Fertility and Sterility On Air - Unplugged: March 2025

In this month's Fertility & Sterility: Unplugged, we take a look at articles from F&S's sister journals! Topics this month include: how attacks on abortion access can threaten IVF (1:58), the prevalence of adenoymosis in young people (12:58), and the impact of short-term Western-style diet and hyperandrogenism on ovarian function (26:02).

Consider This: https://www.fertstert.org/news-do/writing-wall-ivf-access-could-follow-abortion-s-path

F&S Reviews: https://www.fertstertreviews.org/article/S2666-5719(24)00040-9/fulltext

F&S Science: https://www.fertstertscience.org/article/S2666-335X(25)00021-7/abstract

View the sister journals at:

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

Welcome to Fertility and Sterility On Air, the podcast where you can stay current on the latest global research in the field of reproductive medicine. This podcast brings you an overview of this month's journal, in-depth discussion with authors, and other special features. FNS On Air is brought to you by the Fertility and Sterility Family of Journals in conjunction with the American Society for Reproductive Medicine.

Hello and welcome back to FNS Unplugged. I'm Pietro Bordoletto, your co-host, and if you missed this voice, it's because we've been away for a little bit. Our very own Molly Kornfield had a baby, and we gave her a small maternity leave, and of course, being equitable, we gave ourselves a small paternity leave in the transitive property, slash, we just forgot to schedule the January and February date, and things fall apart when Molly's not here.

So if you've missed Molly, I can guarantee you that we have missed Molly as well. But don't despair, she'll be back next month. But we finally got it together and decided, you know, let's get back to telling the story about some literature that's coming out in FNS.

So Daylon, Blake, I truly mean it. It's good to see you both. It's been a minute.

It has been a minute. It really is great to see you all. Molly, congratulations.

We're very happy for you and look forward to having you back. Agree, yeah. Molly, wherever you are, you're better off than us.

I'm looking at these two mugs. I'm missing you even more. Oh, come on.

You should know that I have my video off. So he's really... It's just me. It's just my imagination.

Yeah, I appreciate that. But you're bringing it. I gotta say, for those who aren't here at home, we're bringing a Talking Heads vibe here.

It's amazing. I have a jacket on that he really likes. Members only.

Members only style. Yeah. You can't have it.

Let's jump into some science. I have the first article this month from Consider This. This article is entitled The Writing is on the Wall: IVF access could follow abortion's path.

This is by first author Mattie Boehler-Tatman, who is a resident in OB-GYN at Permanente on the West Coast with her OB-GYN attending Maryl Sackeim. I believe I pronounced that correctly. This article kind of caught my attention.

It came out in January of this year. It caught my attention because this feels like it was the theme of 2024 for me. Our paths intertwined more so than ever before, meaning IVF legislation and abortion legislation, personhood.

So I really wanted to highlight this article as something that kind of puts a name to what we've all been feeling in this last year, that IVF access in and of itself alone is not enough to accomplish the goal of comprehensive access to reproductive health care. And I think the reality is that we all know this to be true. Our job is to help get patients pregnant when they want to be pregnant.

But I think the flip side of the coin is also true. It's also our job as women's health providers to help people not become pregnant when they do not want to be pregnant. And you can't really have one without the other.

Our patients will get pregnant. An unfortunate large percentage of them will need, will have a miscarriage and need access to DNC, but a smaller percentage of them will choose to terminate the pregnancy for a host of potentially medical and non-medical indications. And I know for me, I want my patients to have access to me, but I also want them to have access to that.

This article, I think, walks through nicely why this is really important for the fertility specialist to keep at the top of their mind. One, our patients demand it. They need it.

It's just good health care to be able to support patients when they're not wanting to be pregnant any further. But two, it's really important for us just the bottom line. If we slowly start to see appealing a way of access to abortion care in red states, what follows shortly thereafter is that these personhood laws start to encroach on our ability to practice our job.

And Blake, I think this is particularly kind of sensitive and topical for you guys in Oklahoma. I'd love to kind of get your two cents on how you guys have weathered the storm in Oklahoma. I feel largely protected and lucky in Massachusetts, but I don't want to feel that way.

I want everyone to kind of have similar protections. Share with us a little bit about what the experience has been like, at least in 2024 in Oklahoma. Yeah, it certainly is a sensitive topic for sure.

