Fertility and Sterility On Air - Unplugged: September 2025

In this month's Fertility & Sterility: Unplugged, we take a look at articles from F&S's sister journals! Topics this month include: whether the optimal time interval for trigger varies depending on the trigger medication used (02:36), the mechanisms by which different trigger medications affect final oocyte maturation (16:05), how alcohol alters the blood-testis barrier function (31:10), and an analysis of the TikTok content specific to endometriosis-related infertility (45:15).

F&S Reports: https://www.fertstertreports.org/article/S2666-3341(25)00114-X/fulltext  
F&S Reviews: https://www.fertstertreviews.org/article/S2666-5719(25)00010-6/fulltext
F&S Science:  https://www.fertstertscience.org/article/S2666-335X(25)00050-3/fulltext
Consider This: https://www.fertstert.org/article/S0015-0282(24)00873-2/fulltext

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.

Hi, everyone, and welcome back to another episode of F&S Unplugged. I am your co-host, Pietro Bortoletto, joined by the ever-present, ever-dashing, ever-interesting Molly Kornfield, Blake Evans, and Daylon James. Guys, how you been? Which one of those am I? Am I the interesting one? A gentleman wouldn't ask, and a gentleman wouldn't tell, and I'm sticking to that.

My mom says that Blake is her favorite. I don't know if that's because he's present or dashing or what. Well, your mom's my favorite now, and I want to just give a special shout-out to a couple of longtime listeners, Travis Kelsey and Taylor Swift.

Congratulations on your engagement. We know you're listening. We're so happy for you.

We love you guys. I actually squealed in the clinic with delight, and nobody else cared. It was just me, but all the docs on my hallway, we were all freaking out, and none of our nurses, none of our navigators, none of the patients were particularly excited, but the Swifties all become REIs, I guess.

Well, we could talk all day about Taylor Swift and Travis Kelsey, but we've got to talk about... But unfortunately, we have to talk about science, and we have to talk about F&S reports, reviews, F&S science, and consider this. Molly, you have a really cool article in F&S Reports this month talking about the triggering oocyte maturation and talking a little bit about optimal timing. Tell us a little bit more about that article and how it may be relevant to our practice.

Yeah, thanks, Pietro. This was a really interesting article. It was called Optimal Timing for Triggering Oocyte Maturation During In-Vitro Fertilization Cycles, Berries, Between Gonadotropin-Releasing Hormone Agonists and Human Chorionic Gonadotropin Use.

The first author was Noritoshi Enatsu, the last author ∙ Masahide Shiotani, and the authors were all working from Japan. I thought this was a really interesting study. I think a lot, and we talk a lot here about trigger type, how long the trigger is sustained in the corpus lutea, how it relates to fresh transfer, OHSS risk, how it relates to maturity, anticipating a potentially more robust response, lower risk of failure with HCG trigger.

But I personally have not done a lot of reading about retrieval intervals and trigger types beyond just the basic Yen and Jaffe chapter on it. So I think most of our listeners know about the two primary trigger types we use, either a GnRH agonist to induce the endogenous LH surge and promote maturation, or an HCG trigger, which is molecularly similar to LH, binds to LH receptors and then promotes final oocyte maturation from there. There is some variation between clinics in the interval that they use between HCG or GnRH agonist trigger shots and the egg retrieval.

And the percentage of M2s based on prior data may be increased by a prolonged time from the trigger shot to the egg retrieval itself. Most prior data actually looks at HCG triggers. And I'm assuming that's just because there's less data on GnRH agonists, because there are relatively newer development in our field that we're using these with ANTAC cycles.

So this study by the authors is a retrospective study. It looked at 59,206 IVF cycles at a private clinic over a 14-year period. They only looked at HCG or GnRH agonist triggers alone, and they did not look at dual triggers.

And they included GnRH agonist cycles, GnRH antagonist cycles, and oral progesterone or progestin suppression cycles. Their intended trigger interval was 36 hours. But they talked about how sometimes there are deviations due to clinic practices.

And that was really interesting to me about imagining how this clinic's workflow is. You know, we all have different flows. And they said if they had a late visit on a trigger day, like into the evening, so they're seeing patients for scans in the evening, which I think some of our patients would really love.

If that patient's trigger was really late in the evening, and that could mean that they had a longer or shorter trigger interval. And then if the case was also delayed due to other issues in the clinic or prior retrievals running late, or if the patient's made a medication error. So that's where they're getting this variation from the ideal 36-hour trigger.

And interestingly, the GnRH agonist they used was Buserelin nasal spray, 600 micrograms, and then another dose one hour later. The other group, the HCG group, it was between 3 to 10,000 of HCG or the 250 units or micrograms of chorionic gonadotropin alpha. And they said that the HCG dose they used was often weight-based.

So what did they find? So their study looked at 40,793 GnRH agonist triggers, 18,413 HCG trigger patients. Their average interval between trigger and retrieval was 36.4 hours in both. So off of that target of 36 for their clinic, they probably just expect to run a little bit behind based on how they're set up.

So then they used 36.5 as the reference point, and then they evaluated hourly on either side to look at how trigger type impacted maturity. They had interesting findings. So they found in the GnRH agonist group, they found that more M2 oocytes were retrieved with a longer than 37.5-hour interval, so a longer interval.

And they also saw more blastocysts and higher-quality blastocysts with that longer interval. In the HCG trigger group, in contrast, they had significantly more M2s with a shorter interval of less than 35.5 hours. And the difference was substantial.

