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.
Hello, and welcome to another episode of F&S Unplugged. I'm your host for now, Pietro Bortoletto, and I'm joined by Daylon, Molly, and Blake. Hey guys! What's up? How are you? Pietro, you'll always be here, buddy.
You'll always be in our hearts. Yes. Tarzan reference, Phil Collins, or? Whoa.
Cue the music. I think just Daylon's feelings. I don't think he was clearly referencing Tarzan.
Phil Collins, he took that from me, my brother. Yeah. Bet he did.
Guys, it's delightful to be back together. As I was glancing through today's articles, I have to tell you, we went heavy on the syndromes, eponymous syndromes. We got Turners, we got She-Hands, and we got Endo in the little basic science, so maybe just two out of four.
But we got some fun articles today. I'm excited to dig into them with you. We don't usually start with reviews, but the review article this month is by a couple of friends, Seth Barashansky, Kara Goldman, the Yale Northwestern team coming in strong, and first author from Daylon's Neck of the Woods, Allison Dennis from NYU.
Blake, tell us a little bit more about what we need to know about Turner syndrome and for Prez. I will. Thank you for that introduction.
And since we are talking about New York, I want to just take a moment and say thank you to the next— Go Nicks. Go Nicks. —for beating the Spurs.
Every single person in the state of Oklahoma thanks you. Last time we did a podcast, I was going to Game 7 with my younger son of the Western Conference Finals only to see them lose. And it was a very sad time, but it's okay.
I've recovered and healed, and I really enjoyed watching the Nicks win. So congratulations to the Nicks. I accept those congratulations, Blake.
Thank you very much for saying so. And if it's any consolation, which for me it would not be— You aren't a Nicks fan? Get out of here, bro. If OKC had, you know, had not succumbed, I should say, then they definitely would have beat the Nicks.
So I should be thanking you, partner. Yeah. Yeah.
Well, a healthy OKC team. We had some injuries. But anyways, I could talk about this for the entirety of this podcast, but I won't.
I just wanted to say congrats, Nicks, since we are talking a lot about New York. So I'm going to discuss the title of this article is Fertility Preservation in Turner Syndrome, an updated systematic review. And PHR has already kindly mentioned the authors of this article.
But first author is Allison Dennis out of NYU. So in this systematic review, they wanted to dive in fertility preservation options in individuals with Turner syndrome, which affects approximately one in about 2,000 to 2,500 females and is characterized by, as we know, complete or partial loss of an X chromosome. So this earlier diagnosis is becoming more prevalent through advanced genetic testing and therefore fertility preservation counseling has become increasingly important.
And so why this matters is so one of the hallmark features of Turner syndrome is accelerated ovarian follicle loss leading to premature ovarian insufficiency. Ovarian development appears normal early in fetal life, but there is significant oocyte depletion that occurs around 18 weeks approximately of gestation. And then by birth, most of the individuals with Turner syndrome have little to no detectable germ cells, or very few.
And so clinically only about 30% of patients experience spontaneous breast development or theolarchy, and about 15% achieve spontaneous menarche before rapid progression to ovarian insufficiency. And so as a result, natural conception is not common in these patients, and many experience significant emotional distress, as you can imagine, with regards to their future fertility. And so the authors do talk about mosaicism as well, which is a major theme of this review is the distinction between classic 45X Turner syndrome and mosaic Turner syndrome, in which there's some of the normal cells, some abnormal cells, or that are euploid in the cells as well.
Patients with mosaicism do retain a higher likelihood of having ovarian function, spontaneous puberty, residual follicular activity as well. Multiple studies demonstrate that fertility preservation success is much higher in patients with this cell line, which is why making an accurate karyotype assessment is very important. So the authors then talk about and shift gears to oocyte cryopreservation.
So the most established fertility preservation strategy is oocyte cryopreservation. The authors highlight recent studies that consistently demonstrate that egg freezing is feasible, particularly in adolescents and young adolescents with mosaic Turner syndrome who actually have or have maintained ovarian function. And of course, success rates correlate with markers such as their follicle count or ovarian assessment, AMH, FSH, estradiol.
