Tomer Singer, MD, MBA - Egg freezing Or Endometriosis surgery - what should come first ?!

Thank you. Good afternoon and thank you for having me. Dr. Setchkin. I think it's probably 12 years now. So I'm at the nice age that I see my professors in the audience and some of the surgeons that I operate with, Dr. Setkin, Dr. Nimrov, Dr. Lalas and others. And I have my residents and fellows here. So I mean that sweet spot between. I'm going to be talking to you about different topic like you just said. Talk about egg freezing and surgery. What should come first? And I think that some of the speakers have touched upon the impact of endometriosis on fertility. So we'll go over a little bit scientific background of egg freezing and how that evolved in the past decade. Discuss the effect of endometriosis on fertility and how do we do ovarian reserve testing, what egg freezing involves, and then what the technology that we use.

And then we'll talk about what really we think should come first. Although it's a really case by case basis. I was operating just last week with Dr. Nimrov on a case that we already frozen embryos and then did the surgery and now planning on doing a transfer. Some other patients are coming to freeze eggs before we do the surgery. So we'll talk about the differences. So we know that the optimal age to conceive into freeze eggs is when we're all trying to avoid having kids as teenagers. And most patients who are freezing eggs usually come to us when they're in their mid 30s to late 30s, sometimes even early 40s, way, way too late in the game. Because at that point you have to do multiple cycles to get a decent chance of actually having a baby out of this process. And we know that without infertility, the ficunity rate goes down exponentially when we get to the late 30s.

When you're 22 versus 24, there's not a lot of difference, but when you're 40 or 42, you can see that it becomes really detrimental to try and either be proactive, use ART, and especially the big jump you can see from late 30s to early 40s. People don't realize that when they come for the first consultation that it's 12, 13% chance only when you're 38, but when you're 42, we're talking about really a one digit number per month. The other thing that impacts fertility is really the increased rate in spontaneous abortion with time. And endometriosis just exacerbate that. So what are some of the factors that affect fertility? And you can see here on the right hand side, endometriosis is one of the things that have been missed for so long. For decades, we haven't even mentioned the word. When we saw patient who came to seek fertility, we were trying to talk about FSH and AMH and sometimes blame the husband for everything.

But really endometriosis is a big culprit. And age is the number one, two, and three, of course, as I just showed. I think this is probably the most important slide when we come to decide if surgery should come first or freezing should come first. So we know that almost half of our patient, if you were to do a random laparoscopy because they struggle with infertility, you'll find some kind of component of endometriosis, whether it's stage one or stage three, that's yet to be determined with the surgery. But most women were not even complaining of symptoms. So we know that really it's a very tricky part of our workup. The diagnosis is really sometimes missed by three or five years. Even when you struggle with infertility, and I can't tell you how many patients have struggled and done multiple IVFs and even when there are surrogacy route and then came for a laparoscopy and then conceived spontaneously just with francinator and a glass of wine.

And this is five years later. And how does endometriosis affect fertility? So we know it distorts the anatomy. Everyone here who operates on women knows that when you go into the pelvis, it can be worse than stage three cancer sometimes. And you know that it doesn't really respect the borders and the anatomy lines. Adhesions are often seen and that really has an impact on the ability of the fallopin tube, capturing the egg when a patient is ovulating. Scar fallopin tube can cause ectopic pregnancy, which we struggle in about 10% of our patients. The inflammation of the pelvic structure. Whenever we do a pelvic ultrasound on patient with infertility and endometriosis, you can tell that there's adenomyosis, which is a very close relative of endometriosis. And sometimes the only hint that you get because the patient is not going to present with bilateral endometriomas to the fertility clinic because those are things that are going to be picked up usually by the general OBGYN.

Altered immune system, there's good review by our former speaker about that, and then changes in the hormonal environment. So that has an impact on the transfer. When you actually get that embryo, after you froze eggs, after you inseminate the egg, you have that precious embryo. And if you didn't clean the pelvis, so to speak, and did surgery before a transfer, you may have recurrent pregnancy loss, recurrent implantation failure. So that's where it's tricky because you may need surgery before endometrioma resection, create embryos, do IVF, and then go back to almost get a better status for an implantation. So that's kind of like a concept that we need to take into account. And I know that you all have patient that had multiple rounds of laparoscopy for pelvic pain. And I think that with endometriosis, it may be also a combination, surgery, freezing, surgery, implantation, and not for every patient, but for the patient who failed multiple rounds of IVF, I think that's really could be something that we're missing.

And lastly, reduced egg quality, which is why we recommend at least consulting with reproductive endocrinologists before we actually pursue the endometriosis surgery. So this guideline started in 2012 when really awareness, a lot thanks to this organization, have come to talk about endometriosis and promote with ACOG, ASRM, SGI, and of course ASRM speaking about endometriosis. And I just wait for the day that egg freezing will be a part of a discussion with every patient who's having endometriosis, just like now the American Oncology Association is mandating discussion about fertility. And the more important thing, because I think that's the rate limiting step, is to have coverage for that because every patient with endometriosis is really not a social egg freezer. It's not coming because she just want to freeze eggs because she hasn't found Mr. Wright or Mr. Maybe. She's struggling. There's a medical condition that's causing her to potentially lose her chance of having a genetic child.

