Fertility and Sterility On Air - Unplugged: March 2026

In this month's Fertility & Sterility: Unplugged, we take a look at articles from F&S's sister journals! Topics this month include: ovarian abscesses after ovarian PRP (01:45), immunotherapy for recurrent pregnancy loss (15:55), and the impact of ANA-12 on testicular health in rats exposed to tobacco and nicotine (30:10).

F&S Reports: https://www.fertstertreports.org/action/showPdf?pii=S2666-3341%2826%2900001-2  
F&S Reviews: https://www.fertstertreviews.org/article/S2666-5719(25)00013-1/fulltext
F&S Science: https://www.fertstertscience.org/article/S2666-335X(25)00086-2/abstract

View the sister journals at:

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

Welcome to Fertility and Sterility Unplugged, the podcast where you can stay current on the latest global research in the field of reproductive medicine. This podcast brings you an overview of this month's journal, in-depth discussions with authors and other special features. Fertility and Sterility Unplugged is brought to you by the Fertility and Sterility family of journals, in conjunction with the American Society for Reproductive Medicine, and is hosted by Dr. Molly Kornfield, Dr. Blake Evans, Dr. Daylon James, and Dr. Pietro Bortoletto.

Hey everyone, welcome to another episode of FNS Unplugged. I am your host for today, Dr. Pietro Bortoletto we are waiting on, he may join us later today in this episode, but I am with our other two fearless leaders, Molly Kornfield and Daylon James. Hello everyone, how are you doing? Terrific.

Great to have a competent host for once. Yeah, I wasn't going to say it, but I'm a little happy that Pietro is late so we can do this podcast the appropriate way. So Molly, how are you doing? I'm doing well.

It's good to be back with you guys. Elena did such a nice job filling in a couple months ago. She sure did.

It was really great to have her, but it is also great to have the band back together. So without further ado, Molly, you're going to kick off a case report for us. So why don't you tell us about what you're going to be discussing today? Great.

So most months, I think every month I review a research article, but this month I thought we could talk about a case report that was in FNS Reports. FNS Reports actually has a really nice selection of case reports and I think we're all really aware of the important role that case reports can play in our field and in the literature. Not everything has happened enough times to be developed into a research study, but it's good to get something out there so other people can see that and collaborate with you to hopefully get to a research study.

So this one was entitled bilateral ovarian abscesses following platelet-rich plasma injection for ovarian rejuvenation. And they actually put ovarian rejuvenation in quotation marks, which I thought was important. A case report by first author, Vanessa Kalinowska and last author, Elnur Babayev.

Just talking a little bit about what is platelet-rich plasma injection for, quote unquote, ovarian rejuvenation. So when my patients are facing really challenging odds, I know that my patients are on the internet, they're on their Facebook groups, they're really looking for any intervention they could possibly find to improve things. And I'm always having to weigh the risks and benefits of what we're doing.

And if I think there's limited evidence that something's beneficial or limited benefit to them, really thinking about what is the potential for risk of this intervention. And so I think this is a really important case that highlights a very, very serious complication that may or may not have been beneficial or offered benefit for this patient. So platelet-rich plasma or PRP injections are used in many different specialties.

And in ours in particular, they're using it for thin endometrium, ovarian failure and diminished ovarian reserve. And the data so far has been pretty mixed or even conflicting related to this. Ovarian PRP has been explored to enhance ovarian function.

So some of the initial studies did show potential improvements in ovarian reserve markers or IVF cycle outcomes, but there was a recent RCT. I think it was presented ASRM maybe two years ago, but I'll have to check back on that. And it showed no improvement in outcomes.

Furthermore, the authors highlight that the safety is just not really well established. We don't have enough numbers or enough data yet to really see what the complication rate could be with this. So the case they're talking about is a 45-year-old with fibroids, ovarian cysts and dysmenorrhea.

And they don't really describe what kind of cysts those are. And I don't think the author is new actually from her prior history. She received ovarian PRP injections from an outside provider for ovarian rejuvenation.

And then one week later presented with signs of infection. The outside provider started her on augmented endoxycycline. And then one week after that presented to the emergency department and was found to have bilateral ovarian abscesses versus super infected endometriomas.

