing that's happened on this podcast. I see eggs, I see embryos, maybe something like that. I'll keep workshopping.

You didn't say bank goodness, did you? You said thank goodness? Because if you said bank goodness, that's pretty good. Anyways, sorry. Did I? No, I didn't know.

Yeah. So anyways, but of course we know these approaches are limited by how many eggs we get at egg retrieval before chemo begins. And sometimes women can only undergo one cycle before they undergo chemotherapy.

Ovarian tissue cryopreservation is another option, particularly in prepubertal girls, but as many follicles potentially can be lost during this process, according to the authors. GnRH analogs have been utilized and are used often as well. Randomized controlled trials have demonstrated limited efficacy in these as well.

And of course, add in barriers like cost, access to care, and just the stress of undergoing cancer treatments in general. And so a lot of women ultimately don't pursue these options. So then enter mTOR inhibitors.

So a mechanistic target of rapamycin, as we discussed, is a pathway that controls cell growth and survival. And this process is overactive in many cancers. So thus inhibiting it is going to be beneficial in a cancer.

mTOR regulates cell proliferation, cell survival, cell metabolism, and immune responses through phosphorylation of key effectors or key modulators. And drugs like rapamycin or everolimus are FDA approved for certain breast cancer treatments. So excitingly, and in lab animal studies, these drugs have been shown to actually protect the ovaries from chemo damage and even ovarian aging and tissue cryopreservation as well.

So they presumably will preserve ovarian reserve by modulating intracellular signaling pathways by suppressing the primordial follicle activation and reducing the amount of exposure to chemotherapy. Consequently, they hold promise for mitigating cancer treatment associated follicular loss. They also, the authors discuss, that they may prevent endometrial hyperplasia effects and polyp formation from tamoxifen use in patients with breast cancer.

And so a couple of the things that the research shows. So there's preclinical studies that show that mTOR inhibitors preserve ovarian follicles when given alongside chemo. It may also improve age-related fertility decline, which, wow, wouldn't that be wonderful? But preclinical studies suggest that mTOR inhibitors can preserve the primordial follicle pool and improve oocyte quality.

But current ongoing trials are currently looking at these effects. There's been preclinical studies that show that this may improve graft survival in these patients that undergo ovarian tissue transplantation due to the ischemia and the reperfusion damage that can occur to the follicles. And reluctant to kind of say these next couple of things, because I fear that a lot of patients are going to take the mTOR inhibitors as the new McDonald's fries approach after an embryo transfer, but the authors quote that there's improved IVF outcomes in some models when looking at egg yield and live birth rates in patients who have had implantation failure.

And get this too, there's a mouse model that shows that you reduce OHSS, which I'm just picturing Dalon giving a little mouse ascites, and I don't know, it just seems like a wild thing. How do you give a mouse OHSS, Dalon? Let's just pause there. Let me get back to you on that one.

Exactly. Well, apparently mTOR can help that too. You can just take mTOR for everything, apparently.

And so what, despite promising preclinical evidence for looking at these things, clinical applications for fertility preservation using these mTOR inhibitors remain largely unexplored. So some challenges and risk of this approach here. So side effects are definitely real for patients.

Mouth sores, high blood sugar, high triglycerides, and even immune suppression. So when you consider a lot of these things that our patients have found on TikTok and they're doing just based off of what their friends are telling them to do, this is something that could potentially cause damage. So this is not like taking CoQ10, for example.

And so a lot of patients stop these medications because of these side effects. The authors pose that there are some ethical concerns too. So using these drugs is off-label for fertility preservation without strong clinical data is a risky approach, obviously.

They also say that safety in pregnancy looks manageable. So if drugs are stopped a few months before getting pregnant, it seems overall safe from what data we know so far. So looking at the future for mTOR inhibitors, researchers or the authors, as always, they're calling for dedicated clinical trials in young women who have breast cancer, seeing if this is efficacious.

The authors state that the trials should track ovarian reserve markers like AMH. Obviously, that would be a very good clinical correlator to see is this preserving ovarian reserve and, of course, pregnancy outcomes subsequently. So until then, mTOR inhibitors remain promising, but experimental nonetheless at this point for fertility preservation.

