PATIENT AWARENESS DAY 2018:
LIVING YOUR BEST LIFE WITH ENDO
Sunday, March 18, 2018, (8am-5pm) Einhorn Auditorium (131 E76th st) at Lenox Hill Hospital, NYC
Fertility workup and preservation in patients struggling with endometriosis
Tomer Singer, M.D.
- Glad to have the opportunity to link these two and give you some important information that a lot of the patient are not aware of. As I probably mentioned, we have a very large program that tried to promote freezing, either of eggs or embryos, in women who are diagnosed at a young age with endometriosis. We know that what has been happening in the last 10 years is that women have been diagnosed with endometriosis, they will have surgery, and only then the talk about fertility comes up when they get married or they have a partner or they decide to use donor sperm and conceive on their own, and we're trying to change that paradigm. We're trying to do fertility preservation before the disease gets to the point that it's sometimes too late or maybe unfortunately, not feasible to help them get pregnant. Mel warned me that there's some issues with this. I think I'm gonna ask... Unfortunately I don't have anything to disclose, so we'll go to the next slide. The objective of today's talk is to give you a little bit of the scientific background and then to outline the process of the egg or embryo freezing for the endometriosis patient, and then to give you a few sentences regarding how a patient should be counseled when they're seeing their PCP or general OBGYN or their endometriosis specialist. Next. We know that female infertility affects about 10 to 15% of the population. If you look at the breakdown there, you'll see that a great portion is patients with endometriosis. This pie chart... If we're going back 20 years or 15 years ago, this was not even included in the pie chart. Endometriosis was a non-issue, no one really gave it attention, and I remember in medical school that this was really included in the pelvic adhesion component or the tubal factor component and now, endometriosis has its own section, so we've made a lot of progress in the past two decades. Next slide. We know that in order to get an egg to release from the ovary, there's about a 40-day process from the first day of the period until the patient will ovulate, and as you know, most women have 28 to 35-day cycles and after about 14 days the egg gets released and if that patient has been exposed to sperm, the way we like to say it, that means that that egg has about 24 hours chance to fertilize, travel in the fallopian tube for about five or six days, and then travel back into the uterus and implant. We know from the endometriosis geology and the pathophysiology that the endometriosis can affect every organ from the ovary to the fallopian tube to the pelvic organs that are adjacent to the uterus and of course, the uterus. Next slide. In those five or six days that the egg is getting fertilized and the embryo gets developed, the embryo is growing in size from the two-cell into a four-cell, eight-cell, and eventually a blastocyst that's over 100 cells. That process depends on that fallopian tube, so when I speak to my patient who have endometriosis and we order a test for the hysterosalpingogram, which is the fallopian tube test, I try to explain that if we see a dilated fallopian tube, if we see a blocked fallopian tube, then the chances of getting pregnant are diminished significantly. There's also increased risk for ectopic pregnancy, and there is an increased risk of having a pregnancy that's gonna be at the corner between the fallopian tube and the uterus, something we call cornual ectopic, which is a life-threatening diagnosis. We know that the patency of the fallopian tube and the integrity of the fallopian tube is key in order to achieve a viable pregnancy in order to have good implantation. Next slide. This is just a slide showing you where endometriosis is seeding, right? We can see the uterus right in the middle, we can see the ovary on both sides, we can see the fallopian tube. We can see the adhesions marked here in white that can affect anywhere in the pelvis. The fallopian tube can be attached to the uterus, can be attached to the ovary, can be attached to the bowel, and those of course have an effect on fertility. If a patient ovulates with the left fallopian tube on the left ovary and the fallopian tube there is attached to the bowel or attached to the side wall, the fallopian tube is never gonna capture that egg and the patient will not be able to get pregnant. In those situations, IVF is the treatment because we're bypassing the fallopian tubes. This is just an example of how we see a patient with infertility and what are the outcomes that this patient has. We also know that even if there is a blocked fallopian tube and you're bypassing that blockage by doing IVF by retrieving eggs, fertilizing them with sperm, and creating an embryo in a dish and then transferring it back into the uterus, a patient with endometriosis will have about 50% decrease in their fertility rate so that means the average endometriosis patient who is undergoing IVF will need more cycles in order to achieve a pregnancy. Next slide. This is just intra-op findings of our patient so you can see that the pelvis is angry. The patient is experiencing severe pain. The endometriosis lesion affect areas that are crucial for fertilization or for implantation and the surgery that the endometriosis surgeons are doing reduces that disease load, allowing us as a fertility specialist to go in in a much quieter pelvis and allow pregnancy to occur. Next slide. Next slide, I think it's going. Here we go, okay, no. Next slide, another one? Perfect, so this is the American Society of Reproductive Medicine diagnosis criteria. Their endometriosis is divided into stages. Stage one is minimal disease. That means there is very few superficial implants that can be seen during a laparoscopy. Stage two is considered mild. That means there are more implants, but not to a point that it has a significant effect. Stage three is moderate. That means a lot more implants, the ovaries are affected, and then the adhesions are already starting to be present. Stage four is obviously a very severe disease. You can see endometriomas which are cysts, or chocolate cysts as we