And I think some of us have dealt with similar findings on imaging and trying to figure out what to do in that situation. So they gave her IV antibiotics. She still was pretty sick.

And so had really severe pain, persistent cysts on ultrasound. And so they actually consulted IR to drain the bilateral cystic structures. And there was a culture that resulted streptococcus anginosis.

And then she improved, but it took a few months to really feel back to normal. So in the discussion section for the case report, the authors talk about infection after egg retrieval is less than one in 200. When I counsel my patients, I think I usually quote about one in 300 for a clinically significant complication like that lands in the emergency room or the hospital.

But with PRP, you know, I think I've always thought about PRP injections as sort of similar risks like having an egg retrieval. But what I didn't think about is that these injections are introducing a blood product which can further increase infection risk potentially. Are we putting an agarose plate in the ovary in this situation? The bacteria isolate in this case was vaginal or skin flora.

So it would be a contamination from the outside. And the patient had this history of the ovarian cysts. She has a history of dysmenorrhea.

Were these cysts previously endometriomas? And that probably would have increased her risk. They don't know whether they were super infected endometriomas or de novo TOAs. And they do cite, the author cited another case study where someone got PID and actually bacteremia from ovarian PRP with endometriomas in place.

So the authors of the discussion overall appropriately state that intra-ovarian PRP injections really should be probably limited to clinical trials. And then another point they make is that we probably should be a little bit thoughtful about who's getting and who's a candidate for this and people with endometriomas that we may decide as a field that that's a contraindication. I think about my egg retrievals for IVF and I'm always a little bit more on guard for my patients with endometriomas thinking, hey, if she calls it pain after I'm bringing her in because she's higher risk for infection.

Interestingly, the authors described that REI physicians may also be qualified to drain TOAs, which I've never thought of as part of my scope of practice, but can totally see why that would be a reasonable statement. And especially in the days before IR, I wonder how often REIs were doing this. And I think overall, the authors just say, hey, we really need more data on ovarian PRP, but we just want to highlight this as a really serious complication that happens or that has happened, it could happen, and we have to be very thoughtful about this.

And there's also an opinion piece that accompanies this case study as well. It's written by Devika Sokdeg and Jason Franasiak. I would definitely check that out as well.

They have a really nice additional overview on PRP. So, you know, I think of one of the most serious complications in our field after egg retrieval is pelvic infection. It is luckily also one of the most rare, but, you know, we all know from our training in the age before broad-spectrum antibiotics, mortality rate for PID with TOAs could be 50%, could mean that someone needs a hysterectomy.

Luckily, we have broad-spectrum antibiotics. We have interventional radiology. We have a lot of other options now, but it's definitely something that we should be very on guard for and a concerning thing for these patients.

So, I was wondering, have you guys recommended, have you performed intra-ovarian PRP? Is it common among your patients? Have you encountered any of these complications in your practice? And then maybe one for Daylon, who might be thinking more about the mechanism. I think, you know, one of the theories about why PRP helps is these mechanical injuries. And then I would think, well, wouldn't just doing an egg retrieval, most of these really DOR patients were doing multiple cycles anyway for banking.

Wouldn't the egg retrieval have just the same benefit and probably lower risk of infection? So, what do you guys think? I personally have never done PRP infusions in any fashion. I know that that's a hot topic and there's more data that's mounting on it. I couldn't agree more with the commentary from Dr. Frenasiak, as well as Dr. I'm sorry, I can't pronounce it.

Is it Sakdev? So, I'm sorry if you're listening, if I mispronounce your name horribly. But I agree with what they're saying, though. I mean, there's the evidence is lacking overall with this, with PRP, especially the safety profiles of this.

So, we as physicians, of course, want to do what's best for the patient. And our field can be really tricky in the scenarios where we don't know what else to do for patients. We've exhausted all of our typical recommendations and it can be tough whenever you're facing a patient and you don't know what else to tell them, aside from, hey, we should just do donor egg.