And several important findings emerge from this review. So in these patients, multiple stimuli... Actually, let me pause there. Do you guys have patients with Turners? Do your clinics allow them to carry? That's a good question.
I have never had a patient where they have a diagnosis of Turners and are interested in carrying, and that may be a bit regional where they're so plugged into their specialty clinic down the street at Boston Children's, they've been counseled for forever that they shouldn't carry, so it doesn't even come up. Right. I've managed one or two gestational carrier cycles for Turner syndrome patients who want others to carry on their behalf.
What about you, Molly and Blake? Yeah, at our two sites, one we would allow and the other we would not allow. And then mosaic is more of a case by case depending on other comorbidities. Yeah, that's mainly the same here.
I mean, we've had some patients that will undergo all the appropriate counseling with cardiology, MFM, and still decide they want to carry or use an egg donor. We've made rare exceptions, but just in general, we're similar at our facility. So a lot of what I'm going to discuss in this article is contingent on the fact that can you have them carry or does your clinic allow them to carry based off of the medical risk with aortic dissection, for example, is the most important bugaboo.
So the authors discussed several important findings in the reviews. So patients oftentimes need multiple stimulation cycles necessary to obtain an adequate number of oocytes because their pool is very depleted. Patients with Turner syndrome may require more frozen oocytes than the general population because higher miscarriage rates, increased rates of chromosomal abnormalities because of Turner syndrome.
And as implied earlier or discussed earlier, most successful cases occurred in patients who have mosaic Turner syndrome. And one particular notable milestone is around 2023, the first live birth from a previous cryopreserved oocytes in a patient with mosaic Turner syndrome was reported. So I found that interesting that that was not very long ago at all.
Apparently that was the first case reported. The patient ultimately delivered a healthy term infant following thawing fertilization, embryo biopsy, and then doing an embryo transfer. The review also highlights a remarkable case of successful oocyte cryopreservation in a prepubertal six-year-old girl with mosaic Turner syndrome, which suggesting future expansion of fertility preservation options and these younger patients.
So which segues into the next section of the review. Ovarian tissue cryo was a major strategy discussed for these patients as well. And this can be particularly valuable in prepubertal girls who are not candidates for egg freezing.
Key findings in this section of the review are that follicles are far more likely to be identified in patients with mosaic. We've already discussed that. And then, of course, it correlates with the ovarian reserve levels as well.
Large prospective studies have shown that about a quarter of patients to one-third of patients undergoing tissue cryopreservation had detectable follicles in their preserved tissue. And so although tissue cryopreservation has resulted in several pregnancies in cancer survivors, evidence in Turner syndrome is still quite limited. And the authors discuss that there's one reported case of ovarian tissue re-transplantation in a Turner syndrome patient that has led to conception thus far.
And unfortunately, that pregnancy ended in a miscarriage. Then, of course, pregnancy risk. An important reminder that this review is that fertility preservation does not automatically mean that pregnancy is advisable.
So a lot of clinics are going to be different. Some are just a hard no, cannot have these patients get pregnant. Although some may do a case-by-case exception, as we discussed.
Individuals with Turner syndrome often have significant cardiovascular abnormalities. So that's the big concern, right? And even in a setting of a normal workup, they still can have a really high risk of a cardiovascular event happening. So pregnancy-related mortality has been estimated to be about 100 times higher than the general population.
So not a number that sits well with most clinics. So therefore, a very comprehensive cardiovascular evaluation is critical before pursuing pregnancy. And in some cases, of course, as we mentioned too, gestational carrier is advised.
So the last couple sections of this is that the authors, they devote significant attention to fertility preservation. Candidates are maybe adolescents raising questions about informed consent, autonomy, long-term decision-making. They highlight that key ethical concerns regarding this is that there's limited data regarding actual live birth outcomes.
It's difficult to predict who will actually benefit from FertPrez, potential psychological harm when patients learn they have no remaining follicles, and then balancing parental decision-making with adolescent autonomy as well. So clinical takeaways from this article. So discuss fertility preservation as early as possible after diagnosing.
Assess their ovarian reserve markers. Get a detailed karyotype analysis. Consider egg freezing as the preferred option when ovarian function is present, because as we discussed, the follicle pool depletes quite rapidly in these patients.