It was 5.5 versus 3.2 M2s. But interestingly, they also saw higher number of blastocysts between 35.5 and 36.5, and then the highest-quality blastocysts were between 36.5 and 37.5. So even though they're seeing more M2s with this shorter trigger type, it's not really improving the blastulation, and the blastulation may still benefit from a little bit longer, similar to the GnRH agonist. They also broke it down by age, because I think we're all thinking this really matters based on the patient's age.

They saw the same trends in the older age group, but the differences were actually more pronounced between the trigger types. They also did look at number of M2s per total oocytes retrieved, and they did not see a difference in that case between short and long intervals. And they looked at risk of cancellation from ovulation, because I think I start sweating at the 36-hour point, and I don't want my case running late because I'm worried about premature ovulation, especially for DOR or AMA patients.

And they actually did not see a difference in cancellation from ovulation for their patients. But they did talk about that there could have been aspects of partial ovulation going on, so they were getting fewer eggs in certain outcomes. And is that because there was partial ovulation? Was there premature luteinization, which is, I think, where my mind was going? And they were thinking HCG triggers may get more M2s with the earlier trigger, because the potency of the HCG trigger increases the progesterone much faster.

Are we getting more early luteinization in that case? They did do a multiple regression, looking at the things that we all think of, age, AMH, and then they looked at number of ARTU cycles, and I think that's kind of a proxy for prognosis in this group. And the main findings they had really persisted even after those controls. Longer interval with more maturity for GnRH agonists, shorter interval for more maturity with the HCG trigger.

In the discussion section, the authors actually talk about some data that I hadn't looked at personally myself yet, that increasing interval from HCG trigger to retrieval actually improves clinical pregnancy rates, but there also is some data that didn't really show much of a difference. Because, of course, this study is using kind of the proxies of blastocysts, good quality blastocysts, but not showing us those pregnancy rates. The authors also note prior studies looking at GnRH agonist triggers for shorter or longer intervals and didn't really find much of a difference, but they think those studies were probably underpowered, and in these authors' defense, they had 59,000 IVF cycles, so they were probably powered for what they were looking for.

I think the basic physiology of GnRH agonists and HCG triggers don't quite support their findings. I'm still kind of adjusting to how I'm thinking about this. After a GnRH agonist trigger, LH is peaking about four hours later.

HCG trigger is about 15 hours later, so I think, okay, later LH peak, wouldn't maturity be later as well? But the authors point out HCG is about five times as potent as LH and has a greater affinity for the receptor. And so there might be earlier stimulation of the human granulosis LCA and P activity, and then you might be resuming meiosis earlier with your more natural surge. The clinic actually described that based on the findings from this retrospective study, they are extending the GnRH agonist triggers after 37 hours, and for HCG, they did stick with the 36 hours, but they make sure to run on time for the older patients, which I think makes sense.

Something I just noticed about this paper, the egg counts that they were getting were quite low for the patients, and the patients did a lot of stimulations. And so I don't believe they broke down the different cycle types, like min-stem, standard dosing. And so I wonder if they're doing more min-stem cycles with fresh transfers here.

I don't know what common practice is in Japan. I believe it is a state or a country that does cover IVF for patients. And so I don't know how that plays out in actual practice.

Other limitations, you know, intranasal buceryllin is going to be different from injectable GnRH agonist. And then the authors point out this is a predominantly Japanese population. And of course, it's a retrospective study.

There may be some differences in how we're managing these patients. And as we'd expect, the population with HCG triggers had a little bit lower ovarian reserve than the GnRH agonist triggers, but they did nicely control for those things. So my takeaways, I think it inspired me to be a little bit more brave with my trigger lengths.

And to do a bit of a deeper dive into the literature myself about what's already out there. And there may be people who are going to ovulate, but most people won't. And if I'm having a maturity issue, I could push a little longer.

What do you guys think about the article? What do you think about the findings? Are you guys going to go longer for this GnRH agonist? And I don't know what to do with HCG based on these findings. Do I go shorter? Do I go longer? I'll probably just stick where I am at. It's hard to not think pretty seriously about making changes, just given the sheer volume of patients that they have in this study.

But us REIs are typically a little reluctant to make such drastic changes, especially if it's a matter of changing this long when you do a retrieval. This shows on some of these, they had 37.4 hours plus or minus .8 hours. So getting close to 38 hours after trigger.

We do 35 here at our program. In my fellowship training, we did 36. So waiting that long, I agree with you, I'd be sweating.

But with this volume of patients too, it's hard to not ignore. I'll be honest, I don't know if I'd make any direct changes after this, but it's certainly something to think about more. Can I just ask a question from where you go with this standpoint as a clinician who has an interest in science? Do you initiate a study in a different center? Because I wouldn't say irregularities, but the differences that you see in the egg yield and the ambiguous nature of the HCG, is this enough, would you say, to launch a perspective? Or is the first part you just go into someone else's data set and find similar groups? Like what's the protocol here? I think the first tenet of science is to try to replicate it.

And this is a nice retrospective cohort. See if you see the same signal in different lab, different patient cohort. And I think if there's enough noise in there, then obviously going to the perspective, randomized into that nice homogeneous group to really try to measure an effect.