Fortunately, as of now, nothing has changed for us in Oklahoma in terms of how we practice, which is great. My sincere hope is that is maintained, but I'd be remiss if I said that we weren't concerned that although we're kicking the can down the road further, at some point the can will not be kicked any longer and then another personhood bill is going to come up. But even just in the past calendar year, we've had to discuss with congressmen at the Capitol about how these personhood bills could adversely affect access to IVF care, could potentially make me a criminal as trying to help build families.

And most of these congressmen have no idea or congressmen and women have no idea that what these bills are writing can adversely affect IVF access. And when it's brought up to them about what this could mean, they're like, oh, we had no idea. Like, I have a nephew from, you know, IVF or I myself had to do IVF.

I'm like, well, with these personhood bills, you could make IVF access illegal or you can make me a criminal. So fortunately, not many of these individuals want this to happen. It's just almost an inadvertent consequence.

Now, that's not the case for all states. But so far, what we're finding is they just keep wanting to pass these personhood bills. And every time it's brought up, it's the same thing over and over.

It's like, hey, remember when we talked about this previously? And I've even had some patients come through who are congressmen and congresswomen. I'm like, hey, let me talk to you about these personhood bills. And it's a very unique opportunity for me to talk about that with them.

And so hopefully, just little seeds being planted like that can have them in our corner moving forward whenever these bills come up again, because I'm sure they will. So, but yeah, it's certainly a hot topic here for sure. So can I just, someone who has nothing at stake, so I want to, I want to lead with that.

Paul, you have everything at stake. Well, I want to say it's not my, it's not, I'm not put in a tough position to make those tough decisions with and for patients in some cases. So I want to lead with that.

And in terms of like declaring my own ignorance and lack of, I think, a personal connection to this, because I want to game out and lead by saying, of course, I agree with this standpoint, and I agree with both of you and sympathetic Blake in particular to you. But I just want to, you know, it behooves us now in the current political climate to like kind of game out that political ideological viewpoint, right? So that you can see what is the argument. And so I would ask you, is there a position? Is there an REI who would say, I mean, because the case we made here is that, you know, ART is inherently intrinsically linked to abortion rights, as you kind of made the case, Pietro, there are patients for whom you need to proceed medically or other reasons.

So, but is there an REI who would say, no, no, no, like, I will, I am in the practice of assisting, you know, conception up to this point. And if you seek that further care, you can go somewhere else. Because I think that if there's an ideological point, or a viewpoint that that REIs, and I'm sure there are some, there must be right, who feel that way, or maybe not, I don't know, I'll leave it to you guys to weigh in on that.

But I feel like there is a position where, where, where people can say and feel, I think, you know, that they're taking the moral high ground in saying that no, you can't make that case that they're intrinsically linked. Like this is kind of a little bit of a manipulation, like you can have ART without abortion. What do you guys say to that? I think, unfortunately, or unfortunately, and I'm trying to not to use charged language here.

But I think there are people who do espouse those beliefs, where they want protections around what they do, but don't want protections around other aspects of women's health care. And I would argue that they're the same side, they're two sides of the same coin, can't have one without the other. And I don't, I personally don't want protections for IVF if it means that my patients don't then have reproductive choice that extends to termination of pregnancy as well.

But that's Pietro Bordoletto's opinion, not Fertility and Sterility's opinion, not Cornell's opinion, not Boston IVF's opinion. But what I think this article does a good job of flagging for all of us is that these issues, for better or worse, are inextricably linked in the minds of a lot of people. And unfortunately, there's also a lot of off target effects when you start chasing down one to limit access, as Blake has already shared, that you inadvertently start to restrict our ability to do our job.

And to me, the most practical solution here is fight both fronts, not try to carve out protections for one, but not the other. But Blake, from a pragmatic standpoint, like you mentioned, a lot of these people are like, oh, wow, like, I know someone, or I am someone who is, you know, personally affected, or I've utilized these ART services. And like, from a pragmatic standpoint, I think that's how you win, is that you get these people to cross the aisle on in this one case.