Consider tissue cryopreservation for prepubertal girls. And then a multidisciplinary approach is crucial when considering pregnancy for these patients. So bottom line, fertility preservation and Mosaic-Turner syndrome is rapidly evolving.
Egg freezing currently has the strongest evidence base, particularly in patients with Mosaic-Turner syndrome. And tissue cryo offers hope for these younger patients who may not have undergone puberty yet. So a nice thorough review.
These patients, we certainly see very commonly. Actually, as very interestingly, I had in my inbox a Mosaic-Turner karyotype. Literally as I was going through the articles to send to you guys, I just saw that result come into my inbox.
And I was like, I need to call this patient. And then I saw this article pop up and I was like, I'm going to do this one for this month. So nonetheless, certainly see this in our clinic.
And I think it's a really nice highlight of the syndrome. Any thoughts you guys had? I agree. It's something we encounter pretty commonly in our practice and is a frequent discussion.
And depending how diminished ovarian reserve they are, if they're able to still freeze eggs, it's a really nuanced discussion about how many cycles they might need, aneuploidy in the embryos and all of that. So thank you for sharing it, Blake. Blake, any thoughts about how much pre-anesthesia clearance or assessment these patients might warrant before they undergo an egg retrieval cycle in an outpatient setting? I'm now practicing in a private practice community setting.
And when you are doing egg retrievals at Cornell in the inpatient side with all the bells and whistles, there's a certain layer of safety. But do you think all these patients need an echo? They need clearance from a cardiologist? Or is that overkill for this group? I mean, I think it's not a bad idea. It's a lot of testing.
And many of these patients are going to have, even like mosaic Turner syndrome, they still could have possibly the same risk. Although I know that's not as clear. But I feel like undergoing an evaluation is still going to be crucial and just cross all your t's and dot your i's, just knowing that there is that risk.
I personally feel that they do. Do you feel otherwise and feel that if a healthy individual, do they need to undergo all the echo, cardiology, pre-anesthesia assessment? I think it would be a good idea. I'm in a funny practice environment that I have all the bells and whistles of Boston academia in my backyard.
So most of these patients are already coming to us, diagnosed, worked up, and have all of this info. It's pretty rare, I think, for us to be making the primary diagnosis of Turners when they're coming to us for the first time, but not unheard of. Mosaic, probably a little bit more common in those severe early DOR patients.
I don't think you're ever wrong by airing conservative and making sure that they're appropriate for care in a slightly less resourced setting, like an outpatient retrieval area. And do your practices treat mosaic Turners the same as Turners? If they're going to carry, if they still have ovarian function and they're going to consider carrying, do your practices still allow that after undergoing a multidisciplinary approach? We haven't had one yet, but I think in the appropriately counseled patient with the right supportive obstetric environment, it's not unreasonable at all. I like the kind of pre-evaluation as well, because it may help with counseling about gestational care versus not, and talking about, hey, we should probably get like FDA labs and exam done when we're starting your egg freezing cycle to keep the doors open that you can use a gestational carrier in the future.
And sometimes I think it becomes part of that conversation to have them see MFM when you're talking about egg freezing. Yeah, good thoughts. All right.
Thanks, Blake. And thanks to the authors, a killer group of people. Molly, we're going to stick with the eponyms.
Tell us a unusual case of not a little delayed, but almost teenager age delayed condition of Sheehan syndrome. Yeah, her child was probably graduating high school when she had the diagnosis. Make us a believer.
Yeah. This is a case of a delayed diagnosis and treatment of Sheehan syndrome, a case report by first author Sarah Vargo and last author David Chia from UCSF. So it seems like every test in medical school had Sheehan syndrome on it.
So we're all pretty familiar, but just to review, Sheehan syndrome is a luckily pretty rare complication of a postpartum hemorrhage after delivery. To review the pathophysiology, the pituitary gland enlarges during pregnancy. And so it's especially vulnerable if there is an ischemic event related to massive blood loss and hypotension after delivery.
And usually the anterior pituitary is what's most affected, but the posterior pituitary can also, wow, that's a, that's a tricky one. Posterior pituitary can also be affected. And growth hormone prolactin and gonadotropins are really the most likely hormonal deficiencies that we'll see occurring.
