Fertility and Sterility On Air - Unplugged: October 2024

In this month's Fertility & Sterility: Unplugged, we take a look at articles from F&S's sister journals! Topics this month include: mechanical contractions and fibroid progression (2:22), endometriosis classification and risk of infertility (15:15), the roles of endometrial and mesothelial cells in endometriosis formation (29:36), and fertility coverage for military personnel (43:30).

F&S Reviews: https://www.fertstertreviews.org/article/S2666-5719(24)00036-7/fulltext
F&S Reports: https://www.fertstertreports.org/article/S2666-3341(24)00090-4/fulltext
F&S Science: https://www.fertstertscience.org/article/S2666-335X(24)00053-3/fulltext
Consider This: https://www.fertstert.org/news-do/building-family-while-serving-our-nation

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 to another episode of FNS Unplugged. I'm your host Pietro Bortoletto, and I'm joined with the triumvirate Blake Evans, Molly Kornfield, and Daylon James. Blake, Molly, Daylon, how are you guys? Terrific.

Great to see you guys again on the Zoom. Doing well. Great to see you guys.

Next time I believe we see each other, we'll be in person, right? ASRM? That ASRM thing has a wave coming up every year and it sneaks up on you, and I don't know about you guys, but I always have that little bit of tachycardia that I'm going to get the time zone wrong for stuff. That stuff kind of starts to fill my calendar. When's this talk? When's that talk? When's this lunch? When's that dinner? Real nervous about mixing up the time zones every year.

It's always a hot mess. Well, the good thing so far is everything for me is happening at the same time. Yeah, as it often does at ASRM.

Yeah, so I'll probably see everyone for 10 minutes at each different place. Or nowhere. Or nowhere, correct.

As always, we will be podcasting live from the meeting. There will be a fertility and sterility booth. If you're a listener and you'd like to come see what Daylon looks like in real life, he's not just a voice, he's got a decent face too.

You can stop by the booth, say hello to the FNS team. We'll be there, we'll be recording live, and we'll also be hosting our journal club global on the topic of obesity and how it affects assisted reproduction, which I think will be a great topic and a rich discussion with some experts in the field. But enough about the meeting, let's talk about the science.

Blake, we never start with reviews. I feel like reviews gets a bad rap. It always ends up in the middle or the end.

Let's bring it front and center today. Why don't we start with reviews and see where it takes us? Yeah, best for first, as they always say, isn't that the saying? I'm going to talk to you guys about fibroids. You might have heard of them, but the title of this article is called Stressed Out, How Forces from Uterine Contractions Influence Fibroid Progression, a narrative review by first author Megan Sax out of University of Cincinnati.

Diving into a little bit of a background, as we know, fibroids are very common. The authors quote about 50 to 80% lifetime incidence, and these are usually estrogen and progesterone dependent, grow during reproductive years, and there's still a lot of unknown about the underlying pathophysiology. Fibroids are exposed to significant mechanical forces due to monthly uterine contractions in someone who's having normal menstrual cycles and have also been found to generate contractions in the junctional zone or the inner myometrium.

These are not the only mechanical forces that uterine fibroids experience, but they also undergo compression and strain due to stiff extracellular matrix within the fibroids. The forces may vary by location within these tumors, and strong uterine contractions not only cause pain to patients, as we well know as we take care of these very commonly clinically, but may also contribute to uterine fibroid growth, which in turn may lead to worsening symptom severity. So this review discusses uterine contractions in the non-pregnant uterus and what is known about the impacts of the mechanical forces on uterine fibroid cells.

So I'm just going to divide up the different areas that they look at, first starting with muscular contractions, and the authors discuss that depending on the phase of the menstrual cycle, the pressure and the frequency of myometrial contractility will of course vary. Myometrial contractions that surround the fibroids will impart mechanical stress onto the fibroid, particularly cells in the periphery. And this then undergoes a process that the authors discuss quite a bit in this paper called mechanico-transduction.

So this is basically a process where you turn stresses and strains into chemical signals that can lead to complex interactions of, for example, integrins that anchor proteins to the extracellular matrix of fibroids. And this elicits a complex change and growth of the fibroids. They look at effects of cyclic strain.

Cyclic strain promotes collagen synthesis and forces generated that direct collagen alignment, which in turn influences cell alignment in these fibroids. And when they looked at fibroid cells or they discussed articles that look at fibroid cells compared to myometrial cells, they discussed they've been shown to have altered signaling pathways that up-regulate in response to cyclic strain, which result in rapid misaligned growth, which kind of gives that characteristic swirling appearance that we see when we take out fibroids. They look then at the effect of compressive forces.

So fibroids have significantly higher glycosaminoglycan content compared to myometrial tissue. And when this undergoes compressive forces, this can lead to tissue stiffening, which as we know, fibroids are very stiff. They look at the interaction between tissue stiffness and contractions.

Let me just pause there. Do you guys, I know, Pietro, you do quite a bit of surgery. You do quite a bit of myomectomies.

Molly? I love a good myomectomy. I'll tackle it hysteroscopically, laparoscopically, robotically, and even open if we have to. Big fan.

One of my favorite procedures. Yeah, likewise. They can be very challenging at times too.

But how about you, Molly? Do you do myomectomy still? Usually just with MIGs at this point. I'm more focused on hysteroscopy in my practice. Gotcha.