Easier said than done, right? But you look at this patient, you know, possible endometriomas and 45 years of age, I mean, is doing any measure really going to improve her outcomes, especially something that's still experimental and there's not a lot of good data on it. So, we really do have to be cautious when we're offering these treatments that have the safety profile is lacking and the benefit overall, I mean, is that going to really change anything about her aneuploidy rate at the 45 years of age? A lot of clinics wouldn't even offer this patient any type of treatment rather than just saying, hey, donor egg is just what we need to do at this point or donor embryo. So, of course, that's just an end of one with this case report with this 45-year-old.

So, I don't want to get and talk about how old or at what age should we not be offering patients treatment, but this is a scenario in which we just got to really cautiously and carefully think about, should we be offering these treatments to patients? And this is a pretty extreme example, right? So, I imagine of those who do offer PRP, this is something that's very rare that happens, but it can and it does. And so, we need to be considering these things when offering treatments like this. Do you guys offer PRP at your institution or have you ever done it before? We don't perform it, but we have had patients fly to other providers outside of the Portland community to have it done and then return for IVF cycles.

And I think this is important for me to read because I'm thinking, okay, I'm not the one doing the procedure. I'm not the one counseling them about the risk and benefit. I'm also about limited data or mixed data.

But if my patient has endometriomas, I'm going to say, hey, this could make things worse. I don't know what the percentage risk of this is, but we're dealing with 5% rates of success for IVF for some of these patients. I don't want to deal with that extra 2% complication risk or whatever it may be.

Tell him. Yeah, absolutely. Yeah.

I mean, to answer your question there, yeah, I do wonder about the mechanism with all of these. And it's a familiar story. I mean, there was endometrial scratch, right? Remember that? And then there was this take the ovary out, chop it up, and then transplant it back in.

AKT signaling, HIPPO. I mean, there's a lot of ideas. And I think there's a really high tolerance in assisted reproductive tech for these ideas and trying them out.

Because I think, you know, IVF was born of this kind of living experiment of clinical science, but sure, very experimental. A lot of experiments that probably wouldn't be tolerated now with the current IRB climate. And still, I would say, looking back 20 years from now, I think we're going to look back on a lot of studies with this being one of them, where we're like, wow, we were just shooting from the hip.

But you know, I should say I don't practice. What do I know? I have no idea about whether or not it could work. I think the idea has been pretty well fleshed out in different forms.

I worry about stuff like this, because I think it can be a real black eye generally. But like I said, there's a high tolerance for it. In this case, I'm impressed that there was a case report published that was like negative.

You know, I feel like a lot of times you want to only put out the encouraging results, which I think can lead to a lot of buy-in, inappropriately so, right, with lacking the end. So, I'd like to see this kind of countermeasure. And the last thing I'll say, you know, to my earlier point about what do I know, and the state of the field, the state of the art, it's tough, right? Because it's so opaque in terms of the endpoints.

You don't know if they're not pregnant or not live birth because your intervention didn't work or any one of a number of other things, right? So, it's really hard to rule out efficacy. And I think that that can lead to a lot of, I don't want to say harebrained ideas, but really far out ideas. And sometimes they work.

But there's a quote from this guy, the other podcast I do, I'm a real podcaster, unfortunately not an influencer, just a podcaster. I just speak into the vacuum. But this other guy interviewed, Alfonso Arias, who's a big deal scientist, brilliant guy.

He left a great impression on me when he said that the difference between, you know, what defines science is that it's reproducible. And if it's not reproducible, it's not science, it's art. And so, you think about like practice of medicine, in many ways, you don't even know the mechanisms for, you know, aspirin as an example.

Like, do we really understand completely how all these things work? No. And sometimes you got to be pragmatic about it. But in this case, I would say there's a lot more art than science.

Maybe that's why they call it ART. Cha-ching. I love it.

See what you did there. Well, I think that the authors of this paper too, you know, you mentioned a case report that's negative rather than positive. And I think that they, it's pretty clear they're wanting to basically put this out as a warning sign and just kind of a red flag.

Hey, I know that we're understanding that this is an investigational treatment. It's offered by a lot of providers throughout the country. But here is something that actually can happen that's very serious in case you all are not aware.

So, if you're considering offering this treatment to patients, just know that these type of things can and do occur. So, I think it's unfortunate that this happened, but it's good that this is being published and something that we can keep in the back of our minds. And patients are like, I want to do this or I want to do this.