The really classic test question in medical school was, okay, she delivered, she had this hemorrhage, her milk doesn't come in. And then some signs of adrenal crisis develop or what testing do you get next? And I think that's how we're all familiar with it. But, you know, based on this case and based on some prior case reports as well, it's also possible to present many, many years after delivery with pretty nonspecific symptoms like fatigue and weakness.
And this case is one of those. So this story is a 45-year-old who'd had one prior vaginal delivery. She presented to the emergency room with lightheadedness, nausea, and vomiting that had been preceded for about three days by sore throat and cough.
So maybe a viral illness. And she reported 17 years of weakness, pallor, decreased appetite, brain fog. And at age 28, so about 17 years before, she'd had a vaginal delivery complicated by a three-liter hemorrhage due to retained placenta.
And postpartum, she had agalactia, so her milk didn't come in and she had amenorrhea. Now, how many times did someone's milk not come in or not come in robustly after delivery? And we say, oh, it's just because of the hemorrhage. She's hypovolemic.
And so I think keeping our minds open here is important. Interestingly, for a few years, she was able to use either progestins or traditional Chinese medicines to induce menses, but this stopped working around age 31. And after that, she sadly did desire pregnancy, but never had a fertility evaluation or treatment, potentially due to some lack of access to care.
So in the emergency room, back to how she's presenting, she was hyponatremic at 115. She had prolonged PR and QT intervals, and she had low blood sugar. She had an undetectable serum cortisol, a low ACTH at 1.9 picograms per milliliter, and undetectable thyroxin with a technically normal TSH at 1.78. So they diagnosed her with central adrenal insufficiency and hypothyroidism that was concerning for panhypopituitarism.
She got IV hydrocortisone and resolved pretty quickly. They waited until day two to initiate levothyroxine treatment because treating your thyroid first can then worsen your cortisol deficiency by increasing metabolism. That's just a point for the fellows.
Pay attention for your boards. And she got D5, she got desmopressin, and her sodium slowly recovered. They did an MRI that showed empty cella, reduced pituitary volume, and a mild leftward deviation of the pituitary stock.
And then they did further workup and found undetectable IGF-1, estradiol undetectable, undetectable LH, and then super low prolactin at 1.2 and FSH of 2. So she was discharged from the hospital with ongoing hydrocortisone and levothyroxine management through endocrinology. And then the, I assume, REI or OBGYN team initiated OCPs, but she actually had not had withdrawal bleeding by like eight months out. And they did get a DEXA scan, which was great.
And that was unfortunately consistent with osteopenia. So I think the lesson from this case, it's a pretty simple one. I think REIs probably are not going to miss this diagnosis in the like postpartum period.
And I think the endocrinologist consulted to see this patient in the emergency room are not going to miss this diagnosis. And I think a basic oligo or amenorrhea workup at some point would have picked this up, I would hope, but I think there's ways that it could have been missed all these years, even if she had walked into a clinic and had a fertility workup sooner. So for example, at OHSU, our lab automatically orders TSH with reflex to free T4.
It doesn't automatically order a free T4. And so I always tell my fellows, if you're worried about a central cause of hypothyroidism, you got to make sure you're getting that T4 because your TSH may be falsely normal looking where this is 1.8. I mean, it's actually still hypothyroid. It's not responding well.
Her FSH was a little low. I mean, it was two, but I could see someone in the community saying, okay, it's not undetectable and not checking an LH, right? A lot of us aren't checking LHS routinely if we're not worried. So again, emphasize that the OBGYNs we're training in our clinics, as well as our fellows, make sure you're getting an LH if you're worried about that central cause to be a little bit more thorough.
And then I could see her going to an OBGYN and someone saying, well, we'll just start some birth control pills and really not having an answer because a lot of these symptoms were pretty vague that she was experiencing. You could imagine someone saying, it's postpartum period. It's being a new mom.
It's, yeah, it is this hormonal deficiency, but not really looking at all the other pieces. And I have to admit when I first see a patient with amenorrhea after postpartum hemorrhage with a DNC, for example, I'm really thinking Asherman's first before my brain bumps to Sheehan syndrome. But this may be more common than we're realizing and really could have been quite catastrophic for this patient.