And it's interesting too, you know, when you go, whoa, whoa, whoa, whoa. You didn't ask Daylon. Well, Daylon, do you do myomectomies in mice? Yeah, sure.

I mean, really, we did not have to draw attention to the fact that I don't do myomectomies in anything. I try to stay away. That's unfortunate.

It sounds like a lot of fun though, the way you guys talk about it. But, you know, I just, I'm not ready. Snooze you lose.

They are. But it is interesting that they are different too. As you know, sometimes you'll have a real necrotic kind of gooey, squishy fibroid.

That's a little bit more challenging to get out. And it's a lot more difficult to get out. So it's, it's interesting looking at these different factors that influence how these fibroids grow.

So then they look at interactions between tissue stiffness and contractions. The authors discuss that an increase in fibroid stiffness has shown to result in increased transcriptional expression of genes involved in cell proliferation, such as IGF-1, insulin-like growth factor, TGF-beta, transforming growth factor, as well as estrogen receptor alpha, and also vital components that are involved in the extracellular matrix production. They talk about the exterior cells of fibroids are typically exposed to more higher contractile forces compared to interior cells exposed to little to no mechanical stress.

And this may account for some of the heterogeneity in fibroids in terms of the stiffness or lack thereof. And then lastly, they dive into mechanosensors in uterine fibroids, more so as a potential targeted therapy for treatment. So they particularly talk about G-protein coupled receptors.

So as we know, transmembrane receptors, and these are found in fibroids. And when these receptors undergo compressive or tensile or shear forces, they undergo conformational change. And this can make new binding sites that are newly available or some that are even unavailable or downregulated.

And so because of these changes, this can lead to alteration in the growth of these fibroids. So the authors discuss how these receptors make for promising targets in the treatments of fibroids. Because as we know, a lot of the treatments that we currently utilize suppress ovulation, and so our patients can't get pregnant whenever they're utilizing these treatments.

Or many of the treatments are also some of which that we typically don't want patients on whenever they're trying to get pregnant or are pregnant. So in conclusion, the authors talk about how myometrial and fibroid cells use different pathways to translate mechanical forces due to cyclic strain imposed during contractions. They talk about dysmenorrhea can cause strong contractions and should be considered as more than just a symptom of fibroids, but as a possible contributor to fibroid growth as well.

And then lastly, they discuss or conclude that with further research and funding, of course, as most research papers say, we can look further into this subject on treatment of patients and further look at the role of mechanico-transduction treatments for these fibroids. So nice summary. I commend the authors.

This is a good summary of what's currently available and this pathology of fibroids. Very, very, very common in our patient population. So I enjoyed reading it, enjoyed summarizing it.

So well done to the authors. I want to just ask a couple questions here. First, I'll say it's quite a synthesis, and I really do appreciate the role of mechano-transduction in particularly like cell fate and cell differentiation as like a cell developmental biologist.

That's something that's really picked up a lot of momentum in recent years, rightfully. I wonder, is the synthesis here and like the role of mechano-transduction of all different types described compression, strain, cyclic stretch, etc. Is that like, has there been a link there to the actual behavior of fibroids? I don't know.

I didn't look too deeply into this one because while I can understand that these forces, mechanical forces, biomechanical force in particular has like a input in like a cell sensing its environment and like kind of knowing what it's going to do, or even maybe even the context of like cancer spreading, right? EMT and metastasis. I could see like, you know, the physical disruption of the tissue leading to spread. But here, I'm kind of like, the question I'm left with is kind of like, how? Like does it cause them to grow faster or bigger? Or does it cause them to like maybe see little kind of mini-mets of fibroids spread into the matrix? So just like kind of like the mechanistic link here to the force, to the pathology and progression, I would ask.

And after that, if there was like, and what do you do then? Is like an idea like therapeutically that we would try and like minimize contractions during menstruation or something? Is there a pathway to trying to slow fibroid growth or something? What are we talking about here in terms of the translational value here? Or is it just really academic basic understanding we're trying to get from this? Yeah, I think it's a little bit of both. I mean, it's of course, summarizing what we think we know about this topic in regards to fibroids. Certainly, there's a lot of gene expression and alterations when we see these contractions occur in fibroids.

And so the authors try to link that and the growth factors and genes associated with that with fibroids. But in terms of translational, in terms of treatment, of course, you know, we all would love that treatment where, hey, take this. This is going to minimize your fibroid growth, but you also can try and get pregnant while taking this too.

And so that's just, that's something that more for a call for pointing this out for attention if we need to look into it further. But in terms of what will that be, hard to say. I like this paper and more of a comment than anything.

It just really stretched my brain and how I think about fibroids and where they come from and why they grow. And it's interesting, all this new focus on contractile strength and contractile patterns. And I think about how my fellows in 10 or 20 years will think about fibroids potentially totally differently from how I think about fibroids.

And also adenomyosis is a great area of research. And as, you know, I think we're pretty good at treating bleeding related to fibroids. We have a lot of trouble preventing and treating bulk.

And so if this has any promise, I'm really excited to see where we go from here. It's stretched your brain while it's strained and it's stressed mine. Good one.