I have a couple of misgivings about this study. I think if we're talking about elephants in the room, one of the major elephants in the room here is that they didn't really stratify or control for method of fertilization. One of the common things that we talk about after eggs are retrieved, regardless if it's 35, 36, 37 hours, is do we keep the cumulus cells in the gap junctions intact through conventional insemination for an additional 24 hours overnight on that egg? Or are we mechanically or chemically stripping those cumulus cells, breaking up those gap junctions and performing ICSI within two, three hours afterwards? I think that's a huge elephant in the room.

And in the method section, I was combing through it while we were talking. They just kind of said IVF or ICSI was performed, and I was barreling through the tables to see if there was any stratification, any adjustment for it, and there wasn't. I think that's a missed opportunity here to kind of tackle that question of does keeping the cumulus cells together after a 35, 36, 37-hour trigger modify that effect? Or does it confound it? I think it probably does.

What do you think, Molly and Blake, from a clinical perspective? Do you have kind of the same intuition that you'd want to see that? I do agree with you, and I have a couple of other kind of eyebrow-raising numbers, too. Like, Molly, you alluded to a couple. Like the oocyte number, I just find some of these quite a bit different than what I would expect.

You know, if I have a patient with an AMH of 2.2 plus or minus 2.6, and the number of M2s per cycle is 3.5 that they're getting and ultimately having one blast, that's just a little surprising to me. So maybe these eggs are being ovulated into the abdomen. They're not retrieving them because they're waiting 37 hours.

So I'm joking, but also maybe serious. Those numbers seem a lot different from what we would expect in that patient. So I have some questions about this study in general.

I don't think it's going to make me change necessarily, but I agree with what Molly said. I think maybe we can be a little bit more lenient if we're in a bind and need to wait a little bit longer for various reasons. I think a patient with real maturity issues, I have tried a later trigger.

I've done 37 hours, and they didn't ovulate. So I think for the specific patient, this gives us a little more comfort with that. But yeah, I think this plus hopefully some more similar studies would be ground for justifying your perspective or randomized trial on a similar topic.

Jealous of 59,000 cycles available for review, though. That's pretty rad. Right.

All right. Let's stick with the topic of maturation and the oocyte. It's not often that we have kind of similar theme articles across the sister journals, but Blake, you have some from F&S reviews.

I do. Thank you. And I apologize if you can hear sirens in the background there.

There's something that's happening. But yeah, very nice segue to this paper that I'm going to go over. It's entitled Final Oocyte Maturation for In-Vitro Fertilization, a Comprehensive Review.

And so this is by first author Evelina Manvelyan and also Dr. Rachel Weinerman out of the University Hospitals Cleveland Medical Center. A little bit of background. I wanted to also just put a plug in for all the fellows out there.

This is a fantastic review that I would strongly recommend reading over. I actually had sent this to my fellows before we did our podcast today and said, hey, you guys need to check this out. This is great.

But it really goes into some nice physiology of the medications that Molly was just talking about and breaking down just some of the details between the different types of triggers. So a little bit of background per usual before we do these review articles. ART success rates have, as we all know, improved greatly since IVF was first developed in the late 70s.

Complications such as OHSS have also dramatically declined due to changes in how we give trigger shots and protocol adjustments as well. Final egg maturation is achieved typically by one or two medications and sometimes a combination, HCG or gene or H agonist, as Molly had discussed. These lead to oocyte maturation by allowing the resumption of the first stage of meiosis.

So for those of you taking score at home, this is the diplotin phase of prophase one that it is arrested in until the trigger shot occurs. And this review explores how the different triggers can lead to the final step of egg development at the time of egg retrieval. So going to break down these different trigger shots.

First, HCG trigger. This mimics the body's natural LH surge, but it lasts longer. It supports the luteal phase, but raises the risk of OHSS.

So I'll get into that here in a second. HCG administration has shown to increase the cumulus and granulosa cell production of VEGF, vascular endothelial growth factor, in a dose as well as time dependent manner, which we know is largely VEGF is the culprit for how OHSS can develop and lead to those leaky capillaries, so to speak. Giving HCG alone assumes a couple of things.

For one, the alpha as well as the beta subunits of HCG are binding similarly to LH receptors. And two, the LH surge alone is sufficient for achievement of final oocyte maturation. But we know that the LH surge is also accompanied by a little bitty FSH surge as well.

And this has been shown in previous studies to also be important part in the final oocyte maturation process. However, there was a study, a 2012 study by Casarini et al. that showed that when they look at the second messenger systems between HCG and LH endogenous LH receptors, they actually act a little differently.

So LH, or excuse me, HCG was shown to produce higher CAMP, second messenger downstream effects. And LH on the contrast was more involved with the ERK1 and 2 and AKT pathways in the non-pregnant patient. So they work a little bit differently in their second messenger system and possibly behind why these things may lead to different outcomes when you look at endogenous LH versus HCG.

So then shifting gears to GnRH agonist trigger, this simulates the body's own release of LH as well as FSH. It is safer in terms of OHSS risk reduction as in these patients that are high risk for OHSS, but we know that it's quite luteolytic. The half-life is very short.

It's not bound to these cells for a very long time. And because of this, it has been associated in some studies with lower live birth rates and a fresh embryo transfer cycle. For those that would be giving a Lupron-only trigger and a fresh embryo transfer cycle, I realize that's something that's not going to happen hardly ever, if at all, this day and age.

Hey, I've been there. I've done it. No judgment.

No judgment. I'm just saying it doesn't happen often. OK, pop quiz.