So until those are going to be addressed in the community, I think we'll still struggle as reproductive endocrinologists and as a surgeon. We know that the IVF success rate in women with endometriosis, and those are the highlights on the right causes demished variant reserve. It basically causes less likelihood of IVF, cycle to succeed. On average, we say that a patient with endometriosis compared to someone without will need double the number of cycles. So if you have a 40-year-old who takes two or three cycles to get to a euploid embryo, take into account the endometriosis, you may need five or six cycles. So just think about that, the cost, the emotion, everything that goes into that. And also we know that there's obviously complication once they conceive. There's more preterm delivery, there is more bleeding, antepartum bleeding complication, and of course C-section rate. And without going too much into that practice bulletin, I think it's a very important summary that the benefit of laparoscopic treatment of minimal or myeloendometriosis was insufficient.

And that's why a lot of patient really go through surgery before even having a discussion about egg freezing. And there's been some study that showed that only when it's stage three or stage four will the patient benefit from surgery prior to egg freezing. And definitely in young patient, when we have a lot of eggs and the eggs are healthier, I think the jury is still out whether or not we need to freeze eggs before we're embarking on the fertility journey. Or if the pain is the main factor, we can potentially start with surgery. These are a couple of slides that are showing essentially some of our patient that you go in and the patient has infertility and you don't understand why she gets three euploid embryos, which are tested embryos. You put them back in month after month and she gets chemical, she gets a negative pregnancy test.

Thoma and I have patient that have done seven and eight IVF cycles and only on the ninth IVF after he did surgery, the patient took a baby home. I mean, just imagine if she had the surgery before, right? How much time and effort and heartache would've saved. And you can see that endometriosis behave differently. We can affect just the ovarian flow side. It can affect the mesosalpin, it can affect the ovary, it can affect the uterus. When we do a pelvic ultrasound on every patient that comes for the initial consultation, we'll take a very deep dive into how the ovaries are looking, what's happening in the perimetrium, what's happening in that next structure next to it, whether or not the IUD there has been there for a long time and maybe cause some scar tissue, whether or not the patient has adenomyosis. All those things have an impact.

And we know that the staging is a nice tool to just talk to patient about, but it could be that the patient with stage one or stage two really will struggle more with infertility than a patient with stage three or stage four. We all had those patient that has bilateral endometriomas and conceived spontaneously every time they use their husband toothbrush versus the patient with stage one, stage two having multiple failed IVFs. So we don't know a lot, that's the honest truth. And when we add that to the age factor and delayed in diagnosis, most of our endometriosis patient are in their mid to late 30s because they've had been on birth control pills for 10 or 12 years, masking some of those symptoms, then getting married or trying to establish a family and then stopping the pill and then everything all help break loose and then you're starting to pick up weight.

You have this and you have that and let's get an HSG and you have hydrocelping and we need to remove the tube and so forth. So how do we tackle it? Let's start by talking about what's the initial discussion. So I think that the general OBGYN should really start by talking about what are your fertility goals? What are your family planning? Let's run a simple blood test. We now run a blood test call at AMH. 25 minutes later, we know where the patient falls compared to her peers. And you can see here a summary that the patient who's 25 should have an AMH of 5.4. Just five years later, it drops by two points, five years later it drops for another point. So that could be a marker, almost like a PSA and the guys who are in their 50s now and know that needs to be doing it on an annual basis, you can see that there's a drop in AMH and you don't really have an explanation.

Maybe that's a hint that maybe there's endometriosis. It's sometimes a tricky number because PCOS patient will have a very high number, almost like forcedly reassuring, they'll have an AMH of six or seven or 10. So a drop from 10 to nine may not mean much. So I don't think that that will apply. And a lot of patient will have both PCOS and endo. But for the vast majority of patient, that could be a good marker and it's a simple blood test. And now I'm a little bit concerned when we are spacing out the pap smear now to three years and sometimes five years, because see the drop. If a patient saw you at age 30 as a general OBGYN, she ran an AMH and guess what? It wasn't 3.5. It was 2.6. You're not making a big deal. You're not going to have a 30-minute discussion about what impact it has.

And then she comes five years later and 0.5, that's a problem. And sometimes the OB-GYN are the only PCPs. They're the only one who are guiding our patient with what they should do, vaccination and others. So AMH is a simple blood test. The second thing is genetics. Just this past week, I've seen a lot of patient with fragile X premutation. And if you don't run it, you don't know. And if you have a premutation that's in the 60 or 70 or 80 CDG repeats, guess what? Patient will present with premature ovarian insufficiency and you're going to have to do many, many more IVF cycles. And the last letter, the E in the age visit is talk about egg freezing, embryo freezing, drop a note, send her to a referral for at least a telehealth or a 10, 15 minutes discussion with a nurse practitioner or reproductive endocrinologist.