Blake, what do you think about the kind of the clinical maneuver that we all do where we, patients who are symptomatic with fibroids, we put them on NSAIDs or we put them on continuous oral birth control. And we know a certain amount of these fibroids stay the same in size, a certain amount of them regress in size. Knowing what we know about mechanotransduction right now and potentially as a inciting event for fibroid growth, do you think we should be potentially more aggressive about suppressing the cramping associated with fibroids and the uterine contractions with NSAIDs, with continuous OCPs? So larger doses of Motrin, is that what you mean? A fistful of it to be specific.

Yeah. And then develop an ulcer as well. But yeah, I mean, I think ideally, I mean, that would obviously that'd be something that would be ideal.

But again, I mean, you know, if you're a lot of our patients are trying to get pregnant, at least the majority of the ones that I see are trying to get pregnant. So it's difficult, you know, kind of similar to endometriosis, it's very hormonally related. And so, you know, only so much you can do when they're trying to get pregnant, aside from you just do surgery, excise some lesions, do pelvic floor physical therapy, but, you know, so much of it is hormonally driven.

So it's, it's tough. It's a tough situation to be in for sure, for these patients that are wanting to get pregnant. But I do think that there's something there and that when in terms of minimizing menstrual cramps, potentially lowering prostaglandin development, then and the authors talked about how excess and prostaglandins can lead to fibroid growth as well.

So, you know, minimizing all of these things, I think would be ideal. It's a tough situation to be in though. I would welcome your perfect answer, whatever you might have.

I don't have a good one, but it definitely made me start thinking about, maybe there's something there about being more aggressive with symptom control, because the symptom is the canary in the coal mine for impending growth, or this review suggests. Absolutely. Very good point.

All right. Well, thanks, Blake. That was great.

I'm glad we started with reviews. This is a nice article. And for the people who are fibroid minded, point people towards that article in FNS Reviews.

Molly, let's pivot over back to FNS Reports. What do you got for us? We're keeping the GYN pathology topic today. We're going to talk about endometriosis.

So much to talk about with endometriosis. So the article I chose this month is, Is Endometriosis Typology a Potentially Better Classification System for Assessing Risk of Female Infertility? By first author Karen Schliep and last author C. Matthew Peterson. And so this is a really interesting prospective study, and I'll talk about it in more detail, but briefly, they surveyed a series of patients about their history of infertility or subfertility, and then they went into surgery and found out if they had endometriosis or not.

So a little bit different study design than I've seen before in the literature. Usually in my practice, I'm meeting patients when they've already experienced a period of infertility and either have a history of known surgically diagnosed endometriosis or were pretty suspicious of it, or I'm diagnosing it during their workup. And I think we've really seen how the severity of endometriosis and more specifically the ASRM endometriosis classification system, which is fantastic for describing surgical findings, does have some limitations.

It just doesn't correlate perfectly well with either risk of infertility or symptoms from endometriosis for that matter. But occasionally, I do see a patient who's coming for a preconception visit and they say, hey, I know I have endo, and I just want to learn more. What is my chance of fertility? Should I come see you right away? Should I try for a few months first? What is my chance when I begin conception attempts? And for these patients, this study is really perfect to inform these conversations.

So the authors of this study wanted to look at a different system than the ASRM classification system by grouping endometriosis into three different subtypes and then examining the impact on fertility. So they looked at ovarian endometriomas, which they define as mass lesions in the ovary, deep infiltrating endometriosis, which they define as endometrial tissue invading in the organs of the pelvis and elsewhere, and superficial endometriosis, which involves only the surface peritoneal implants or endometrial tissues. And of course, some people fell in multiple groups.

So the study design, as I mentioned, was a prospective cohort study. They looked at 473 women, all at multiple surgical centers throughout Utah and California. So you can imagine how those populations might be similar or different.

And all of these patients had no prior endometriosis diagnosis and were going GYN-focused laparoscopy or laparotomy for all GYN indications. And they were looking at how likely endometriosis was found incidentally during these surgeries. And then they asked the women before their surgeries occurred to think retrospectively about time to conceive, prior fertility attempts, how long did it take.

Their exclusion criteria were people with previously surgically diagnosed endometriosis or who'd had a hysterectomy, cancer, and then also were breastfeeding recently or using injectable hormonal therapy like Depo-Lupron, Depo-Provera, assuming for both that and Depo and for breast feeding that it would decrease the incidence of being able to find endometriosis, since they're all pretty suppressive. And the authors nicely controlled for known confounders of fertility, including age, BMI, and smoking. And they also did control for surgical site, which I thought was interesting, maybe because different surgeons may be more or less sensitive to identifying endometriosis.

So I think this was really a creative study to take another look at the general incidence of identifying endometriosis incidentally for all comers to GYN surgery. And can also inform, you know, we're finding endometriosis overall in our field, we're operating on a lot less people when we meet them at first. And so what is the incidence of endometriosis for just patients in general? And they can help us to counsel patients who have known endometriosis, what do I expect once they try to conceive? So what did we find? So the participants underwent surgery for various reasons, as we'd expect 42% were for pelvic pain, so a large proportion for pelvic pain.

And so you are expecting to see, you know, a higher proportion of endometriosis in that population. And only 7% were undergoing surgery for infertility. And the remainder were kind of split evenly between surgery for pelvic mass, for irregular menses, for fibroids, or for tubal ligation.

So interestingly, some of those were fertility ending surgeries. So people who'd completed their family building were ending their fertility journeys. So of all these patients, 40% of the participants had endometriosis identified intraoperatively.