What do you think about this? That reminds me of a similar case report published a couple years ago about mesenchymal stem cell transfer, which I mean, you guys know what a debacle that's been. But two old ladies who had injected into their eyes for whatever, glaucoma or whatever, ended up having their eyes enucleated. I mean, this is like, yeah, these are the case reports we need to be like, wait a minute.

Let's be careful. Yeah, that's quite scary. Well, Molly, thanks for summarizing that article.

And as a good segue, I'm going to talk about something that is a similar wavelength in terms of topics that are difficult for us as providers to counsel patients on and for patients to hear, hey, I don't recommend doing anything different at this point. But nonetheless, recurrent pregnancy loss is a very difficult and challenging subject. And there are a lot of investigations that are out there that are offered by various providers that may or may not have good data, and some of which may even cause potential harm.

So, the evidence is lacking, safety profile is lacking on a lot of these. So, I'm going to talk about the article is entitled The Evidence-Practice Gap in Immunotherapy for Recurrent Pregnancy Loss by first author Ida Mahler and senior author Henrietta Nielsen out of Copenhagen. And if you all remember, about four years ago, it's hard to believe we've been doing this podcast for that long, but about four years ago, we had someone.

So, Dr. Genevieve Genest out of Canada had come on to our podcast and talked to us a similar article, but now fast forward a few years and they're readdressing this. It's a different author, but it's the same topic. And so, I'm going to talk about this here.

So, a little bit of background on this. RPL, as we know, recurrent pregnancy loss, typically defined as two or more miscarriages, and it affects up to 3% of couples and carries, of course, emotional consequences, but potentially long-term health risk for women as well. And as we know, pregnancy is basically considered an immunologic balancing act.

So, it's an immune reaction, right? So, the immune system essentially sees the fetus as foreign. And so, the body has to undergo a lot of modifications to adapt to that pregnancy. So, it's easy why immune problems can often get blamed for issues with pregnancy loss when there's no clear cause for miscarriage otherwise.

That belief has led to something important. A lot of immune-based treatments are being used, even though the data is lacking evidence of clear benefit. And so, historically, when we look at identifying who needs treatment, there's a lot of studies that are still investigational, but you've probably heard a lot of excitement about natural killer cells or autoantibodies, cytokine levels, immune cell ratios, but none of these have been validated in a way that lets us, as clinicians, confidently say, yes, this patient will benefit from immune therapy.

And so, while immune tolerance is very essential for pregnancy, as you know, the authors of this article emphasize that apart from antiphospholipid antibody syndrome, there are no clear immune biomarkers that exist to identify patients who would benefit from these treatments. And so, as a result, a lot of these studies are enrolling patients of very mixed populations, which make it very difficult to detect the true treatment. So, it's difficult.

I know I personally struggle with... There are patients who will come to me and they've read the stuff online, and they've heard about different immune markers, and even though they're not well understood or well known, what do we do with this information? It's hard to counsel them on what do you even do with this information. So, obviously, we want to help them, but we don't have clear data on what to do with some of these markers. And so, the authors look at what treatments are currently being used.

So, despite the lack of clear diagnostic tools, there's a pretty robust list of immunologic treatments that are being offered in various parts of the country. So, steroids like prednisone, IVIG, lymphocyte immunotherapy, blood thinners like aspirin or heparin, calcium urine inhibitors, so immune suppressing drugs, colony stimulating factor, hydroxychloroquine, and other experimental options too. Naltrexone, that's one that I hear of very commonly too.

And some of these treatments are actually pretty expensive, and they can potentially have adverse health consequences when they're used off-label. And so, what does the evidence say? So, when the authors summarize what the evidence says, they looked at studies over the past several years, and here's what they found. Not surprisingly, you probably can tell me the conclusion before I say this, but most studies are observational, methodologically weak, and small studies.

There are a few high-quality randomized controlled trials that they included in the analysis, but they often show that there's no clear improvement in outcomes or live birth rates, which is our goal, of course. And when the benefits do appear in these studies, they're inconsistent and usually limited to very, very specific or poorly defined subgroups. And so, in other words, the science doesn't support the routine use of these therapies for unexplained RPL.

And there wouldn't be an FNS Reviews article without a really great summary table. So, there is a table one for you, Daylon, that summarizes, they look at, it's called immunomodulatory treatments for RPL and the guideline comparison. So, it's kind of cool.