I mean, it was catastrophic, but I'm glad that she landed in the emergency room when she did when her sodium was already down to 115. Something that was really interesting that came up in the discussion for this case report that was I think new for me, I don't think I'd heard this before, was that you can have a progressive hypopituitarism secondary to an autoimmune response to the necrotic pituitary tissue. And although it's not totally established in the literature, you actually can check pituitary antibody testing to assess for this.
So I do have a case in my clinic where I was kind of suspicious. She's had, she had a postpartum hemorrhage and then she did have menses for a few years, and then the menses stopped, a lot of other big symptoms. And I'm starting the Sheehan workup now, but it felt a little far-fetched because I said, well, she was having cycles for a year or two.
And now that I know this extra piece about the autoimmune more progressive piece of it, I think, yeah, that's not a totally worthless workup to do as well. And yeah, these really nonspecific symptoms, fatigue, weakness, anorexia, I think could easily be chalked up to something else. And so it's on us to make sure that in our own clinics, we're evaluating them and we're really training our trainees who are potentially going to family medicine, OBGYN, and then our REI fellows to keep their spidey sense on for this.
Have you guys seen much Sheehan syndrome in your practice? Was any of this new to you? In Boston, I see a lot of patients with the last name Sheehan, but I have not myself taken care of a Sheehan syndrome in my patient population. Yeah, same here. But this is a really cool report and a really nice physiology review.
I think I have been inspired to turn this into a case presentation slash quiz for the fellows. So if my fellows are listening, then pretend it is. Plan accordingly.
Yeah, plan accordingly. It's coming. But very, very interesting.
That's pretty wild. So the logical next question, as we know that there's a lot of reasons why we've moved away from eponyms in the literature and in medicine more broadly. If you were to rename Sheehan syndrome, Molly, what would be the appropriate term for us to be using that kind of appropriately captures the condition? Oh, I mean, I think I'd just say panhypopituitarism or partial panhypopituitarism related to obstetric blood loss.
But is there another term out there? No, I think that's it. Describe what it is. We haven't totally done away with all of them in REI land, but this is a good example of probably a more descriptive way to describe it that does not acknowledge sometimes some problematic individuals in the past.
Not that Mr. or Mrs. Sheehan were problematic. I don't know that for effect. So it'll be called what? Pobble? Panhypopituitarism for obstetric blood loss or Pobble for short.
Yeah, I like that. Got a case of the Pobble. A very cute name for a not very cute condition.
All right, Daylon, you're not going unscathed today. You, for better or worse, do have to tell us about your favorite article in F&S Science that it just so happens that this article is talking about menstrual effluent, which I have long thought is a really wonderful way to learn a lot about the function of the uterus, but sometimes tricky, messy, culturally sometimes inappropriate way of ascertaining information. I love the title of the article, Flowing Differently, colon.
Tell us more. Yes, colon, the symbol, not the organ. Yeah, you know, speaking of syndromes and naming, this is an example of NewTech.
We're NewTech, and that's where I'm leading this, what I'm leading with. This is like NewTech meets old diagnostics. And I want to start with that, this idea of collecting menstrual blood as the diagnostic.
Do you guys know about this QVIN? Have you heard of it? It's this health tech company that uses menstrual blood as a quote, non-invasive alternative to lab blood tests. Good idea. And their flagship product is this QPAD that lets users collect diagnostic samples by wearing this modified pad that you then wear during your menstrual period.
And the pad has this embedded removable strip, this collection strip that then you take out of the pad, you mail it to a clinical lab, kind of like a Cologuard. Have any of you guys done Cologuard? I mean, the branding on this thing and the marketing, this menstrual thing probably wouldn't be the same issue, but I did it one time. And I have to say the worst part of the Cologuard is you got to walk down the street with a box that says Cologuard on it, and everybody is looking at you, and they know that you got a turd in that box, much less the UPS guy who sees you coming a mile away and puts on his medical gloves as soon as he sees you walking through the door.
But I digress. Definitely knows you haven't washed your hands. Definitely.