So of course, that's not population, it's not all women, you're going to find 40% endometriosis, it's all these people presenting for GYN surgery and making it to the OR. And 36% of those who actually gave information on prior conception attempts had endometriosis. So how did it distribute between the different types of endometriosis of the people who were diagnosed? So 25% of women were diagnosed with superficial endo only, 5% had the ovarian endometriomas, and 6% had the deep infiltrating endometriosis.

5% had both ovarian endometriomas and deep infiltrating endometriosis. And then 60% of the patients had no endometriosis at all. So compared with women with no endometriosis, they then looked at prevalence of subfertility, and they defined that as trying for a year under 35 and trying for six months over 35.

And they found that women with superficial endometriosis had a 1.58 higher adjusted prevalence ratio or APR of having subfertility compared to people with no endometriosis. So 1.58 or about 1.6 for superficial endo. And then for ovarian endometriomas and or deep infiltrating endometriosis, it was 2.41 higher adjusted prevalence ratios, about 2.4. And so what you would expect, it's worse to have endo and it's worse to have bad endo.

Compared to people with no endometriosis, in addition, women with ovarian endometriomas and or deep infiltrating endometriosis had a 53% lower historic fecundability. So they also looked not just at fertility, did they conceive or not, but also looked at fecundability for those that conceived month by month. However, interestingly, they found no association among women with superficial endometriosis for decreased fecundability.

And if you check out the paper, always check out the paper. There's a lot more than what I can tell you in 10 minutes on the podcast. Figure one, they actually used a survival curve for fecundability, which is great to look at.

And you'll actually see the proportion that were not pregnant. They look at proportion not pregnant by month over a 12-month period. And for the superficial endo and the no endo group, it's actually identical.

And we're really seeing the difference in ovarian endometriomas and deep infiltrating. I did find myself wondering about miscarriage rate, which wasn't reported in this study, just because I think we haven't really teased out endometriosis and miscarriage very well yet. And they did cite prior published research from the same study from these authors that showed that deep infiltrating endo was associated with a threefold increased prevalence of miscarriage, but that neither superficial or ovarian endometriomas showed an association, just for people who are thinking about that as they're thinking about this study.

And then as expected, they also did do a sub-analysis for adhesions, and that's in the supplemental tables. Sometimes the really interesting parts of a paper are in the supplemental sections. And we can all imagine there's many different mechanisms for why endo causes infertility, but one of the major ones, the easiest to understand at least, is adhesions, pelvic adhesions.

And they found that adhesions were twice as likely to be associated with infertility, which is kind of what you would expect. So overall, I thought this was a really nice study. Definitely adds to our body of literature, looking at patients' fertility, but kind of ability, and looking at those who didn't already have an endo diagnosis, so you're not going to have that recall bias, because I had endo, I tried for much longer, and so on, and who had planned surgery.

There's probably still an element of recall bias, and I estimate that in general, people probably underestimate their time to conceive if you're having patients report it. I think especially when I'm talking to patients in clinic, they have a much longer period of not contracepting, and then a shorter period they really consider, okay, now we really started trying for OPK testing and all of that. And so I think we should take patient reported time to conceive with a grain of salt.

And I think this does include, of course, a higher risk cohort of patients. We're seeing 40% incidentally found endo, where it's closer to 7% in all comers for surgery, because I think our medical treatments are better and better, and we're doing fewer and fewer GYN surgeries, so it's really a patient who's already symptomatic, and that might be because of endo when we're going into surgery. Another point is that sometimes surgeons bill for diagnosis codes that they know insurance will cover.

So someone might have surgery for pelvic pain and infertility, and we're going to bill for pelvic pain, because we want to make sure that they can get good coverage for that. So the fact that only 7% were having surgery for infertility, it probably was, or may have been higher than that. And so I think just one criticism I was going to make of the study was that not every surgeon is going to catch subtle endometriosis, but the authors did actually make sure that all their participating surgeons had appropriate surgical training and diagnosis and staging of endo, and then they also did control for surgical sites.

I thought that was a nice way to try and make up for that. So what do you guys think of the study? Did it mirror what you kind of expected to find, and in terms of the association of given degrees of endo and infertility, and will this change how you counsel patients or impact how you think about patients at all? I love a study that confirms my biases and lines up with my counseling, and I think this one did exactly that. When I have patients that I know have endo and I'm taking to the operating room to improve subfertility, I commonly tell them the bigger and the badder the endo I see, probably the bigger of an impact it's having on your subfertility.

So when I see deep infiltrating nodule on their uterosacral ligament, when I know that there's ovarian endometriomas or kissing ovaries and a frozen pelvis, that's a patient where I think I have the biggest opportunity for improvement with surgery, compared to the patient who's got superficial endometriosis, where if they have a quote-unquote normal GYN skin or normal MRI but have significant pelvic pain and subfertility, there's going to be some benefit to surgery for that patient, and there's plenty of good data to suggest that. However, I think once I see deep infiltrating and covarian endometriomas, I know I can really move the dial for that patient, not only from a symptomatic perspective, but I think that's where the biggest bang for our buck is. So this patient does that, but kind of in a roundabout way, kind of proves that the biggest impact on time to conception is probably the big bad endo.

It doesn't answer the question of does fixing it improve that at all in the future, but I love this study. I thought it was great. Yeah, I agree.