At least she knows what it entails because there's a lot of stories out there that it takes three months to freeze eggs and so forth. And as I'll show you, it takes really 10 to 14 days and the patient is done. So when do we freeze eggs? Just to review that. Patient who are embarking on chemotherapy or radiation, that goes without saying. It's almost like a second nature. Everyone knows here if a patient is about to receive chemotherapy, she should see a reproductive endocrinologist, freeze eggs. And I want that knee-jerk reaction, that immediate, spontaneous, like a reaction to be with every patient with endometriosis. Wait, you have endometriosis. Let's talk about kids. You may want two or three kids. You're 35 and you're embarking on a big laparoscopy. That may not be so easy if we're not talking about it right now before. PCOS, the same thing.

Fibroids or immune condition, those are some indication to freeze eggs or embryos before. Genetic condition, as I've mentioned, failure to obtain sperm, which was the whole development of egg freezing was for patient with cancer and patient that their partner didn't have sperm. We were doing two weeks of stimulation, doing an egg retrieval. The guy cannot produce sperm and then we had to discard those eggs because we just didn't have the technology. So we would call our urologist, come with a needle in a syringe, not fun, but try to aspirate and salvage those eggs because if the eggs are not disseminated within two to four hours, that's it. They're done. And then elective and social indication, which I'm sure all of you are well aware of. It's the one biggest portion. If you look at the SAR data in the past decade that have really tripled the amount of patient that we see since 2012 when the American Society of Reproductive Medicine have relifted the experimental title.

And of course, egg donation. A lot of our endometriosis patient will see us later and we'll need an egg donation. And thanks to egg freezing, we now have many more options for them, whether they would like to have a certain ethnicity, certain religion, they would like to do it mid-April and not wait three to six months to find someone who's going to be a good match. So that made it much more user-friendly. The vitrification is the way we do it. In the past, we thought that we need to freeze the eggs very slowly, three to five minutes and drop it by one degree each time. We now know that actually dropping it in liquid nitrogen within five minutes is the best way to preserve the egg. And this is the technology that we use. In the past, we used slow freeze. So this was the American Society of Reproductive Medicine that essentially said it's no longer experimental and we should be discussing it with every patient.

The risk with egg freezing, it's not free of any risk. And of course, when you have a patient with endometriosis, the risk of infection is slightly higher. As I mentioned, the anatomy is not the same. So you need to have someone who knows what they're doing and looking well at the pelvic anatomy and the uterine artery and iliac arteries are right there. This is a nice slide to keep in your office to just do that blood test and give that to a patient to understand where she falls. Is it in the third percentile, fifth percentile or 98th percentile? And then when we talk to couples, I usually bring both option of eggs versus embryo, even in the setting of endometriosis, because egg freezing, essentially it's the patient's property. Embryo freezing, it's a mutual property. And patients that have had in the past who separated after freezing embryos because of multiple challenges of years of infertility could not use the only chance of having a genetic child.

So a lot of those cases in front of the hospital, I'll mention, we should focus on you for now. Let's freeze eggs. By the time we get the semen analysis, the genetics, we can do a second round and freeze embryos. This is the process of egg freezing, and this is probably the second important slide. I call it a triple L because endometriosis patient, unlike social ache freezing, are struggling. They have pelvic pain. They're nervous about the ovary growing during the stimulation. So we give them letrozole, which is aromatase inhibitor to keep their estrogen at bay, which will be about a third or fourth of the level of estrogen that someone else will see. We use a low dose stimulation not to hyperstimulate them, which will add to their pain. And we give them a Lupron trigger, GnRH agonist instead of HCG to reduce the hyperstimulation to about 2% versus 10%.

This is the process. The patient will do 10 to 12 days of stimulation. We'll do an egg retrieval transvaginally. We usually, when we create embryos later on, we'll test the embryos for chromosomal abnormalities. You don't have to do it if the patient is in her 20s or early 30s. And we know that the neonatal outcome based on multiple studies is very reassuring. We now have about 3% of the population born via IVF, and egg freezing is really contributing to that a lot. When we look at the liquid nitrogen that we're freezing eggs, I joke with my patient that 30 eggs is enough for three husbands, so start going. And how many eggs to freeze? That's another question, but I think that really at least 10 eggs will give you a decent chances. And this is a good table to have. A patient who's 30 to 34 years of eggs product to egg freezing doesn't know really what are the odds.

So you tell her before endometriosis surgery, if you have 20 eggs frozen, your chance of having a baby is 80% and about 50% for a second baby if you wish to have. So in summary, the advantages obviously of egg freezing really changed everything that we do in reproductive medicine. About 20% of our patient are freezing eggs for the future and not trying to have a baby right here and there. The demand have went up significantly. The general OBGYN should be doing some testing, AMH being the hallmark, because you don't have to be cycle dependent and bring them on day two, which is always a struggle. And patient who are freezing eggs for non-medical indication because they just don't have the right partner still compose the biggest part of the patient who freeze eggs. But I really think that insurance, once they start paying for egg freezing, for patient with endometriosis, once AAGL and ASRM and ACOG and all of the organization will say, "This is really a part of the algorithm when a patient struggle with infertility or struggle with endometriosis will really increase their awareness and will allow us to help the next generation." Thank you so much.