They look at ASRM guidelines, ESRI, and then ASRI, the American Society of Reproductive Immunology. And then they have another column that has their consensus on what they take of all of these different guidelines. And it includes the mechanism of action of all these different treatments, the strength of evidence or lack thereof, key studies cited, and estimated costs.

So, it's kind of cool to have like dollar sign and how expensive things are. And this is something, too, I feel like is a counseling tool that we can show patients to say, hey, here's this nice summary of all of these treatments that you may have heard about online or that you're asking me about. And it shows here there's really just not good data at all.

And you can actually see how expensive it is, too. So, if anything, for those of you who might have like a Rolodex of PowerPoint slides, I personally have like one that I shuffle through. I'm probably going to add this into my counseling PowerPoint.

And so, the authors talk about risk benefit. And so, this is where the authors say that a lot of the tension comes in. So, some treatments carry a risk of infection, hypertension, gestational diabetes, preterm birth, fetal growth restriction.

Things are quite serious and cost thousands of dollars, sometimes tens of thousands of dollars, and even per pregnancy attempt. So, doing this multiple times per different pregnancy, if you're miscarrying more than one time, for example. And of course, these come with a significant emotional consequences, too.

So, the authors point out the offering these therapies can feel compassionate, especially to patients who, as we know, are desperate for answers. But the authors argue that hope alone is not a medical indication. So, then they conclude talking about the evidence and practice gap.

So, there's a gap between what we as providers wish immune therapies could do and what the evidence proves. And because we can't accurately identify immune-mediated pregnancy loss, clinicians are often treating blindly at times. And the research keeps repeating the same mistake, as the authors say, by enrolling overly broad patient groups.

And so, moving forward, as you probably could guess, the authors say that we need to have better trial design, precision medicine approaches, biomarker discovery built into the trials, international collaboration, and restricting immune therapies to clinical trials until evidence does improve. So, until then, the authors discuss that it's important that we have supportive care, honest counseling, and remain the most evidence-based approach for most of these patients, which definitely agree. And so, bottom line, they say that right now, immune-based treatments for unexplained RPL are mostly theory-driven and not evidence-driven until we can reliably identify who actually benefits from these treatments.

These therapies do risk offering more promise than proof and sometimes more harm, too. So, I felt like that was a good segue after, Molly, after your case report. So, what are your thoughts on this? This is something I personally struggle with a lot, and it's hard to tell patients, like, all right, we've done all this workup, and there's really not anything good we can offer you at this point.

It's tough. So, what do you guys think about this subject? I'm just laughing because, for once, I'm not the only one with a story about experimental clinical applications here. In fact, it's a threefer.

You know what I wonder about this type of stuff is, and this is very specific, but there are, there's at least one practice that I'm aware of that, like, I wouldn't say exclusively, but is super enriched. You know, it's like the number one referral for these patients. So, I'm like, if you have that volume of patients, why can't you throw together, like, a pretty comprehensive study? And, you know, first, cynic in me is like, because it doesn't work.

But the reality is that, also, these patients are tremendously complex, and it's the same thing. You can't put your finger on what the etiology of their struggles are. And in many cases, maybe there is an immunomodulatory component, but without really defining the nature of the problem, it's hard to see whether you're addressing it, right? Like, number needed to treat on this, you're never gonna have any idea.

So, we're totally in space. And while I think there's a lot of optimism in your story, I think this is one of those things that we need a kind of a paradigm shift in order to understand and, or, like, address this in a rigorous, you know, effective way to get this an answer. So, I'm very, very bearish on immunotherapy for all those reasons that you said as well, just because it's not just, like, the lack of evidence that it'll work, but it's the cost, you know, emotionally and economically to the patient.

So, at least there's no risk, right? You're not gonna get oophorectomy after it. So, I guess it's better than at the PRP. DR. HOFFMAN-WILSON I don't know if it's better than the PRP.

I mean, steroids in pregnancy is no joke. But, yeah, I agree completely. I'm glad this exists.