So like, is there a way to really capture those people and make the case that no, it's not just about, you know, some of these patients? Like, I just wonder if you can make a stronger case. It's not just some patients who undergo ART will need an abortion. I wonder if there's a stronger link that you're alluding to there, Pietro, I think, but I wonder if there's a way to make it crystal clear for those people who have such deeply held political viewpoints related to abortion.

Yeah, I mean, and this is a subject that we could just have a podcast on in and of itself, and we could talk about this for a long time. But it's a fine line to walk, right? Like you, although I agree, and I totally see what you're saying, but when you are talking to these representatives, they're very limited on their understanding of this subject. So if you talk about how like embryo disposition, you know, you're discarding embryos, they see that even though we understand that just because an egg and a sperm have fertilized, they may very well stop progressing and may never lead to a pregnancy based off of how it's looking in the lab.

They foresee that as you're murdering a child. And we know that that's just bizarre. And we know that as a fertility physician, I'm not going to put this embryo back in because it will not lead to a pregnancy.

They don't see it that way. And so you have to kind of approach it as even though we are proponents of both, you know, abortion access and IVF access as well. You almost have to be careful on how you discuss and say, like, we are pro family building, you know, and what we're doing is helping people access to building their families.

But if you give them too much information, then they kind of take it and run with it. And then they're like, oh, well, that we just have to shut down IVF altogether, because you're murdering children, which we know is absolutely not what is happening. But that's unfortunately how it's perceived.

So it's a fine line that you walk and you have to approach it very delicately. And it's a very tough scenario. One of my partners who he just the way he phrases things in the worst thing is just so intelligent and delicate that he he's kind of our liaison.

And he'll go like Carl Hansen, I'm sure you guys heard of him or know him. And he'll go to the Capitol and talk with these individuals. And it's usually very fruitful conversation and leaves with positive outcomes.

But it's it's tough. It's tough to approach both sides of things. Like you said, Blake, I think this is a podcast episode in and of itself.

And I'm sure there will be more forums to kind of continue this discussion. But kudos to these non REI authors, including a resident publishing something in FNS, to really call attention to this important issue that affects all of us, but also their patients who they receive on the other end who are pregnant. We're going to keep moving along, we're going to move away from consider this and we're going to go over to FNS reviews this month.

Blake, tell us a little bit about your article. Thank you, Pietro. So I'm going to discuss a important, very common topic of adenomyosis.

The title of this article is prevalence of adenomyosis in symptomatic adolescents and young women, a systematic review and meta analysis by first author Paolo Vercellini and senior author Edgardo Somigliana from Milano, Italy. I'm so sorry, I probably said that wrong. You offended me.

I know. I know. I should have had you say it.

I'm sure it would have sounded very eloquent, but I digress. So some background on this over the about the last couple of decades, we've witnessed a transition and increasing in focus of adenomyosis for a non-invasive diagnostic modality. So pelvic ultrasound and MRI, they've been shown to be highly reliable actually in techniques for detecting adenomyosis rather than doing a hysterectomy than having the pathology come back and saying adenomyosis.

So additionally, adenomyosis has been considered diagnosis among Paris women or women who've had children, women in their 40s, for example, but rarely if at all exist in young women and or adolescents. Many adolescents and young women experienced dysmenorrhea or painful periods, which is a condition that is often trivialized or overlooked, but can cause substantial deterioration in health related quality of life. So as fertility physicians or fertility providers, we can appreciate how challenging of a diagnosis that this can be as it relates to outcomes with fertility treatments.

So therefore, these authors conducted a systematic review and met to investigate the overall prevalence of symptomatic individuals that have had either ultrasound and or MRI diagnosed adenomyosis and patients that are aged 12 to 25 years. Looking at the methods, they looked at data published as far back 2015 up to 2024. The main outcome was prevalence of adenomyosis among symptomatic adolescents, which they say is midpoint of the study range or less than 20 years, and young women is the other category.

So midpoint of the study age range greater than or equal to 20 years. They ultimately looked at three meta-analyses that were included, categorized by age, and performed to pool adenomyosis prevalence data from selected studies. They included observational studies, cross-sectional cohort studies that assessed and defined the number of patients with the diagnosis of adeno as the numerator in a study population of adolescents and young women undergoing pelvic evaluation by ultrasound or MRI, primarily for dysmenorrhea as their symptom.