Do you all know why it's called Lupron? I love the quiz. I love the quiz. I don't know why.

The subunit change within the decapeptide. Yes. OK, so I love asking my fellows this question.

So it's a decapeptide and there is a substitution for a D-amino acid in the 6th position just prior to the leucine amino acid. And then next to the 10th position, the proline, there's a substitution and an addition of ethylamide to increase the half-life, basically. So leu and pro are where the substitutions occur.

So hence the name Lupron. I hope that for some of our listeners, Travis Kelsey and T-Swift included, that is news to them. And they've learned something today.

And Ganirelix and Cetrotide follow the same pattern. Indeed. It's really nifty once you actually start to look at the chemical composition of these molecules.

It was a lot of trial and error. They just had to like switch around this amino acid for that one, see if it did anything differently. So clever.

It is. Agreed. It's just fascinating.

So anyways, back to the article. So GnRH acts directly on gonadotropin receptors, and this causes an endogenous LH as well as FSH surge produced by the pituitary. So notably, the benefits of a GnRH agonist trigger may go beyond safety.

There's previous studies that have been demonstrated to show an increase in the production of mature oocytes as well as improved fertilization rates with these oocytes compared to an HCT trigger. And so therefore, to obtain the benefits of both of these, alas, the dual trigger has become very commonly utilized. So the authors talk about a dual trigger, which is, as the name implies, a hybrid between the two.

And there are quite a few studies, and you better believe there's a big old table in this article that has tons of studies. And it shows the HCG dose, the GnRH agonist dose, the outcomes that are superior, and most all of these superior outcomes in terms of oocyte maturation and fertilization rates and blastulation by a small degree, but it is certainly there. So the dual trigger has been shown to have better pregnancy rates compared to GnRH agonist, according to the authors and the studies that they reviewed.

And this is expected given the prolonged alluvial support from HCG. So it's higher affinity of binding, it lasts a lot longer, but also it's been shown to be superior to just HCG alone, which is not necessarily expected because these are both going to be binding. When you give a dual trigger compared to HCG, they're going to have a lot of similar binding for alluvial support.

But the possible explanation is an improvement in oocyte maturation because you have that endogenous surge of the LH and FSH. And so this has also been shown as improved outcomes when you include also fresh and frozen embryo transfers from the combined dual trigger. So they, again, just think that there's something innate in the improvement of oocyte quality and blastulation quality as well.

And the authors say that to the best of our knowledge, there have not been any dose finding studies to identify the ideal combination for those. So you guys use a dual trigger pretty often in your practice. So the HCG, and I know I've texted Pietro about this too in the past, but the HCG dose really, it varies a lot from clinic to clinic.

We typically give at least 5,000 if it's someone that's not a high risk for OHSS, but we're still maybe considering a fresh embryo transfer. Or if they are at somewhat of an OHSS risk, but we're still maybe considering a fresh transfer, give 2,500. But then you give increased estrus and progesterone and alluvial support.

And that's kind of what the authors have found here. So they kind of break it down into what based off the data shows and what their recommendations are. And yes, you guessed it, a nice little table.

But they say that in normal responding patients, they ultimately recommend based off the data to give a dual trigger with a small amount of HCG, such as 1,500 to 2,500 and at least two milligrams of leuprolide acetate. We give four milligrams. And so that made me feel better that we are giving more than what a lot of these studies show.

For poor responders, they say, OK, OHSS risk is low. Still give a dual trigger because there's data showing improvement in outcomes. So give 6,500 of HCG plus at least two of leupron or some variation of that.

And then for high responders, it's obvious leupron only is what they recommend. They even discuss some studies will show that even in high responding patients that are at OHSS risk to still give 1,000 units of HCG. And these overall still have an overall low risk of OHSS.

So kind of my comments on this. This is a great review for fellows, and I had sent it to my fellows before we started this podcast. It goes into some really good physiology of the trigger shot.

And I think it's important to you that I think one size doesn't fit all. When we consider these trigger shots, we need to consider, of course, patient safety. Are they doing a fresh versus frozen transfer? And then the authors conclude by saying there's a large body of evidence suggesting that advantageous outcomes of utilizing a dual trigger over HCG alone.

And similarly, several studies indicate benefit and dual trigger over even a generic agonist alone trigger. So I thought it was a nice segue from Molly's study, too. So what are your thoughts on this? Very few good, compelling reasons to not give a dual trigger.

I think the only one is cost. And then the second injection. But for a patient who's already committed to two weeks worth of injection, that second shot that night.

Yeah, very little downside. I think the elephant in the room for so many underwhelming IVF cycles or variability. I think there's a medication error.

I think patients mess up things and don't share it with us because they contribute a lot of time, energy and effort to this. And oh, my gosh, I can't believe that I messed this up. I leaked out half of the medication.

The trigger shot is so important. And I think you'd be foolish not to use two medications to make sure it goes well. And you kind of have the benefit of both the short acting and the long acting and the dual coverage of if one fails, the other one should work just fine.

Cornell spent a lot of time thinking about the triggering dose. They did a lot of internal review of their data and published a lot of it. And one of the things that they did was they used a sliding scale HCG dose based on the estradiol at the time of trigger.

The rationale was the higher the estradiol dose as a proxy for a strong ovarian response, risk of OHSS. And Cornell is still a program that does a fair amount of fresh embryo transfer. So to allow for the fresh transfer and risk reduce as the E2 went up, the HCG dose dropped.