Why didn't you just put it in a tote bag, Daylon? Just put it in a little box? I'm not ashamed, all right? My colon needs attention for diagnostic purposes. Anyway, this Cologuard Coralit here, Cuvin, for the menstrual pad, it's been cleared by the FDA to measure and track health metrics like A1C, fertility hormones, obviously, but even like general wellness measures like anemia, makes sense, inflammation, pathological threats, looming, occult, like HPV, all that makes sense. So first, I'll say, what's your take? I mean, you hadn't heard about it, but it's in the vein of these new kind of, I don't want to call them wearables, but I see it as akin to this kind of constant monitoring.
Do you incorporate any of that? I mean, it fits, good alignment with ART. Do you have that as like integrated into common practice, the kind of real-time elements with your patients? And if so, what kind? I think probably where most of us intersect with this is the at-home menstrual tracking apps, number one, and then number two, the Inedo's, Mira's, Uva's of the world, where patients are peeing on a stick and getting usually some quantitative information on urine analytes. But I think there's more coming, and this is an example of what's coming down the pipeline, where patients are going to be increasingly empowered to collect information, but it's incumbent on us to figure out, is that information valuable? Does it change clinical practice? Is it accurate? But I think patients will drive this.
It's not actively being driven, I think, by clinicians. Absolutely, Pietro. And I would argue patients will drive it.
Marketing firms and big tech in BC is going to drive it too. But as you said, this is representative of this wave of health tech that's designed to either minimize discomfort, hassle, see Cologuard of diagnostic medicine, not embarrassment or shame, no minimizing that with the Cologuard. Come on, guys.
But all these methods to provide like real-time continuous monitoring, I think it's trending, right? For me, it feels like a kind of a gamification of healthcare, as you were alluding to there, driven by the customer and their kind of engagements with the process. In some cases, I wonder and maybe fear, I'm a bit cynical about whether we're sacrificing the diagnostic precision or validity in service of this clever, marketable tech. As you said, Pietro, is this information valuable? So the story I have from F&S Science for today, it's an effort to firm up the ground upon which this new wave tech is being built.
It's a tight cohort of 13 healthy women. But I think valuable in this study, Mustafa Barahi's group at Johns Hopkins performed a systematic comparison of menstrual effluent versus peripheral blood in this cohort of 13. They were looking at steroid hormone values, immune cell populations, paracrine signaling profiles.
What they found was significant. There were differences, including in the progesterone cortisol concentrations and perhaps not surprisingly, distinct immune cell profile and elevated cytokines in the menstrual effluent. So again, this is based on a relatively small cohort, but the key findings resonate with me nonetheless in two, I would say kind of opposing directions.
On the one hand, a modern medical practice, these diagnostic tools are so much more sophisticated and they integrate so many more analytes capable of looking deep into the matrix here to actually affect health outcomes in unexpected ways. But on the other hand, I'm looking at the ways that clever tech has tried to bypass the limitations of current practice and fallen short. I mean, obvious red letter example there being Theranos, but like generally speaking, the idea that seems to be trending of minimally invasive or non-invasive saliva, interstitial fluid, menstrual blood here for those diagnostics to replace or extend the reach of current methods.
It's a great idea, but I think here's a clear example where there's not a direct comp. And that's not what they were going for, by the way, but I think as a by-product of the study, we do have some ground truth on what the value of the analytes in menstrual blood or menstrual effluent are. So there you go, in part the answer to your question, Pietro, but cool too.
The tech that this will service, I think is the future, but I think we have to be very deliberate in that application. Molly is the only menstruating member of the podcast. I'm obliged to ask.
Had a while. The marine IUD is a godsend. Oh, bless you.
The question I have though is from a cultural acceptability, ease of collection. I know the Diva Cup has really taken off in modern era. Do you feel like most reproductive age women would feel comfortable with the idea of collecting fluid at home and sending it in? Is there a yuck factor there? What's your take? Not speaking for all women everywhere, but.
Yeah, I think you're totally right that there will be some cultural variation and individual variation, but on the whole, I think most women would be super comfortable with this. There's not much yuck for women around their own menstrual blood, based on my friends and patients, and people are very comfortable handling their own menstrual blood because they do it all day long. Now whether they're using tampons, pads, Diva Cups, all of that.