So that's the denominator. So numerator is patients with diagnosis of adeno. Denominator is women who've had ultrasound or MRI as dysmenorrhea.

For dysmenorrhea. The risk of endometriosis in women with and without adenomyosis was also ultimately assessed as an exploratory and confirmatory investigation by combining the odds ratio estimates from each study using a random effects model. So looking at the results, and I misspoke early, so they said ultimately six studies were included comprising of about 1300 individuals that met inclusion criteria.

They found that the prevalence of adenomyosis ranged anywhere from about six to 46% with a weighted mean of about 21%. But of note, they did say that there was a very high heterogeneity amongst the studies. So nearly a 95% heterogeneity or I squared score.

The generalizability of the findings is limited. Only six studies were selected, five of which were from a single country, recruited predominantly white participants. So that's why the authors say that a lot of heterogeneity and generalizability is difficult to discern from this.

They noted a trend but was not statistically significant towards an increase in adenomyosis prevalence with increasing age observed. The estimates were about 17% in adolescence and about 30% in young women. They also found that the risk of endometriosis in patients with adenomyosis was significantly higher than that in patients without adenomyosis.

So a strong correlation there. That had a pooled odds ratio of 3.4 and this without a statistically significant heterogeneity across studies. So in conclusion, on the basis of the results of the available prevalence studies, the authors say that approximately one in five adolescents and young women complaining of severe dysmenorrhea had either ultrasound or MRI diagnosis of adenomyosis.

Pretty high number. The authors also state that the findings of this review should mandate a, so they have a strong stance on this, they feel like this should mandate a systemic in-depth evaluation of all adolescents and young women with otherwise defined primary dysmenorrhea. So these young patients that present with primary dysmenorrhea, they strongly feel that this should trigger a systemic in-depth evaluation of all adolescents.

So I think what's important to take away from these data are that this review should assist clinicians in developing a high index of suspicion for adenomyosis when adolescents and or young women present with chronic or just have severe dysmenorrhea, also menorrhagia accompanying with that too, or either or. And this could limit the diagnostic delay in considering primary prevention, such like medical interventions, suppression, OCPs, for example, GnRH agonists or antagonists, and this may improve their quality of life and also the limit, it will limit the risk of disease progression, and as we know, fertility issues down the road too. So I'll leave it at that.

As always, I always make a plug, I want the listeners to go back and take a look at these studies. These review articles are always very thorough and in-depth, quite a few references, but there's a lot of information to delve into and look at. But Daylon, what do you think? I know, obviously, on the clinical side of things is where we see adenomyosis often.

You probably don't see it in your lab very often, but what do you take of these data? Well, yeah, I mean, I guess I could provide my lay curiosity and ask you in terms of what the impact and scope is, because whenever I see these meta-analyses, and it seems like a strong, a pretty definitive recommendation at the end of this, after synthesizing all these studies. So a few questions occur to me. One, first and foremost here, is like, what is the downside here, right? Like a number needed to treat or whatever.

I guess they made a case that there's a lot of downstream, you know, quality of life and pathological sequelae that are real. But like, what is the impact of that definitive diagnosis there? What do you have to do? We're talking about a bunch of scans. Yeah.

So do you have to do hysteroscopy? Like, yeah, what is the degree to which you got to go in there to really get a clear diagnosis? Right. So depending on the findings of, you know, ultrasound, obviously would be cheaper and probably easier to obtain rather than MRI. But it's expense is probably going to be the biggest thing.

For an MRI, you got to schedule an appointment and the cost associated with that out of pocket expense, possibly depending on your insurance. But that's probably the biggest thing is, is the expense associated with that. So, but you could also argue to on the other side of things.

So getting this up front, having a presumed diagnosis of adenomyosis with imaging, whether it be ultrasound and or MRI. Downstream, you think about all the possible surgeries this patient could avoid, all the fertility treatments they could avoid. So when you look at it as in that way, then you potentially could be even saving a lot too.

But not to mention too, just helping their quality of life along the way. And these patients too, they present and have severe dyspnoea and you scan them after years and years of having symptoms like this. And they're just all, they have a bunch of cysts or endometriomas or their uterus is asymmetrical and pregnancy rates are a lot lower if they have adenomyosis.