That worked really well. I can tell you that in three years of fellowship, I saw two cases of hospitalized OHSS and neither of them were our patients. They were from other IVF clinics in the city.

So I've kind of brought that into my practice and we'll kind of tweak the HCG dose depending on my threshold of worry. But I really like that approach. And the way that we kind of calibrated it on the back end was we would always check post trigger lapse.

So if they triggered with HCG, we would check an HCG level. If they triggered with LH, we would check an LH and a P4. And that gave you some really nice feedback to see what was the effect of that trigger for that patient with that E2 and with that BMI.

And really kind of allowed you to calibrate that, like, is this enough HCG to get the job done but keep them safe? So I really dug that approach. And there's lots of published literature from Cornell's group on kind of their practice with the sliding scale. Yeah, no, that's excellent.

And one of the things that the authors had mentioned too is they had looked at BMI. It was one of the things that you had mentioned. And they found that there's not much of a difference in terms of which dose you should be giving based off the BMI.

Do you all see that as well in your practice? Stick with the same dose of Lupron regardless of BMI? I've very seldomly changed the Lupron dose. There are some patients who have done dual Lupron triggers, the night of and the morning of. And if they've come from another center doing that, I kind of keep it going mostly for the voodoo of it all.

But I'm pretty consistent with an 80 milligram Lupron dose. Or 80 IU Lupron dose, excuse me, for milligrams. For milligrams, yeah.

How about you, Molly? If someone has a higher BMI or higher weight, I'm more likely to want to check post-trigger labs. Lupron, I would always, Lupron alone, always check post-trigger labs. But in terms of with HCG, whether I'm more worried about a risk of failure in that case.

So you don't routinely check post-trigger labs? I don't routinely. I feel like a dual trigger with a solid HCG dose, I mean. You're very unlikely to have a failure there.

And what are you going to do differently? You've already done all the things. Although it is, you are going to be curious if you do have a poor outcome. Yeah, it's nice to have those labs.

But it does a lot of drive for me in the clinic. That's exactly, I think, the utility of it to help set expectations. If you see an underwhelming response to the trigger, if you have an underwhelming cycle outcome, and if you're thinking about cycling again, that's sometimes where you can make the dose adjustment where it's like, all right, maybe let's go up to 20,000 HCG because of your BMI.

Maybe let's try the dual Lupron trigger where you do one in the evening, one in the morning to mimic that physiologic double hump that you see. I think it's really a, so you have a card up, a trick up your sleeve. If these things don't go well, that's really the utility of it.

But you're probably treating nine patients to maybe add some benefit to one by routinely checking post-trigger labs. The number needed to treat, if we're using a scientific term, is probably pretty high. Yes.

Thanks, Blake. That was a nice paired article with Molly's from NFS Reports. Daylon, before we get to my Consider This article, which again is a lighthearted topic this month, it's on TikTok and the Instagrams, the social medias.

Let's dig deeply for a hot second into science before we get lighthearted at the end. Tell us what you have for MEFNS Science this month. Delighted to tell you about the science I have this month.

It is salient with summer coming to a close, all those boozy barbecues, day drinking, as they call it, heavy episodic drinking. I mean, I haven't done that since college. But it's a thing, and people still like to get down.

And, you know, it's pretty obvious alcohol abuse disorder or just getting lit, turning it up on a given night can't be good for you. You're poisoning yourself, right? What's your guys' advice? I mean, some people must ask. They're desperate, right? I'm sure every patient says what they should do at their alcohol consumption.

Do you advise abstinence? Do you say that there's any link between alcohol use and fertility? Do you advise them to, you know, taper down as they're trying to get pregnant? What's your guys' advice to patients about alcohol use? Molly's probably having to have the conversation about cannabis use in the Pacific Northwest. Oh, yeah, all the time. I always have to say, do you use any drugs? What about marijuana? Oh, yeah.

Well, we get that a lot, too. Yeah. Yes, if you, no, I don't do any drugs.

Like, well, I have my medical card. I'm like, okay, in terms of what I care about here, your reproductive health, that still is considered a drug. Yeah.

Do you smoke? Nope, just vape. So, yeah, my practice for alcohol for men, we know that heavy alcohol use can definitely impact sperm parameters. And so I counsel about that.

And for women, the tough thing is for women, often a larger or a lower quantity of alcohol will have potentially more physiologic impact just based on the data on binge drinking. And so I usually just say at most one or two glasses and try to limit as much as possible. I love it.

Conservative. And I take a lighthearted approach. I tell them reduce for sure, but improve the quality.

So get rid of the two-buck chuck from Trader Joe's and improve the quality of your wine, because if you're going to reduce the quantity, the only thing that can get better is the quality. That's very economical too, Pietro. I love it.

I think all of you have a relatively conservative and sound approach, and I concur. Because, yeah, it's obvious that alcohol abuse, it's going to affect your whole physiology and therefore presumably your fertility. But the numbers are back.

And particularly, Molly, you said it, in men, alcohol use disorder affects male fertility significantly with decline in testosterone levels, alterations in Leydig cell count, in the morphology, overall impairment of reproductive function. And in fact, chronic alcohol abuse, alcoholism, I mean, as you might imagine, is linked to decreased sperm concentration. All the parameters, really.

Concentration, motility, abnormal morphology, yeah. And the rest. Those sperm are crunked up.