call them, in the ovaries. We know that there are dense adhesions, the fallopian tubes are usually involved, and the uterus is involved as well. The thought process is, in general or kind of like a rule of thumb, is that as long as the patient is suffering for stage one or stage two, surgery just for the pure reason of improving fertility is not indicated. In fact, there is a very nice study that looked at patient with mild or minimal endometriosis and the number needed to treat was 17, meaning if we have 17 women with mild or minimal endometriosis and all of them went through endometriosis for the purpose of fertility only, that means only one will get pregnant spontaneously after that surgery. But most women with this mild or minimal disease are not going for a laparoscopy because they are infertile. They are going because they have pelvic pain and that's how the diagnosis is being made. At that point, this is a good junction to refer those patients to a fertility specialist. She had surgery, the pain is much improved after surgery. Instead of waiting two, three, four, five years before the disease becomes much more severe, and at that point, it's gonna be much more challenging for us as fertility specialists to help them, this is the time to refer that patient or the patient themself to go seek an advice from an OBGYN, from a fertility specialist. At least have a discussion and we'll talk about what that discussion should entail. Next slide. At that point, the patient comes in and we start an analysis of their ovarian reserve because endometriosis has an impact mainly on the ovaries. We know that the ovaries basically have follicles. Those follicles were there from the time that they were born. In fact, when we looked at the chances of getting pregnant, the younger the patient is, the better the chances are. The best chance of getting pregnant is when everyone is trying to avoid pregnancy in college, right? Later on, they start making plans for fertility and at that point they're usually in their mid-20s, late-20s and in New York, of course, mid-30s, late-30s, sometimes 40s. At that point, sometimes it's very challenging. We know that age is the main factor, so a young patient with endometriosis, even with the low ovarian reserve, has a very good chance of getting pregnant. Keep that in mind, age is the main factor. But when you have an older patient with endometriosis, that combination can be very challenging. We perform a transvaginal ultrasound and during that ultrasound, what we do is we count follicles. Follicles are equal to eggs. We also try to assess the ovarian volume, we try to rule out endometrioma like this picture shows, and we draw a blood test on day two or day three of the patient period. We check an FSH. That's a Follicle Stimulating Hormone. We do that always with estrogen in the background because we know that's a culprit and the FSH needs to be in the one-digit number, meaning if a patient presents with day two, day three blood that show that the FSH is in the two-digit number, 12, 15, or above, then there is a reason to be alarmed and to be a little bit more proactive. There's really no specific cutoff, but FSH less than 12 is still considered normal and above that is considered more challenging. In addition, there is a very good test that has been around for over a decade now called Anti-Mullerian Hormone. I know Dr. Sejka and Dr. Goldstein are testing older patient for AMH before surgery, during surgery, after surgery so this is a very important marker. This is the equivalent of the guy's semen analysis. It gives you a rough estimation of what's the ovarian reserve at any given time and the big advantage is that you can compare it from time to time, from six months to a year, and you can also draw it at any given time so you don't have to come on day two or day three of your period. A lot of our patient with endometriosis will be on birth control pills, as we know, to avoid this ovulation and the pelvic pain that's associated with menstruation so those patients were never gonna be able to get an FSH unless they were off the birth control for a month so AMH is helping us in assessing them, along with the ultrasound. Next slide. This is just an image of a 3D ultrasound of the ovaries that we conduct. You can see that each follicle, or each color there, has one egg in it. When we stimulate patients' ovaries for IVF or for egg-freezing, we know that the patient with a lot of follicles will have a better chance of getting pregnant compared to patient with small amount of follicles. There's a straight correlation between this and the AMH. The higher the number of follicles, the higher the anti-Mullerian hormone, the AMH. AMH cutoff should be above one. Below one is concerning and telling us that the patient has diminished ovarian reserve. There's also correlation between the number of follicles and the FSH that I've mentioned, the follicle stimulating hormone. The higher the FSH, the lower number of follicles that we'll see and at that point, we'll have a discussion about what are our options. Next slide. The day three, as I mentioned, doesn't have a strict cutoff but we know that a level that's above 20 is concerning. In fact, a patient who's younger than 40 who has an FSH greater than 40 is diagnosed with premature ovarian failure. We have seen a lot of patients with endometriosis who had severe disease and started to present with hot flashes in addition to the pelvic pain and that's because the endometriosis got so deep and so involved that the blood supply to the ovaries is diminished and the ovaries are not producing enough eggs or releasing enough eggs. Any FSH less than 10, everyone agrees that it's a good level, but there's really no absolute threshold between normal and abnormal, especially when it comes to our young endometriosis patient. Also, we know that patient have fluctuating FSH, so going to your OBGYN and having a low AMH and a normal FSH doesn't mean that you're out of the woods. You would wanna check that FSH a couple more times during that year. Even one abnormal level can suggest diminished ovarian reserve and you may wanna act on it. Next slide. This is a nice summary of the correlation between IVF and FSH. FSH is a hormone that's produced by the pituitary gland in the brain, and it tells