So it's more preventative is the main thing. Well, looking at the numbers, I mean, yeah, it's a big range there. Right.

46%. So I trust them on the average of 20%. And so one in five.

And as you're describing what the reality is downstream, it's just, you know, you got kids, I got kids. I think it's increasingly clear to me that there's certain facets of medication, let's say, to take, for example, like ADHD medication, which is just like hair trigger prescribed. And, you know, when you put that next to this, in terms of a strong recommendation, because I think the unintended consequences of overtreatment is a real thing in the modern era.

But of course, as you described, the consequences of not recognizing and perhaps the impact of that prophylactic either, you know, confirmation diagnosis or care, I think that this for me, Blake, as a clinical naif, it's made its case, I'm on board. And I'm a real cynic when it comes to medical intervention. I think Dr. Vercellini... There you go, that sounds better.

Maybe better than you, but I don't think Pietro's gonna let me get away with that one. But the esteemed doctors as a part of this group have made their case. I'm buying this one.

Yeah. Yeah. And Pietro had to step away for a minute to do a procedure.

But as someone, he operates often too. So I'm interested in his take on this. But this is something, adenomyosis is really challenging.

I can count on the times with one hand that I've actually tried to take on an adenomyoma and resect it. And I didn't feel great about any of them. I mean, it's so bloody.

And I always think this patient just needs a hysterectomy. But could that point be prevented and avoided to get into those surgeries where they're in that scenario? And so that's the case that they're wanting to build with this in terms of a number needed to treat would be hard to conclude with such a high heterogeneity in this study too. But even saying one in five, that the prevalence of it being so common, rather than dismissing these young girls or these adolescents who have just really, really painful primary dysmenorrhea and or menorrhagia, because oftentimes, it's just dismissed as what these authors discuss too, which is so common, like, I just started your periods.

Yeah, that's normal. I have really painful periods. But are we just dismissing a potentially very significant medical condition that we could at least temper the flames and keep it from progressing so severe later in life? So no, that's real.

When you bring it down to that, the granular level of the patient and like, you know, the psychosocial, psychological element, it's real. Last question. Yeah.

How do you design like a trial to see whether or not the payoff is there for this? Or is it obvious just based on the retrospective analysis of the numbers? No, I mean, I feel like I'm taking oral boards now, Daylon. Design a trial. Yeah, so I think... I guess better question.

Could you do a trial? Or do you think this justifies a trial if one is doable? Yeah, I mean, I think that as the authors point out, the generalizability is it needs to be expanded. You know, this is very focal and a lot of from the same country. So getting more studies even for different areas of the world or having larger numbers, I think, would be more helpful.

And I suspect you would probably find similar outcomes if you did that. Of course, it's going to be a little trickier to design a randomized controlled study. But yeah, in this scenario, I think the more, like all things we discussed, more data, the better, bigger numbers, oftentimes the better.

But I think making it more generalizable and having more studies from different areas of the world would be helpful. All right. Well, you passed, buddy.

Welcome. Thank God. There we go.

Coming from a clinical idiot, I'm sure my approval has real value. While Pietro Bortoletto finishes his whatever, his proceduring over there, I'm going to take the helm and finish up with the story. It's about PCOS.

I mean, you talk about high prevalence. You were up there in range of 46%, which may be a bit high. But PCOS has a similarly wide range.

I actually had a conversation about PCOS with my mom. Awkward, you might think, but it wasn't at all. She's 77 on her second knee replacement and still seeing patients in an urgent care.

And the pith of that conversation was that she was seeing a lot of patients who were surprised over the last few years to find out that they were diagnosed with PCOS upon changing primary care physicians. They're like, did I suddenly get PCOS? No. The diagnostic criteria changed or your clinician or primary care physician, they had a different view.

And so that's why the chart changes, what she's explaining to all of them. But she's asking me, why is this such a moving target? But it's totally consistent with this highly variable estimate that I alluded to of reproductive age women that have PCOS that's ranging roughly from 5 to 20%. And also the moving target that forms the basis of diagnosis, which is currently presentation of two out of three features defining the Rotterdam Rotterdam criteria, which are one, oligoannulation, two, hyperandrogenism, and it's in the name, three, polycystic ovaries.