So you need to cut it down. If you're trying to get it done, so to speak. Also, you know, azospermia has been implicated with a link to alcohol use.

And interestingly and importantly, withdrawal from alcohol can reverse this condition. So there's nothing terminal here. You can turn it around, unlike chemotherapy in women, where there's really no replacing that reserve.

In men, you can get your sperm parameters back. At least that's what some of the evidence suggests. And while we're talking about global effects, the mechanisms by which alcohol undermines sperm quality and or reproductive function in males, not really well defined.

But one idea is that it affects the blood testis barrier. And the blood testis barrier is made up primarily of Sertoli cells. And there's evidence that alcohol can compromise the junctional proteins within the blood testis barrier within those Sertoli cells.

And also something important to consider. While you think of anything like blood-brain barrier, blood testis barrier, as a defined barrier, it's dynamic in reality, particularly in the testis, because it has to allow for migration of the differentiating spermatogonia into the luminal compartment of the seminiferous epithelium. So the question here in this study, which was led by R. Clayton Edenfield, who's over there in your neck of the woods, Molly, at the Oregon National Primate Center and Oregon Health and Science University.

The question here was to try and deconstruct on a molecular, cellular level what alcohol is doing to the blood testis barrier. And the way they did that was to generate this novel in vitro model, because, of course, limited accessibility to human specimens. They went to macaque, hence the Oregon National Primate Center.

You ever get down with those macaques over there, Molly? I'll assume that's a no. Stick with the humans. Yeah, I did my thesis out there, but I worked on a mouse model.

But I could go see the monkeys if I wanted to. Oh, I was so excited. And then you went to the mouse, which we all hate.

Who cares about the mouse? No, I did mouse work before, and I'm just comfortable with the mice. And I like playing with them, you know? You've dabbled in the humans and the mice. It's time to get to the macaques, Molly.

But getting back to the story, if you don't want to get into the macaques, R. Clayton, he's doing it for you. He's got the R. Clayton, sorry. They generated this model, which was pretty innovative.

Granted, it's a cell model. You're not recapitulating the testis in a dish, but who can actually do that, right? So what they did here is they got testicular biopsies from rhesus macaques. They digested the hell out of them.

They selected the Sertoli cells based on this differential plating that everybody does. I'm not going to lie. I don't love this differential plating approach.

I'm hardcore. I like to sort them cells. But I'll take it.

Because they do a lot of back-end validation of the Sertoli cell purity in this case and show 95%, at least by morphology. Point being is that they're setting up this cell culture system. And the blood testis barrier is really made up of these junctional proteins between the Sertoli cells.

That's what is allowing for this dynamic interface migration and barrier function. So there's a strong rationale for setting up this cell culture model and expecting it to recapitulate some of the effects of alcohol. And that's what they did.

They added alcohol to these cultures. And then they looked at the blood testis barrier, well, a surrogate for the blood testis barrier integrity and permeability here, looking at trans-epithelial electrical resistance, and these dye flux assays, looking at the movement of dye back and forth. And what they found was, well, they did this dose response, which I thought was interesting, of three doses, 160 and 100 millimolar, which means nothing to you.

But notably, they described it as enough to get, I guess, buzzed, drunk, and then to need to be hospitalized. So that's the range here. We're talking about throwing one back.

Wow. A trip to the ER. And they dumped that.

Yeah, let's party, right, Blake? I can see you lighting up. You want to get down with that 100 millimolar dose. I don't know.

They just really jumped to conclusions there that these men that we're counseling are being hospitalized. But yeah, perceive. Well, I know next time I'm at the club, I'm going to ask if they have anything in 100 millimolar dose.

And they're going to look at me funny. Anyway, they dump the alcohol on the cells, which I mean, some may argue that that's not exactly the mode of exposure that humans or even macaques, their testes at least, will see. But nevertheless, you do what you can.

And what they found here, I think it validates the utility of the model. Whether or not it can be relevant to physiology and the clinical impact of alcohol and fertility, they did show an effect. And you should look at the paper.

There's a lot of effects in the gene expression and that trans-epithelial electro-resistance and the Sertoli cell, the junction genes. So there were some differences, also cytokines. What I thought was really interesting was that.

The low and the middle dose were reversible. The ER dose, not reversible, Blake. So you might want to take it back to 60 millimolar next time Noted.

Thank you, my friend. Noted. All right.

Good for you too. Molly, go ahead. Go crazy.

Dale, can we talk about this methods for a second? I'm having a hard time wrapping my head around them thinking that just dumping ethanol onto cells. Oh, boy. Wouldn't that destroy any barrier? I mean, that's going to destroy everything, right? Like we use rubbing alcohol, isopropyl alcohol to like sterilize benchtops and lice bad things.

Is this like the right way to do this? This isn't like naked cells sitting there dry and then you're bathing them. Are you doing a lavage, a microfluidic approach? It's a dose. It's a dose.

And in fact, if you look at the numbers, I'd be willing to bet that 60 millimolar, I mean, we're talking about like BAC. I got to tell you, Daylon, for the clinicians out here, those numbers mean nothing to me. You might as well be talking about who's a what's and what's a where's in terms of... It means nothing to me.

It means nothing. It means nothing to me neither. But what I can tell you is that they leveled their doses to approximate, yeah, the blood alcohol concentration.

So, you know, when we're talking about that ER dose, we're talking about a BAC, I don't know, what does it take to get you to the ER, Pietro? 0.25? Probably more. You're a hard rock, I've heard at least. Never partied with you.