I think the survival curve is definitely reassuring. You see the superficial slash known endometriosis lines are just overlapping entirely. So that was nice to see in comparison to the more severe diagnosis.

My question I had was more in regards to the fallopian tube. So I was wondering what your all's thoughts were on including patients who are just having a tubal ligation in terms of lumping them into patients that may or may not have infertility. I thought that was interesting, but also maybe I missed it, but did they, when these patients had their surgery, did they do a chromoperturbation to see was tubal disease the reason why they weren't getting pregnant? Was that part of the study? No, I didn't see that they were including that in the study.

So yeah, that would be interesting. I got to say that the fact that they go in agnostic on the endo I think is really cool. It's the coolest element of this study.

And that's my takeaway and in line with all the everything that you guys said in terms of confirming the bias and not unexpected in terms of the results and being able to iron out in terms of the fecundability, the infertility challenges in that superficial endo group. So as you guys said, something that can be overcome without necessarily infertility treatment. But as you said, the 40% number jumped out at me because it's really pretty starkly misaligned with what our general understanding of prevalence is.

And when you look down in the numbers in terms of percentage within each of those groups, it seems like the patients that were affected with endometriosis were heavily skewed towards a lot of those metrics with pain and cycle and dysmenorrhea, or everything. So I think that as you alluded to there in terms of, I wouldn't even call it a criticism, but something to bear in mind is that this patient population, while it is agnostic with respect to the pre-diagnosis of endo, I think it is a skewed population that's not necessarily representative. And just to add to jumping back to Pietro's point about who does he think surgery is going to be most beneficial for, and it's kind of the poorest prognosis patients.

And I think I think about it the opposite where I think, ooh, I'm already seeing deep endometriomas on just my baseline ultrasound. Hey, I'm going to lean towards IVF because your prognosis is poorer. I could make a difference with surgery, but I think we're already there.

So it's just funny how we can be two sides of the exact same coin. We look at the same data with opposite conclusions. Well, IVF I think is an essential part of this, right? I'm not going to take a patient with bilateral six centimeter endometriomas to surgery because I know I'm going to, no matter how good I am, I'm going to hurt that ovarian reserve.

But if I can access those ovaries safely and get some eggs out, make some embryos beforehand, and then treat her endometriomas, I think I'm going to make her feel better. I think I'm going to improve her implantation rates and lower her miscarriage rates. I think.

Asterisk. I think we all know that you know, Pietro. I got the plural of anecdote is not data.

Well, it's a great angle, as I said, that endo-agnostic approach. I got another spin on this, which is just taking the pathology out of the human altogether with a cell-based study. But it is human cells and it is patient derived, and I think well-designed with some, I think, meaningful conclusions as well.

So I'm going to share that with you guys right now. I mean, we've talked a bit about the endo, but you know, the number is 10%. Generally, the consensus is that it's around 10% prevalence of reproductive age women.

Globally, I mean, that's still a huge number, talking about like close to 200 million women. And it's a chronic disease, right? Severe impact on quality of life, physical, mental health, no cure. And that's the thing, given the prevalence, unmet need, it's, we really don't know enough.

It's almost embarrassing. And the treatments are just about like mitigation, right? Or getting around it in order to, you know, build a family with some surgical intervention, but not always that effective. And as we're alluding to here, maybe the worst part here is that, you know, lack of treatment because we don't really have a good understanding of what the root cause of the disease is and the cellular mechanisms that drive the pathology, right? But of course, you guys see a ton of these patients in your practice, right? Chronic inflammatory nature, endometriosis can affect fertility in a number of ways.

You guys talked about it, Pietro, you said it's a question of like, whether or not surgical intervention is going to improve your chances. And ultimately, you're going to go with IVF in most, if not all cases. But what is your general take, just in terms of like efficacy? How do the existing hormonal and or surgical treatments, how do they fare in restoring a permissive environment for reproductive success? I mean, you may not have the numbers exactly, but would you say more patients than not, you're able to treat when they come in with endo that seems to be affecting their fertility? I think the tricky thing for us is that so much of our experience is confounded by the concomitant use of ART in this patient population, right? I think so few of us are just doing endometriosis surgery and then sending them back out into the wild and saying, come back and see me 12 months from now.

And obviously, I think that varies state by state, but in my patient population in Massachusetts that has access to ART and has endometriosis, I use them both hand in hand. Sometimes it's optimizing pain, sometimes it's optimizing environment, optimizing anatomy, but always with ART is kind of an adjunct to treatment. Blake, you practice in a very different environment where you may be seeing a lot more patients for subfertility that don't have access to ART and are looking for surgery to be the fix.

Is that the case? At times, it's more often, I would say, an issue because we don't have the luxury of just starting right away for IVF. We have just, you know, there's so few of us in the entire state and there's so many patients who are waiting to get to do IVF. And so it's sometimes, unfortunately, just a, hey, I want you on suppression so things don't get worse while you're waiting to start.

So that's more of what it is. But sometimes it is also surgery, feel better, and then go and try and have intercourse. But it's more oftentimes than that, similar to your experience, Pietro, of kind of using it in addition to ART treatments in mind.

Whether or not the patients can achieve success and sustain pregnancy, you know, we've talked about it. It's really more than that. You know, it goes beyond your capacity as, you know, REIs.