So Blake, I'll ask you, what proportion of your patients would you say offhand have PCOS roughly? And what kind of range do you see in those patients? Is it all over the map or is there a pretty prominent presentation with a few kind of outliers? I'd say, I mean, so this is the quoted as even the most common endocrine disorder, that's about one in 10 women have it. I'd say that's, you know, of course, in a fertility clinic, we're going to see probably more than that because these patients are referred to us. So our prevalence is going to be a lot higher in our clinic, but this is so, so common.

And similar to the last topic of adenomyosis and how it's oftentimes dismissed, this is also very common. And I see this all the time in which patients are actually misdiagnosed, or they see me and they say, I was told I had PCOS, but this is based off of maybe an ER visit where they had cysts on their ovaries is commonly what we hear. Like that's not actually PCOS.

Or their primary care provider had told them they had PCOS because they have irregular periods. And that's it. They don't do any ultrasounds, no lab evaluation.

They just say, oh, you have PCOS because your cycles are irregular, or maybe they have a little bit of hirsutism. So this is also something that I feel like is very, very, very commonly dismissed. And when they come and see us in our clinic, they actually haven't even been evaluated properly at all.

So we kind of have to start from square one. And there's, it's not uncommon to say, actually, I don't think you have PCOS or yeah, I do, you know, we have confirmed the diagnosis. So this is very, very, very common though.

Well, so yeah, I mean, as convoluted as you describe it, but also complex, genuinely complex as the diagnosis is, the etiology and the passive physiological sequelae of disease are even more inscrutable. So just talking about the health impacts, you were including metabolic syndrome, cardiovascular disease, endometrial cancer. And speaking of like the etiology, there's theories as to causes that include either, you know, genetic inheritance, prenatal androgen exposure, or like other epigenetic mechanisms, and as well as diet, right? And that last diet is the wrinkle that's so hard to put into context in our modern culture.

You look at half the problems with our health, more probably it goes back to diet. Because, you know, more than half the population is overweight or obese, and that number's only increasing. And the Western diet, as it's called, is so deeply embedded in every health metric, as I stated, it's all really much of it stems back to our dietary choices and our environmental exposures.

So you combine that with the range of symptoms in PCOS patients that manifest to widely varying degrees, as you described, sometimes there's a little hair stism, sometimes there's a cyst on the ovary that's misdiagnosed. But even in patients that where you confirm diagnosis, the range, as I'm sure you will attest, can be highly variable. And so it can be hard to make sense of the clinical data out there.

You know, you have, as you said, one in 10 women, but how do you get your arms around them and make sense of anything, the cause, the effect, anything? It's tough. There have been some findings, but it's still very elusive. So I was delighted to read a pre-proof of an article that was accepted into FNS Science from John Hennebold's group, who's at the Oregon National Primate Research Center.

And they leveraged macaques, which is what they do there, to study the combined effect here of hyperandrogenism and the Western diet on ovarian function. Now, this isn't the first study of its kind. Previous work has demonstrated in the same model macaques that were given PCOS level androgens and Western diet before here prematurely, before menarche.

It was lasting three years, 36 months that they were treated with these androgens and Western diet. And they showed, you know, as you might expect, metabolic derangements and ovarian dysfunction. And also, if you treat adult females, so postmenarchal female macaques with that same treatment for one year, so short term, you get a significant, noticeable, measurable impact on metabolic values, body fat composition, etc.

This study from the Hennebold group was looking at a very specific question of arguably greater immediacy. And that is, does this high androgen Western diet combination, does it affect ovarian function over shorter timescales? In this case, just one year. And what they found is that there were changes, even on this short timescale.

Like previous studies, they showed that luteal progesterone was decreased in the treatment group, as well as VEGF-A, cortisol to cortisone ratio, and testosterone and progesterone in follicular fluid, all those values in follicular fluid, were increased in animals that were hyper-stimulated. Oh, and enlarged cystic follicles that are reminiscent of polycystic ovaries. Now, this has been a bit of a lightning rod in terms of like, the anatomical morphology of ovaries, being reminiscent of polycystic ovaries, and that being like a true validation a la Rotterdam criteria is a hot debate around that.

I was in study section at NIH just a few months ago, where that was a very spirited debate. It was a lot of fun, but it was a spirited debate, the most spirited debate of the day, I would argue. But like... And this was about what? The spirited debate about what? About whether or not the animal models of PCOS are valid or not.