This is really helpful for me because sometimes I can't keep track of where the data is on each thing. And I generally think if something seems too simple, if it's simple enough that you can explain it or understand it with a TikTok video, it's probably not effective. Like, you know, with the PRP, oh, it's injury.

Well, it's more complicated than that. And the patients say, well, I think I'm having an autoimmune response to the implanting embryo. Why don't you give me steroids? And it's like, well, I actually do want a little bit of inflammation.

It's a pretty complex process for implantation that's still incompletely understood. We don't want to go the other direction. And so I think there is a role for trying this catch-all approach when nothing else has worked.

I think we're on the fringe of medicine where what's at stake is someone's chance at a child, potentially, and for many people, the most meaningful thing in their life. And so I think if you've tried everything that's by the book, and then you have to go a little outside the book and the patient's well-counseled on risks and benefits, it can be acceptable. But after two unsuccessful euploid transfers, that's not the time to break out the IVIG.

And so a really nice review, really helpful to have in our armamentarium. Can I ask that in this review, is there a consensus in terms of the standard of care, delivery, dose of anything? Because that's the other thing with this. You wonder about science and art, depends on which artist you go to.

Do I want to go to Michelangelo or some kindergarten hack? So I worry about, and I totally agree with you, this is within the patient's, this is their choice, and they should be enabled with information, all that stuff. Ultimately, it comes down to them. But I have so many concerns about can we at least create a framework where these approaches are comparable or standardized? I think maybe that would be a tangible step forward for these practice committees.

Well, and that's, yeah, that's a great question. And that's where this particular article differs from the previous one that I mentioned from Genevieve Genest out of Canada, because that's, their table one is basically what you had just said. It has, similarly to this, it discusses the possible risk, the strength of evidence or lack thereof, what the recommendations are, and it does have dosages of like what was looked at in these studies that we looked at.

So if you are going to prescribe this, here are the theoretical risks, here is the possible evidence or the slight evidence that's there, and here are the doses that these papers looked at. So it does kind of answer your question there, where it gives, it delves a little bit more into that. And a couple of treatments that this particular paper did not discuss that was on the previous one on Genevieve Genest paper, and I see all the time is IV lipid infusion, something that we as adults strive for all the time is to keep our lipids low, but yet certain people will go into different centers and have lipids infused into their body.

And that is something that you got when you really want to consider something that could cause harm. I mean, that's definitely going to be at the top of my list, and is also quite expensive too. But I know that there are places out there and that offer these things, potentially some of our listeners on this podcast too.

So not to knock these clinics, I don't, I've never actually done this for a patient and, but just in the grand scheme of things, data is lacking. And I would like to see more studies put forth on this. The question is why you need the IV lipid infusion if you can go do the post-transfer McDonald's French fries? Yeah.

Yeah. Which we all know has the absolute best evidence behind it. So yeah, we've joked about that before on our podcasts where we have, like literally all of my patients do that.

They say that they're going to do like, you know, I'll have small talk when the embryologist is checking the catheter, make sure the embryo wasn't retained. Like, all right, what are y'all's plans? Like, well, we're going to go eat McDonald's fries. And just literally everyone says that.

I'm like, okay, that's, that's fine. Just no IV lipid infusions. Okay.

So anyways, I digress, but I felt, I felt this was a very interesting article and great for patient counseling. So Pietro, I guess we're not going to see today. He must be tied up, but we will miss him on our podcast today.

But DeLon, why don't you bring us home? The last article we'll be discussing today. Why don't you tell us about that? I will do my best. And you know what this article has that your science, let's call it doesn't, is a model, right? We need a model for PRP.

We need a model for this immunomodulatory therapies. And here we have a model, which is the rat. I know you guys are rolling your eyes.

I'm going back into the animals. This has some relevance. In fact, this is rats doing some very human stuff.

And we're talking about smoking, right? Which you probably like who smokes anymore. And it's, it's true. It's kind of faded out.

It's been shamed away in America. The kids are over it. Vaping still, I guess.

Yeah. Juuls and vape pens now. Giant battery packs that they're smoking.

Exactly. Many clouds. But yeah, I mean, the stats are in, which is that tobacco use is certainly on on the down.

And even nicotine use in certain parts of the world is in decline. But there's still a lot of smokers out there. Still a lot of people using tobacco products.