The physical, emotional, financial, big point here, burdens of endometriosis are pretty big, you know, just in terms of that financial burden between the lab testing, the imaging, the surgical or other treatment costs. Also, the lost wages and productivity are huge to the tune of $80 billion of cost to the U.S. healthcare system and economy per year. So, of course, the curative or targeted therapy, it's a long-sought goal.

But like I said, the etiology remains really elusive. And one of the most outstanding questions, which, you know, they're circling around, I think, a lot of evidence toward a single answer. But the question remains, where do these lesions come from? Retrograde menstruation, that's a major candidate.

It makes sense in terms of like trafficking of uterine cells to ectopic sites. But a lot more women have retrograde menstruation than have endometriosis, right? So perhaps there's a subset of those women for whom predisposing factors play a role, or maybe they all have endometriosis, and they just don't know because it's not presenting or manifest with pain, although we know from a lot of studies that there is no actual pathological evidence on laparoscopy. So retrograde menstruation alone does not account for it.

And there's other theories also that could account for the origin of lesions. But the basic question underlying all these theories is that of this seed or soil conundrum. Is it the endometrium that is atypically invasive, or is it the peritoneum that is atypically susceptible to lesion formation? And many studies have designed exhaustive and or elegant means of addressing this question in a range of model systems, animals, cells, also patients, a lot of clinical data.

Here I'm sharing a nice entry from lead author Virginia-Arlene Goh and senior author Bruce Nicholson, who are both at UT Health San Diego. Here they took patients that were confirmed by laparoscopy to have endometriosis or not. Eight patients in each group, so not a huge number here, but what they did with those patients is important.

They isolated and cultured the primary endometrial or peritoneal tissue from each patient. Then they used this transmesothelial invasion assay to provide a kind of a proxy measure of the cell's quote-unquote invasive potential. And what they found was pretty interesting.

Comparing the peritoneum derived cells from control and endopatients, there was no difference in the invasion of stromal cells. But if you used either a control or a endomesothelial cell line as the substrate and compared the stromal cells from those two patient groups, the endopatient showed significantly more invasiveness of that stroma into the peritoneal derived mesothelium there. So of course, I mean, in terms of like a proxy for lesion formation, I would say a little bit mid to quote my 15-year-old.

That's cap. You disagree. I see.

Well, we'll have to take the debate into the sidebar. But I'm not taking away. I'm just saying there's only so much you can do with a cell-based system.

Also, only so much you can do with a study that kind of excludes the complexity of the in vivo environment. But I like an experiment that reduces complexity, right? I like an experiment that focuses on a single variable. And that's what they do here.

And they do it with a tractable platform, one that I could imagine could be applied in some next level experiments that, you know, do some kind of targeting, test whether that invasive quality can be targeted using like pharma or biologics or something. How about you guys? Any thoughts on the seed versus soil debate? Where do you come down on it? I think like many of these diseases, there's probably a first hit and a second that needs to happen for that to really wreak havoc. And more and more what I've read and what I've kind of experienced in patients is that there's probably an immune surveillance issue in patients who have this predisposing risk factor.

I think a lot of endometriosis is laid down and healthy functioning immune systems are able to clear it and keep it in check. But I think if you have the ability to lay it down and then your system is not actively scavenging tissue healing, reducing pro-inflammatory pathways, that's probably where you get that second hit. And then endometriosis is kind of just left to wreak havoc in the pelvis and in reproductive organs.

So that's kind of how I'm putting it together in my head based on everything that we know now about endometriosis and just the pattern that we're seeing in patients. There's people with just really, really, really, really strong family histories where it shows up in every generation, right? But then there's patients who it shows up for the first time in their generation, but they got this really strong autoimmune signal, right? These are sometimes patients that struggle with ulcerative colitis. They have autoimmune theroditis.

There's something else in their immune system that I think is potentiating a lot of the badness. My two cents. I like your two cents, and I think it speaks to, and forgive me here, but how dumb the seed versus soil hypothesis is just as a principle.

People like to throw that around, but if you've ever been out in nature, you know, it takes the seed and the soil to grow the thing. You need them both, unless we're talking about some hydroponics. But endo is not a hydroponic species.

I think it's clearly a lot of the soil here, and as you were saying there, a permissive environment. I think it's defining exactly what the constellation of factors are, both seed and soil derived, that contribute to that permissive and maladaptive environment. It's fair to say that that could be very different across different patients.

I think maybe like PCOS, maybe we should appreciate endometriosis as a spectrum of disease states and not just a monolith. Yeah, I love that. And kind of extrapolating from that, is there something in the dysfunction of the immune system of the patient that's also causing these concurrent impacts on fertility that may not actually be the endometriosis itself? So are we seeing immune changes in the lining that's not from the surrounding endo, but it's actually a separate issue? So that even if you treat the endo, you have these sort of patients where you're still having implantation failure.

So are there two, this one autoimmune dysfunction is causing multiple issues? I think it's the whole idea of unchecked inflammation. There's no shortage of other examples in the body where we know inflammation is bad. Inflammation leads to atherosclerosis, inflammation leads to neurodegenerative disorders.

There's wonderful examples in every other organ system. And I think we're kind of slow to bring that back into GYN land, because we just don't have a lot of people doing some of this really strong primary research to kind of say, ah, here too, you see inflammation wreaking havoc. And the way that I describe this concept to patients and what the potential role for surgery is in endometriosis is imagine living near a volcano.