More specifically, there's a model of like hyper-masculinization, or, you know, androgen exposure in utero in sheeps, and I'm not going to name names, but it was a fun debate, I would argue. Yeah, well, you obviously can't evaluate heresitism in these animals. Well, not... Yes, so you're too late for that.

But really, the question there was that it's iatrogenic levels. This is a presentation of androgens that doesn't occur in utero, right? So that was the idea here. And in this case, not so much, right? They were really... took careful measures to get the levels of androgens that are present in these PCOS women.

So I think clinically relevant values. And that's the thing for me, that was the real takeaway, is that the model, I'm really bullish on the model, because one of the toughest things about understanding PCOS is the lack of model systems, hence the sheep model, where you hyper testosterone and, you know, it doesn't really exist. But you do what you can with what you have, right? Because there's not a lot of model systems that enable experimental examination.

And this one may be cumbersome, right? With a macaque, but like, you know, you do the best you can with what you have. We published a paper a few years back in Science Advances that use human ovarian xenografts, which we had to carry for like six months, and then present with super physiological AMH, all to model the milieu of polycystic ovaries, focus there on AMH. But here, I think is, you know, humbly, I will say, well, maybe not so humbly, this, this story is a lot better, because it's in macaques, right? It's in a model, it's physiological on a cycling animal, physiological values are pathophysiological values, at least of androgens and Western diet as the backdrop.

So I really loved this story. And, you know, I loved that the intersection of cause and effect, like we found in our story in Science Advances, which wasn't as good, I'll say, but similarly found that the cause and effect in this disease is like this truly kaleidoscopic intersection, right? And finally, I would say that the emphasis on the shorter timescale here, to me, is really encouraging. Because if you can induce something over such a short timescale, I have a feeling like my intuition says, maybe you can reverse it.

And I would, I would bet that there is some early clinical evidence that supports that idea, you know, with in terms of modulating diet and exercises, I think in maybe some, one, a few cross sections, perhaps, of this patient cohort, I feel like the reversibility, this is a validation of the possibility of reversal. So I don't know, I love bringing monkeys to the table for you guys, because I'm usually talking about mice, and you guys are all rolling your eyes, but you got to wake up for a monkey, right, Blake? Yeah, and this is a real treat, I will say. So what, do they go into specifics of what, what do they define as a Western style diet? They do, they do go into the details.

I mean, think McDonald's. This is a reference to you guys, listen, get a fast food, because I'll tell you, you'll read it, and you'll be like, man, I probably have PCOS, I was thinking I might be kicking off a little PCOS in a minute, the way I've been modulating my diet to the negative here, but... I've wondered. It's a good question.

But I don't have to worry about the androgens, that's the thing, very low T over here, Blake, so I think... Okay, all right. I'm sorry to hear that. Well, yeah, so I, I think that that's, I mean, this is helpful too, in terms of patients always want to know what's, what can I do? What are things additional that I can do to help myself? And so being able to discuss things like this, and if diet certainly was playing a role in the etiology of PCOS, and great, modify this and reduce this in your diet.

And this can help in terms of ovulation or response to medications. I think this is just another piece of artillery to have in terms of discussion with the patients, for sure. So a nice shift to have monkeys and not mice, though.

It's great. Yes, I try to bring at least a primate. If I can't get me a study in humans from FNS Science, I'll try and bring a primate.

Yeah, I appreciate that. Yeah, well, I do the best I can with the iPad, Blake. We're all just trying to survive out here.

Well, although we had a bit of a skeletonized crew, we're missing Molly and Pietro ditched us midway through to go do an important procedure. But we are nonetheless happy to at least get you all some content. If you all ever have any comments, criticisms, suggestions, we'd be more than happy to hear them.

And we're always looking to improve and we appreciate you all listening. Hopefully we'll have back the whole crew and the upcoming podcast. And I'll put in just a plug too, we just recently had an FNS Reviews Journal Club Global and had an enriching discussion on endometritis in the setting of recurrent pregnancy loss.

So I would encourage you all to check that out. It should soon be uploaded to our firststert.org website. So until next time, see you all later.

Thanks for listening. 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 and 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.