Yeah, and one of the other things to think about here is the partnerships of these tech companies that they're making with clinics and research labs to try and extend the utility. So while I would say the value is limited, I think we're going to reach a tipping point where we can get information by these non-invasive methods that maybe surpasses or provides another dimension to the existing diagnostics. Yeah, I mean, anything to help improve patient access and, you know, care to our patients and easability of diagnostics is always welcome.
So it'll be interesting to see where this goes. Speaking of which, just quick aside, you know they have this like at-home embryo incubator idea? InvoCell. InvoCell, yeah.
Where is that? Does that like have any traction or does that kind of fade off? It doesn't have a lot of legs, Daylon. I think some of it is yuck factor, some of it is it's a very narrow group of patients that would benefit from using it. Where I think it really adds a lot of value is actually in third party for the patients who want to have equal participation in the process of creating embryos.
One could provide eggs, the other one could culture them through that device. But it hasn't really gained lots of legs, I think, in our community. I don't know if Molly or Blake, it's different where you guys practice.
No difference here. And it's been a hot minute since I've looked into it and I don't want to digress too much. But if I recall, there's only a very certain amount of eggs you can incubate in there.
So what do you do with all the rest of them? And are you eliminating the whole purpose of having it? If you have all these other eggs that you have to fertilize outside or in the lab instead of InvoCell, then what's the point? So we don't use it. I don't want to digress either, but it's a good, I think, comp for how this kind of interface is changing, but maybe, you know, if it ain't broke. Well said.
I could go off about Anito. So maybe the next podcast, let's find an article about that. There we go.
All right, team. Let's come back to Consider This. I want to, as you guys know, Consider This is a multifaceted group of articles, and it could certainly be a Consider An Idea, this article, this thought I've had.
This is really an idea piece, and this is submitted to us by Taryn McFadden and Alavash Margita and Dr. Liu Qin coming to us from Hershey, Pennsylvania in the Yale School of Medicine. It's entitled Endometriosis as an Extracellular Vesicle-Mediated Communication Disorder, colon, Implications for Early Diagnosis in Adolescent Health. I, for one, really, really love articles that kind of challenge our understanding of a disease and open up a different way of thinking about diagnosis, but even just early intervention.
And let me share with you their core argument. So we've long treated endo as a lesion disease. You find the tissue, you remove it, you suppress it.
But this paper asks a simple but potentially uncomfortable question is, what if that's the whole story? The question really they ask is, if that's the whole story, why do so many patients have pain for years before a single lesion is ever found? And why do you see this persistent negative deleterious health outcomes even after thorough surgical excision? You see the persistent cardiovascular risk, autonomic dysfunction, oftentimes persistent pain in patients. These authors argue that the lesions are actually a late event. It's a downstream anatomical consequence of an environment that's already been reprogrammed.
And what do we think does the reprogramming? We don't know, but these authors are postulating that it might be extracellular vesicles, these tiny signaling particles shed by the endometrium with every cycle that carry a disease-specific cargo of often micro RNAs, but sometimes proteins that will quietly and over the passage of time remarkably remodel this peritoneal immune environment, sensitize pain pathways, condition the vasculature, all before there's anything to see with a laparoscope, and certainly before there's anything to see on imaging. Why this matters clinically for us is we all know that there's a big delay in endometriosis diagnosis. It's often seven to ten years, and in adolescence, it's arguably worse.
They have severe dysmenorrhea that gets normalized, their imaging is unremarkable, they're gas-lit, and the bar for them to have a surgical evaluation and treatment is really, really high. And this lesion-first framework essentially has no language for these patients, whereas this extracellular vesicle framework first does. This is the priming phase.
It's not a pre-disease phase, but it's where we're laying the groundwork for lesions that we'll see later on in this disease course. We think, these authors postulate, that puberty is this kind of very important biologic inflection point. We have cyclic estrogen exposure that ramps up, this increases vesicle release, and for the susceptible individual, this is often that second hit, and it starts accumulating early and silently for many, many years.