If you decided to open up a shop and you put your little teepee next to the crater where the magma is, it's going to feel hot. There's going to be heat. There's going to be inflammation.

You're going to have that bystand effect of just like, oh my gosh, I want to move away from here. And the minute you can cap the volcano or move the home away from the magma, the effects of that heat or that inflammation are going to be lessened. And it's just going to be a much more hospitable and pleasant environment for a lot of things, pain, but also reproduction.

So I really think that there's something about unchecked inflammation due to a malfunctioning immune system that really wreaks havoc in endo. And that story, I think, just needs to be better told with some primary research like this. I like your analogy there, bringing the heat with that one.

But I think that's what makes it endometriosis in regards to pregnancy or fertility outcomes too. It's difficult to put into context in terms of what do you recommend to patients. If one patient has a significant amount of inflammatory changes, but someone just has tiny little implants within their pelvis.

And so are we then saying to every single patient, you need to be suppressed for months before we do an FBT because we know that that's going to help you? It's hard to say, but I think it's a very complex disease for sure. And it makes it studying pregnancy related outcomes a little bit difficult as well. All right, guys, let's bring the podcast home today and talk about something that's I think more of a current event and less hard science, but something that I think, particularly in the United States for our American audience is important and doesn't get enough of attention.

So we have a wonderful article from Consider This published just last month entitled Building a Family While Serving Our Nation by first author Wes Urien, middle author Bruce Pier and senior author Joe Sanfilippo. This is a wonderful contribution from folks with real on the ground experience serving in the military, but also as reproductive endocrinologists and people who care for these folks in immensely topical is really proud to see it submitted to Consider This. And I want to tell you a little bit about what these authors put down on paper.

So before we talk about kind of the main gist of the paper, I want to tell you a little bit about let's set the scene. So the United States Armed Force comprises both active and reserve parts of the military. And in total, there's over 2.5 million members with just a little over 1.3 million that are active duty service members of that group of people.

Only 17 percent are female members. That's about 230,000. But there are another 500,000 dependent female spouses to men serving in the military that I think are also important to account for.

It's not clear if this is by choice, by circumstance, by where they are in their life, but about 24 percent of female married soldiers and 17 percent of male married soldiers do not have children. And the CDC estimates that about 16 percent of married females and 9.4 percent of married males will experience infertility and seek infertility services. But a lot of the reporting that has existed from the military says that the incidence of military females diagnosed with infertility is much lower, as low as 0.01 percent.

Obviously, there's some issues here, right? Some of this may be wrong diagnosis codes under reporting because they don't have access to care, but some of it's just absence of reproductive endocrinology specialists on military treatment facilities. A safe estimate of the incidence of infertility in this population of 10 percent would suggest that there's probably 23,000 active duty women and over 50,000 dependent wives who would suffer from infertility at any given time. But a most recent report that looked at data from 2013 to 2018 showed that there was only 8,000 active duty women who received a diagnosis of infertility during that time period.

So, a big discrepancy from what we expect, but what we actually see. So, despite this estimated incidence of infertility among service members, there's really limited coverage that exists through TRICARE, which is the Uniformed Services Healthcare Program for active duty service members, their families, as well as members of the reserve groups like the National Guard. So, under TRICARE, there is full coverage for infertility evaluation and several infertility treatments.

There is a big gap in that there are many shortcomings. Not everyone qualifies for services, and more importantly, not everyone has access to the physical act of receiving treatment because there's such a paucity of military bases that can provide treatments like IUI, like IVF, like ART. So, one of the issues here is, and I guess it's probably just worth naming them, there are only a handful of bases across the United States.

We're talking about the Tripler Army Medical Center in Honolulu, Womack Army Medical Center in Fayetteville, North Carolina, the San Antonio Military Center in San Antonio, Texas, Walter Reed, where, Blake, you have plenty of experience serving as a fellow there, as well as the Madigan Army Medical Center in Tacoma, Washington, and finally San Diego Naval Base and the Wright-Patterson Air Force Base in Dayton, Ohio. So, one of the big things that the authors in this paper are trying to highlight is there are a significant number of obstacles that men and women serving in the military, as well as their dependents, face with the reporting of infertility, getting worked up for infertility, but most importantly, getting treatment for infertility. And I think us in the United States understand the amount of the burden that families take on by having a life in service to their country through the military.

This is one of those things that the minute you start talking about it, you're like, what? How have we not fixed this? Why is there not a better solution for this? We take care of our military in so many wonderful ways, but this kind of really essential part of the experience of being a young adult trying to reproduce, we're not doing a really good job at. And there's a couple of legislative fix that have been proposed. Some updates from the VA, the Department of Defense saying that coverage will be expanded, but they're still kind of just the major, like, if you have infertility today and you're trying to access services, how the hell are you going to do it? Do you travel off base? Do you get permission to leave your assignment to go access infertility services? And we know that none of these things are quick, none of these things are cheap, and there's a serious burden having to relocate to access care.

This paper does a fabulous job, I think, of kind of describing the argument for why this is important, identifying what the problem is, and something that, because it lives in front of our paywall at Fertility and Sterility, something that I hope the lay press takes up, something that I hope we share with our friends, and for people who are listening and have access to the ears of members of Congress, policymakers, and other folks in the military, this is a great topic to bring up at your next discussion, because it's something that should be easily fixed. I like to say that it's not a problem if money can fix it. This feels like one of those things that money could probably fix, in large part, not completely.