20% prevalence rate among adults. I didn't know that. Including a third of all males.

And 40% of male factor infertility is linked to smoking or consumption of tobacco products, which seems pretty high. But hey, the numbers are there. There's a reference.

That's worldwide. And it's not just smoking, right? But secondhand smoke, this so-called environmental tobacco smoking or passive smoking. And I don't know, maybe because smoking has been faded.

Do you guys, I'm sure it's part of the boilerplate counseling, but what's your counseling to patients on whether or not they should stop smoking? Of course, they should stop smoking. Anyone ever like, do I have to? What's your rationale? How do you convince your patients to stop smoking in pursuit of fertility? I recommend three months, stopping for three months for both the sperm and egg contributor prior to proceeding with IVF. If they want to proceed, I'll say, I've had cases where it was fine.

And I've also had cases where despite a good egg count or despite normal appearing sperm, we've had terrible fertilization or blastulation. So most of my patients are self-pay. So most of them are up for a three month abstinence period.

But of course, it's hard to quit. So balancing with that. Yeah.

Well, Blake, you got some counsel? Similar to Molly. I mean, I admittedly don't have like a, hey, you should stop for X amount of time before we start treatments. I mean, it would make sense as to why you would give that timeframe, especially in terms of spermatogenesis.

But I will also tack on to what Molly said and said, there's not really a safe amount that you can, because they're like, oh, yeah, I'm looking, I'll cut back. And we don't really have a safe amount like, well, you can smoke like five cigarettes a day and still probably be okay. So I usually just encourage cessation.

But of course, acknowledge easier said than done. But there's known adverse implications for reproductive health with tobacco, marijuana, smoke, things like that. Yeah.

And that's the thing, right? I think, you know, you counsel your patients and they're just like, yeah, of course I shouldn't be smoking. But there's actually very specific mechanisms that undermine fertility. Nicotine and its metabolite, cotinine, are endocrine disruptors.

And they bind this alpha-7 subunit of the nicotinic acetylcholine receptors that are present all throughout spermatogenesis and spermatogonias, spermatocytes, sertoli cells, even in lytic cells, even these neuron-like cells that are associated. So, you know, there's a lot of direct mechanisms within the endocrine axis and within the gonad. There's also this idea of the brain testis axis that I wasn't aware of, whereby nicotine elevates catecholamine release.

And then that floods these local neurotransmitter systems, namely dopamine and its receptors, D1, D2, that are in the testis. And then there's this other thing that goes on, that I was totally unaware of, where you get altered expression of these neurotrophic factors, one of which is brain-derived neurotrophic factor. And that's what we're talking about today.

So, going after this specific neurotrophic factor, BDNF, in spite of the fact that clearly there's a whole spectrum of mechanisms by which nicotine, tobacco products, nicotine metabolites, etc. can undermine male and presumably female fertility in different ways. They were going after this one specific putative mechanism to see if they could protect, offer some prophylaxis against that.

And this is a group, story is first author Deepsi Rathore, and the senior author is Vijay Kumar Shivgotra. They're from India. What they did is they focused on this ANA12, right, which is this selective non-competitive antagonist of TRACB, which is the receptor for BDNF.

And the idea here was that they would expose rats, in this case their model, to smoking. They got some rats back in the lounge, attacking butts. Actually, no, they had a little smoking chamber, adult male rats that were in these smoking chambers, or they were gavaged with nicotine for oral administrations.

And both those groups, in addition to healthy unexposed controls, were pre-treated with this ANA12, right? And the administration period of the nicotine, tobacco products was four or 12 weeks, right? So a pretty long-term study, kind of, I guess, relevant to those intervals that you guys talked about in terms of cessation, a place to start in order to clear the impact on the endocrine and organadol function. And what they found was as expected. The administration of the smoking or the oral gavage of nicotine disrupted spermatogonias, spermatocyte spermatids, reduced sperm count and quality.

And there was this upregulation of BDNF and its receptor TRACB, beta, and as well as a dopamine axis. It was all upregulated. So I think that was a strong indication showing that there is a link between the tobacco product consumption and the upregulation of this axis, which I think was important.