Never had the courage, to be honest. It's just self-preservation, that's smart of you. I'm trying to live.

But there's a dose. We're talking about a little minor dose here. It's not dumping alcohol on the cells.

But I still would argue that the blood, the whole point of the blood in the liver is to protect your cells from that direct contact. So even a level that approximates BAC isn't necessarily what's going on in the testis, but maybe it is, right? Every cell is three cell lengths away from a capillary. So who knows what the diffusion of that alcohol and the concentration, the point being, who knows what the relevance of the dose is? I think, for me, the takeaway that there is an effect, there is some validation of an in vitro model, a barrier function in these Sertoli cells, and most importantly for my future, if I ever want to have more kids, it's reversible, guys.

So I'm going to slow it down for the rest of the summer, trying to get back in a work mode, no more barbecues for your boy. But I don't feel so much regret about the choices I've made in recent weeks. You have to wonder if some of that reversibility is age dependent, right? Like when you're young, you can do a lot of stuff to your body and you bounce back with no big deal.

What about some of these older dads who are in their 40s and 50s trying to conceive with younger wives who've had a body of work, let's say, on the party scene. You have to imagine that the plasticity of those cells, their ability to bounce back is blunted, fair to say, Daylon? That is such a good point. And I think, to me, we got to ask those next type questions.

I mean, that's among them. I think this may be, I don't know, I would like to see more data in an animal model. I'll take the macaque because the macaque's pretty great.

Before we move into like human biopsies because, I don't know, this is all kind of descriptive science. I don't know what the intervention is here. But as you said, Pietro, if you can like scale it and show that that reversibility attenuates with age, maybe it can inform your clinical advice, right? And when you're talking to these patients, you can maybe stratify their risk dependent on age, as you said.

And maybe there'll be some explanation. Maybe you're going to have to ask, not do you use any drugs, but did you party like a rock star, like Pietro Bortaletto, when you were a young person? It's a good question. Somebody has to ask it.

I think we can at least derive that there's some effect there to some capacity of alcohol on the blood testes barrier and to be cautious of that with regards to reproduction. And before we move on, I just want to say that when you were talking about being younger and bouncing back, it made me think of yesterday when I told my son that I caught him, he ate 10 Oreos in one setting whenever I went to his parent teacher conference. And I had to tell him about, I just imagine if I ate 10 Oreos in one setting, I'd be stuck to my thighs for years to come.

And hopefully he can bounce back from it though. But I did have to talk to him about how you can't eat 10 Oreos. That's extremely bad for you.

Tough dad, Blake. I know. All right, let's bring it home with a nice lighthearted article.

If you've been listening to the podcast, focusing, paying attention attentively, this is your opportunity to maybe turn the volume down a little bit and ease into this next article. This next article is entitled, Not All Posts Are Created Equal, Assessing the Landscape of Endometriosis-Related Infertility Content on TikTok and Instagram. First author, Hajer Naveed from the Icahn School of Medicine and senior author, my old mentor, Mary Ellen Pavone from Northwestern University in Chicago.

Let's consider this article as a simple but important question. What kind of information are patients actually seeing when they go online to learn about endometriosis and infertility? The researchers pulled nearly 200 videos from TikTok and Instagram using search terms like endometriosis, IVF, endometriosis, infertility, endometriosis, hashtag TTC. Together, these posts had over 6 million likes.

As you probably guessed, engagement was higher on TikTok where individual videos averaged more likes and comments than on the Instagram Reels platform. And you're probably wondering, who's posting this content? Where is it coming from? Roughly half of the videos came from patients sharing their own personal stories. Physicians made up about a quarter of the posts overall, the stronger showing on TikTok than on Instagram, interestingly.

And then the rest were allied health professionals, for-profit companies, wellness coaches, kind of rounding out the other lion's share of posters. What's being shared? So if you've been on Instagram and TikTok, you've seen it, but if you haven't, about 55% of content is personal experience-based. 40% of it is educational.

There were some consistent themes across both platforms, stories of misdiagnosis, mistrust in the medical system, advice around diets, supplements, and lifestyles. And commonly, the supplements being mentioned are very similar to what our infertility patients see, magnesium, CoQ10, NAC, Omega-3s, ashwagandha, and B vitamins. That unfortunately did not make the greatest hits, but ashwagandha did.

What did they learn? So the big takeaways here is that when the team scored these educational videos for quality using validated tools that we've talked about before, the discern scale, the JAMA criteria, the results were actually pretty poor overall. The average scores were low on both platforms, especially for videos made by non-physicians. Physicians generated content consistently scored higher, better on sources of attribution, disclosures, acknowledging uncertainty.

But unfortunately, those posts received far fewer likes and comments compared with patient stories. So what does this tell us? Social media is clearly where patients are turning. Surveys show over 80% of individuals with suspected endometriosis seek information online.

And for many, the first recognition that infertility could be linked to endometriosis comes not in the doctor's office, but through TikTok and Instagram. Yet the majority of the content they find there is anecdote-driven and not evidence-based. I think what the authors are really trying to argue here is that we need to meet patients where they are.

We need to create engaging, digestible physician-backed content that competes in the same digital spaces. It's not enough for accurate information to exist. It has to be visible, shareable, and tailored to what patients are looking for.

I think bottom line here, social media is a really powerful tool for awareness. But right now, patient voices and their stories are dominating the physician content. And it's unfortunately being drowned out.