And by the time lesions appear in adulthood, the reprogramming is well underway, the train has left the station, and now we're kind of chasing our tails. And if we accept this framework, adolescent pelvic pain stops being a symptom to manage and becomes a signal to warrant early investigation. This is where we can use these non-invasive extracellular-based biomarkers, micro-inhibitory RNA panels as a potential diagnostic tool for us catching disease before it's anatomically established and found by our traditional methods of surgery or imaging.
The bottom line for this is that these lesions aren't the disease. This is what the disease looks like after years of preparation. And if we can identify potentially extracellular vesicles earlier in this critical window, it could allow for some risk stratification, for some early intervention, and even a new school of thought where we can intervene via extracellular vesicles rather than later via surgery or through hormone suppression.
It's a really cool idea. I think there's so much work that's being done in extracellular vesicle-mediated disease in male factor infertility right now in the UK, Scotland, Ireland. It'd be really cool to see how this extravesicle story plays out in endometriosis for these patients.
Daylon is the resident basic scientist. Extracellular vesicles, a thing? Is it something that we should all be hot and bothered about or is it one of these fads that comes and goes? It's not a fad. I think that the exosomes, as they call their extracellular vesicles, as they've been renamed, came into fashion when they were first discovered, like, I don't know, 20 years ago, maybe now.
And so it's not a new thing. I think that the enthusiasm around them has maybe dampened a bit because it's a really hard thing to get your arms around, right? So these things don't have nuclei, they don't replicate, they're difficult to track and identify what is within them, their generation, like how they're created. There's all these challenges, much less the idea of how they can be deployed, action at a distance.
Conceptually, I think this is a really neat idea. I think the attribution of exosomes, it could be many different things that are priming, including exosomes. I think that the challenge really here is you got to kind of put your finger on a thing, right? The concept has value, but I think we have to be driven by a clear and deliberate hypothesis or an approach to identifying these exosomes.
I don't want to minimize the concept here because it is brilliant, especially in the context of endo in the timing and adolescence. But like, yeah, the easy part is talking about the idea. I think the challenge that everyone has been struggling with for decades now is how do you, one, how do you analyze these things in a reproducible way? And then the other side of that is how do you deploy them in a, even an artificial in vitro system, much less in a physiological system.
So it's tough, but I love the idea and I think it should be applied just more generally, that we should be looking at these patients in the pre-phase because all of these inflammatory conditions are building over many years, presumably. Causality is really, really tough to prove. And I don't know much about extracellular vesicles, but is it the kind of thing where you could create extracellular vesicles that we think are providing this first, the second hit and experimentally test them in the peritoneum of patients and see if you can induce disease? Is that how you arrive at causality for this kind of hypothesis? Yeah, you would have to take a naive system and you would have to introduce a defined element.
I think what people have done in the past is they've taken like cell culture supernatant or something in the in vitro system, which is loaded with, you know, not just the exosomes, but like the cytokines themselves. And the way that you separate this, you do ultra centrifugation to create these gradients that all get a thin band where the exosomes presumably reside, but it's not a well-defined, you know, the constitution of those. It's just tough.
It's such a moving target. It's different every time. So how do you do that experiment that you're describing in a way where you know the inputs so that you can rely on the endpoints? But I don't want to take away.
People are doing this stuff. They're doing it in a lot of near perfect ways, but no one's got the silver bullet. Yeah.
And I think with endo being such a multifaceted disease, we're probably wrong if we take this reductionist approach and say it's just extracellular vesicles. No, it probably is extracellular vesicles plus many other inputs that drive the pathogenesis of this disease. But as a train of thought, a line of investigation, something that potentially has diagnostic and therapeutic benefit, really, really cool to see this and consider this, and hopefully for the scientists out there listening, the clinicians who are thinking about endo opens up a potential new paradigm for exploration.
All right, we've covered a lot of ground, you guys. This is extracellular vesicles, she-hands, turners, flowing differently colon, menstrual effluent and F&S science. So much medicine, so much science.
I got Daylon syndrome, but I'm naming it after my own difficulties. Very bad judgment. All right, you guys can use that with attribution.
It's a terminal illness. Terminal judgment. Yeah.
It's curable, as far as we know. Guys, always good to be back with you, and we'll see you, all of our listeners, on the next pod. We'll talk soon.
Bye. 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. Selena 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.