So while mTOR inhibitors are not yet ready for primetime as fertility-saving drugs in patients with breast cancer, the data is pointing in an exciting direction that one day may give young women the chance to beat breast cancer and also keep their options open for fertility preservation. So interesting summary. What do you all think? I believe there's a clinical trial being run out of Columbia looking at rapamycin, mTOR inhibitor for delaying the onset of menopause.

I may have gotten those details wrong, but there are other clinical trials looking at it in reproduction. I think it'd be really cool if we could do something that stalls this march towards inevitability. Medication is really inexpensive.

It's been around for a long time. It's generally well-tolerated. If you subscribe to the ecosystem of podcasts, hosts, and Instagram celebrities that are all trying to wind back the biological clock, they're all really hot on rapamycin.

Different dosing schedules once a week, micro-dosing it daily, taking it quarterly. If you are also a member of the online Facebook group where we have REIs talking to other REIs, that's something that's come up over the last year where people have shared protocols, personal experience, and treatment experience with patients. I'm keeping a close eye on it.

I haven't used it personally or in patients, but it'd be awesome to have some more stuff in our tool shed. Yeah, that trial out of Columbia from Zeb Williams' group, the Vibrant Study, which is looking for benefits of rapamycin in reproductive aging. That's an acronym, Molly.

It's not a Portland acronym, but it's something. One of those New York acronyms, got to have at least six, seven letters. As you mentioned there, Pietro, the rapamycin has been all the rage with the celebrities and the wealthy with their longevity doctors.

I don't want to say it's fallen out of favor, but one of the most prominent kind of cartoonish longevity billionaires pulled out of rapamycin. Not that he should be our touchstone here, but I guess the point being is that yes, like the French fries, there's all this information and research that's been disseminated out into the zeitgeist. I think that it's going to be tough to define whether there's a benefit, but as you said, these drugs are tolerated and well-established, particularly rapamycin.

I think it's worth looking into what the benefit will be, but I won't be surprised if we can't put our finger on it. One of our OHSU REI fellows did her thesis on rapamycin in the rhesus macaque. I know you're very jealous of our monkeys, Daylon, so I like to rub it in.

I think it should be coming out hopefully in the next year or so, but she did have a presented at ASRM. My takeaway from her presentation was that it was a little bit overhyped, but I think once we have it in manuscript form, hopefully we can take a deeper look at it. Always important to have a good animal model for things you can't do in humans, of course.

Yeah. Like rapamycin, Blake, you already look quite young, quite, quite young, but hey. I wasn't going to use today's podcast to discuss this, but yes, I take rapamycin daily.

Rapamycin or Botox, Blake? What's going on? I do both. I actually don't do Botox. I just have a natural, very shiny forehead.

Yeah, same. Youthful, very youthful. Thanks.

Listener, you can't see this, but I have a nice tight shaved head. Personal story, my son not too long ago did ask me where my forehead ended, which I thought was cruel. Got that infinity head, bro.

I got that infinity head, bro. What was your response? A couple of choice curse words. You mother... You're grounded.

The fruit of my loins disrespected me as such. Apple doesn't fall far from the tree. You got to give him a high five for that.

That's surgical. It was good. It was good.

That's so funny. Still talking about it. Months later, still talking about it.

But anyhow, guys, I told you at the beginning of this podcast, we would cover a pretty wide range of topics from Rapamycin. Oh, here's a fun fact. Does anyone know why it's called Rapamycin? No, I didn't come across that in my review.

Maybe you should learn about Rapa Nui, the island where it was discovered and called as an homage to its discovery site. Rapa Nui being, of course, Easter Island, which many of you may remember those big headstones from. Any volcanoes on that island? Don't put your toes in the magma or your forehead close to it.

You're going to use that analogy tomorrow and you're going to thank me with how well it lands and how well it plays. Anywho, listener, we could go on forever. Thank you for tuning into yet another episode of F&S Unplugged.

As always, F&S on air, anchoring the coverage month to month. And please do share what you think about our new offering, F&S Roundtable, launching this very next month. Until we meet next time, good night.

This concludes our episode of Fertility and Sterility Unplugged, 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 HogenEsch, Dr. Selina Park, Dr. Carissa Pekny, and Dr. Nicholas Raja. 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 host, it is not intended to be the only approved standard of practice or to direct an exclusive course of treatment. The opinions expressed are those of the discussants and do not reflect Fertility and Sterility or the American Society for Reproductive Medicine.