And if we aim to close that gap between misinformation and evidence-based care, we need to step into this space with kind of the same creativity and the same energy as those that are already shaping the narrative online. Blake, Molly, Daylon, have you seen this content on social media before? Is this new to you? I don't exist on social media. But what I do know, because I listen to my son, who's got a new meme every day.

Both of them. Total fools. But what I get from that is that our whole culture, we're driven by the meme.

And no matter how, I'm cynical here, but I do believe that what you said there at the end, like yeah, the physician needs to go out there and be as active and energetic. But one, yeah, they're busy. But more than that, I think what drives interest is what's interesting.

And sometimes the patients, they're interested in the meme more than they're interested in the truth. Or they're interested in validating their own preconception or whatever it is. So I'm very cynical and skeptical of social media just in my life, from hearing the nonsense that comes out of people's mouths, mostly my kids.

But hearing you talk about this study, it's just another validation for me. It's like there was another one you did a little while back, which was kind of a similar idea. But most of the content is generated by the uninformed, and it's generated with the aim of getting likes.

So it's going to be a little bit maybe sensational or diverge from the truth. I don't know. I don't know about evidence-based in any of those posts.

Yeah, this is, and not just endometriosis. I certainly see this commonly in a lot of aspects of our specialty. And I said the McDonald's fry thing jokingly earlier, but it's also, we've talked about it previously.

That's just kind of point in case. I mean, every single embryo transfer I do, you have small talk when the embryologist is checking the catheter to make sure the embryo didn't stick. And every single patient says they're going to eat McDonald's fries afterwards.

And that's derived from zero evidence ever, but every single patient does it, which is fine. Eat your fries if you want. But that's just point in case that a lot of people get little aspects of their fertility care from TikTok or from things that other patients are posting.

So not just for endometriosis, but for multiple aspects of just our specialty of infertility care in general. And so it's not going to go anywhere or go away anytime soon. And I agree with your conclusion, Pietro, that as physicians, I think that it's important to have a presence on social media and post evidence-based and backed posts and inform our patients of what they should be knowing.

Meanwhile, if they say, I'm going to go eat 10 Oreos, you're going to kick them out the door and shame them. Blake, what's up with that? Just my son, not my patients. So I will gently reprimand my patient.

But my son, I was ruthless. Because he didn't save any for you. Yeah, exactly.

Come on. Yeah, it's interesting how much stuff online gains traction. And then I'll go looking.

I'll be like, well, I wasn't aware of the data on this. Let me look it up. And there's no data.

It's not even like a few mixed studies or some small studies. There will be nothing. And I think before, we've talked about the graphenism thing, which I think is very curious.

It would be an easy RCT to do. And there's just like one tiny case report that doesn't even support that it really helped. And that's all I could find.

And so it's weird how the loudest posts that are the most propagated, and it's probably because as you guys are saying, it's the stuff that's attracting attention, that's attention attracting, really aren't bound in any evidence. And there was one post I saw where I think it was a doctor and she said, hey, did you do your own research? Do you know what a P value is? Do you know what a positive predictor value is? Like pretty basic stuff. And she said, if not, then you didn't do your own research.

And there was a huge backlash. It came off maybe a little bit arrogant, but I think it made a really strong point that you need to have some understanding of research and how we're using this. And I think the, I really fear our patients are really losing trust in how we're doing evidence-based medicine.

And they're not really understanding what evidence-based medicine is. Well said. And I think you have, you have competing interests, right? Do you either spend the 15, 20 minutes fighting back on that? Or do you spend 15, 20 minutes coordinating the next steps in their care and getting them closer to the ultimate goal of building their family? And I don't think there's a easy answer.

I think depending on my mood and how riled up I am about misinformation, sometimes I will systematically take apart things in front to patients to kind of prove the point that like, you know who the expert is here on this topic. And I'm gonna flex a little bit and show you why I'm the expert. And maybe by the end of this, I'll convince you and your friends, but that takes a fair amount of energy and there's a certain amount of exposure there with the patient to be able to do that.

Pietro pulling out the decapeptide, decapeptide. I'm not above it. I'll pull out a good graph, nice figure, maybe a table.

I don't know. However, the spirit moves me. Anyway, I won't bore you with that.

Guys, thanks for being here. It's nice to see your faces. One day we'll post our video online.

I think you guys would all appreciate watching us put together this podcast today. If you had seen us, you would have seen me put together about a quarter of the furniture in my office. Pietro, I took pictures.

We could post it on the social media page. I have you with the screwdriver bent over that Ikea desk there. Yeah, multitasking.

Blake has access to the Instagram account. Yeah, send it my way. All you listeners, Taylor and Travis, you can see Pietro building a desk.

Is that a rich mahogany? Perhaps a cherry wood? It's a rich mahogany, a very rich mahogany. My office smells of many leather-bound books. Leather, yes.

Okay, I was hoping. Yep. Excited for your office.

Thanks, guys. Well, that's all the time we have for today. Thanks again for joining another episode of F&S Unplugged.

Please stay tuned for other content, F&S On Air, and then our newest podcast coming out next month, F&S Roundtable. This concludes our episode of Fertility and Sterility Unplugged, brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine. This podcast is produced by Dr. Molly Kornfield, Dr. Adriana Wong, Dr. Elena HogenEsch, Dr. Selena Park, Dr. Carissa Pekny, and Dr. Nicholas Raja.

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