And then further, they go on to show that if you pre-treat with this ANA12, you get a rescue, either whether it's the four-week or 12-week time point, you get a kind of significant rescue and restoration of sperm function, quality, et cetera, as well as downregulation of those kind of neurochemical perturbations. So a very straightforward study using this relatively robust model, I would say, not a large animal primate or anything like that, but the rat is, I'd say, solid. I mean, more solid than mouse, which I know, again, you guys are rolling your eyes.

But I like this because, hey, you know where they smoke a ton? India, right? 120 million smokers in India, 12% of the whole world's population, most smokers are in China. And also, a ton of those smokers are consumers in India. They consume tobacco in this smokeless fashion, almost a third of the consumers.

So I like this study because it's going after a problem that is, you know, at hand. And with all these kids vaping and our population decline, we may need to get some of this ANA12 into the mix over here and everywhere with sperm quality in decline for all these unknown reasons. Here we have a clear reason and potentially some prophylaxis.

So cool study out of India. Light them up, guys. I don't know that light them up is the takeaway here.

Yeah, so do you think that we could conclude that, so with vaping, because vaping seems to be just so common, and unfortunately young kids are doing it. I hope not as much. I mean, you know, you think about when we were in middle school and high school and a lot of kids, like, think, you know, they're cool and they start smoking.

I feel like vaping is even more prevalent than when we were younger. So I do foresee a big problem with all these kids vaping and carrying it into their adulthood as well. Do you feel like this study is, we could say that the harm is equivalent to smoking cigarettes? In terms of reproduction, for sure.

I think it's more the nicotine administration. And I think what you find, which is scary with the vaping, is that it's really high doses. These doses escalate.

These people are taking more nicotine than they would take smoking cigarettes. But obviously, yeah, I mean, I wouldn't put it on par with the general health impact of, you know, all the toxins in cigarette smoke. But for reproduction, I think it's important.

Maybe the only thing we have going for us is that the e-cigarette use is really trending with the girls more than the boys. So I think while the damage there is perhaps equivalent, if not worse, maybe a silver lining for young boys. But yeah, we're all in trouble, Blake.

I would buy up some ANA-12. Yeah, well, hopefully these teens don't find out about ANA-12 and they're just like, oh, we're fine. We'll just, Daylon says, we can just take this daily and we're okay.

It'll be the next TikTok supplement. You take the rats and then everyone just starts taking it with all sorts of toxicities. I think there's some data on vaping out there, not as much as I would like.

And I wanted to do our own study. But when we look at our questionnaire for our clinic, it says smoking, yes or no. A lot of my patients mark no.

And then when I grill them, they're actually vaping or they're using oral nicotine. These like Zin packs are super popular. I think vaping is going to be just as bad in different ways because burning hot plastic is a recipe for endocrine disruption.

And so burning paper with all its chemicals, burning plastic, it's all bad. And I think it's just a lesson for physicians. We have to ask all the questions, but any more data that shows us this is harmful to show our patients and shows us, and anything that could be harm reduction in the future, I think is great.

So interesting new direction. Yeah, for sure. We keep coming up with creative new ways to administer these drugs.

And you know what? It all comes down to the same problem. It's not good for us and we'd be better off cutting it out, but easier said than done, as you both have alluded to. All right.

Well, Daylon, thanks for summarizing that interesting article. And for our listeners, thank you as always for joining us. We greatly appreciate it.

Hopefully next time we'll have the whole band back together. And please let us know if you have any comments or gentle criticisms of the podcast we will consider and take with a grain of salt and Daylon will get responding to in a timely manner. But in all seriousness, we really appreciate all of our listeners.

Until next time, take care. This concludes our episode of Fertility and Sterility Unplugged, brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine. This podcast is produced by Dr. Molly Kornfield, Dr. Adriana Wong, Dr. Elena HogenEsch, Dr. Selina Park, Dr. Carissa Pekny, and Dr. Nicholas Raja.

This podcast was developed by Fertility and Sterility and the American Society for Reproductive Medicine as an educational resource in service to its members and other practicing clinicians. While the podcast reflects the views of the authors and the host, it is not intended to be the only approved standard of practice or to direct an exclusive course of treatment. Opinions expressed are those of the discussants and do not reflect Fertility and Sterility or the American Society for Reproductive Medicine.