But would love to hear, starting with you, Blake, you've worked with service members through your fellowship in the NIH. What does this translate for them and their families in real life, having to access infertility services, specifically in Bethesda? Yeah, I mean, I think this is extremely eye-opening and definitely takes me back to thinking about the difficulties a lot of these patients have to go through. But all of those places that you mentioned that were military facilities that provide IVF, for example, or some form of fertility treatment, they're not close.

They're very far apart, and all the states in between where someone may have TRICARE, they have to drive hours and hours and hours. I recall all the time in monitoring, talking to patients who are just so bloodshot-eyed from having to drive for so long just to get to their appointment. So it is very unfortunate.

And then even also in Oklahoma now, just when you see patients with TRICARE, they have to go through quite a few hoops that I feel really bad for them to, like even just to get a semen analysis. Instead of them just going up front to the front office and having it scheduled, they've got to then go back to their primary care physician, have it ordered, get a prior auth, and then it just takes a very, very long time just to get a semen analysis done, for example. So things take a lot longer just to get treatments going for these patients, and it's more just unfortunate.

I definitely agree that we need to do something about it, and this article is very eye-opening about that, too. I don't disagree at all. This is a problem, and I appreciate the article shedding light on it.

And actually, as you said, Pietro kind of describing the problem. But I have a question here in terms of alternate explanation or interpretation. And that is that if we're talking about the active duty force here, active duty spans two to six years.

Is it possible that like this is just a span of these people's lives where they're just not focused on fertility or deliberately unfocused on fertility, you know, deferring? And to address that, I would be interested in seeing if there was a differential. And maybe the numbers aren't there, but a differential between career military and active duty service members who have like the transient phase of doing their service and then moving back into domestic sphere. So just a question and curiosity, but I don't want to take away from it at all because the problem is clear and the reason it totally makes sense intuitively.

I was just shocked at the gulf. Like it was just so stark, the delta between, you know, generally professional people, same age group in the military. It was astonishing how few sought fertility.

So I was just casting about for alternative explanations for that. Not to mention just some of the exposures that these folks take on by nature of their service, right? Exposure to radiation, chemicals, trauma to reproductive organs in combat situations. There's even a strong argument for just simply offering these folks fertility preservation before being in active duty in a combat zone.

People having these conversations about female astronauts before they go into space and expose their ovaries to ionizing radiation. That's like four people a year who stand to benefit from that. Here we're talking about tens of thousands of men and women that are going above and beyond the call of the average American citizen to do something on behalf of all of us.

It seems like one of those, gosh, can we just fix it? Yeah, slightly unrelated, but I think, you know, there's just a need for improvement overall, especially for women serving in the military. I caught the end of a radio story that I think was about abortion access for people on active duty and that part of the challenge is that you need to get special permission to leave your base. And so if somebody finds that they're pregnant, it's really hard to even take a pregnancy test or obtain it and to take it on site privately.

And then if they finally need to leave the base to obtain an abortion, the logistics around that, I can't find the original article. I just caught the end of the story, but it was just all these things I would never have thought of that really limit access to reproductive care overall. Yeah, well, kind of in the same, and that's a good point.

But similarly to, you know, with everything that happened in Alabama with frozen embryos, you know, that whole issue. But you think about our patients who are in the military and they are very, very frequently moving into different areas and they may need to ship their gametes or embryos to a different location. That's just another obstacle that they may have to encounter because they might move several times within a calendar year or with, you know, however many times they have to move, which is very often.

But if they have embryos frozen, they want to do fertility treatments and they need to get it shipped, but there are states that are now restricting it. So that's just something else that I really hope never happens, but it's just one other obstacle that these patients might have to encounter. I just have to make a very important plug because the first author on this was my former intern.

And so I used to call him Baby Intern Wes. Very nice piece, Baby Intern Wes. Thanks for writing for us to review today.

And if you're listening to this and you have something that's interestingly topical, niche, but important for other people to listen and learn about and you'd like for us to talk on the podcast, consider submitting something to the consider this section. We would love to hear from you on current events, ethical issues, ideas or hypotheses that you're mulling over that are pertinent to our patients in our field, but also other papers published in other journals that you just want to talk a little bit more about. Consider this as the home for all of those ideas and thoughts.

So submit. It'd be great to have it. Great to discuss on the podcast.

We've covered a lot of ground today. There's a lot of great science, obviously, in all of our journals. I think I speak on behalf of all of us.

This is a labor of love for us. We really enjoy doing it. And it's fun to see what we're independently coming up with each month as an article type.

Sometimes you get two endo papers back to back, but it's not by design. It really is because it interests us from these individual sister journals. I also think I speak on behalf of all of us.

We're really excited to see all of you, our listeners, in real life at the ASRM meeting. If you're going to be by the booth, please come by and stop by. There's going to be a special fertility and sterility section, a plenary presentation at the ASRM where we highlight our favorite papers of this last year from not only Maine FNS, but also the sister journals.

So that'd be a good opportunity to check that out. And some awards given to young investigators and folks who have been excellent peer reviewers. So thank you for all our listeners for one, listening, but two, keeping up with what's happening in fertility and sterility on air.

That's all the time we have for today. Blake, Molly, Daylon, thanks for being here. See you all next time.

See you in Denver. 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.