us how hard the brain is working to convince the ovaries to produce healthy eggs. The higher it is, that means the brain is working hard. Kind of like hyperthyroidism, right? Women with very high TSH have hyperthyroidism, meaning they're missing the thyroid hormone that the treatment will be giving them, Synthroid or Armour Thyroid or what have you. Same thing here, if the FSH is elevated, that means the ovaries are not producing enough eggs. The estrogen is gonna be low, and there's less likelihood of having a healthy egg. That's why IVF or egg-freezing will include injecting that hormone that's called FSH, Follistim, Gonal-F, and others. Next slide. We can see that the age factor plays a significant role here and we can see that this is without the introduction of endometriosis in the general population showing us the chance of getting pregnant. We see that the chance of getting pregnant with a woman's own eggs at age 45 is already less than 3%. This is without any hormone. This is just Frank Sinatra and a glass of wine. We can see that at age 30, there's already a drop and every two, three years, you see a significant drop there. By age 40, it's already less than 10%, so this is why we need to act on this earlier on especially in lieu of endometriosis diagnosis. Next slide. This is really a slide that's showing the correlation between high responders, normal responders, and reduced response. You can see antral follicle count, AFC and AMH have a nice correlation. The higher the AMH, the higher the antral follicle count, the more eggs that we'll be able to obtain. We decide, you can see that there are different treatment strategies on the right. In an IVF situation, you have at least five, six protocols that we use in patient, depending on their AMH and AFC. We can use certain medication. Sometimes we use Lupron, the same Lupron that we treat patient with pelvic pain, to quiet down the ovaries before stimulation and then starting stimulation at the same time so we don't have a large endometrioma or we don't have a dominant follicle that's gonna reduce the chance of getting pregnant. There's a straight correlation between how many eggs we obtain in the retrieval, whether it's for egg-freezing or IVF, and the likelihood of conceiving. Next slide. This is a very good slide that basically shows there is a decline in fertility already at age 30, even before that. We know that the best chance of getting pregnant is really in the early 20s. We know that at age 37, 38, the significant decline is starting to be presented. At age 38, when we do IVF, 50% of the embryos will be abnormal. 50%, so even though life expectancy is about mid-70s nowadays, 72, 74, we know that women were not tuned, were not designed to get pregnant at age 50 or 60. Just 150 years ago, before antibiotics and vaccination, women and men died in their 40s and 50s, right? Definitely now, we're trying to challenge the medical field by pushing it. We have patient now in their 40s and even 50s that are pregnant, whether it's donor egg or their egg. It's a different story but we can basically bypass a lot of those challenges that nature gives us. The earlier the better, that's what this slide is showing because on average, women will go into menopause at age 51 in the US. Next slide. This is what I started talking about, the aneuploidy rate. What is the aneuploidy rate? That means how many of the embryos that are derived from the eggs will be abnormal. Down Syndrome, Trisomy 16, 18, Turner Syndrome, meaning an increased risk for a miscarriage, increased risk for abnormal embryo that may need to be terminated or essentially delivered and have special needs. We know that at age 25, the likelihood is 1 in about 500. At age 35, it goes down to 1 in 178. At age 40, that's already 1 in 60. That's a real number. And at age 45, it's 1 in 20. Next slide. This slide shows what we usually do in a fertility population that are over 35. We essentially do retrieval, we inject the sperm, and in addition to the IVF, we introduce something called pre-implantation genetic screening. This slide is taken from CooperGenomics, which performs the analysis on the embryos that we are biopsying in our lab, and you can tell that at age 38 to 40, only 30% will be normal when we analyze them, meaning if I had three embryos of a 38 or 39 years of age, two will be abnormal, one will be normal. That means that patient only has one embryo to work with, and you'll see that a lot of patient will decide to bank embryos. They get married at a later age, they decided to have their first child at age 38, they realize that if they just work with that one embryo and they come back and deliver, whether they have a C-section or vaginal delivery, that will delay their next child by a year and a half to two. By the next time they come to see me, they're 40, 41 and at that point, only 14% of their embryos will be normal, meaning they'll need about eight embryos to get the same one normal embryo. What they do is they freeze embryos because they have a partner, they selected Mr. Right or Mr. Maybe, and at that point, they're basically freezing embryos. Next slide. So, why would you freeze eggs? There's definitely several clinical implications or indication, I should say. Patient who are undergoing chemotherapy, those are the patient that basically helped us come to that understanding of how we should freeze eggs and what are the chances of getting pregnant with frozen eggs. In the 80s and in the 90s, patient who were undergoing chemotherapy signed consents. It's called an IRB consent and the institution, whether it's Lenox Hill or another institution, will tell the patient we're gonna freeze your eggs but just know that it's experimental. That all changed since 2012, and that's why we see such a big rise in egg freezing. Nowadays, we're communicating on a daily basis with insurance company. I feel that endometriosis, because of the impact that it has on fertility, should be treated just like any other cancer prior to chemotherapy. You don't have to get Cisplatin or any other chemotherapy to know that the effect on the fertility will be there. It's just a matter of time, so insurance companies should be covering this treatment. If you have a patient with endometriosis who wants to freeze their eggs, they should not be looking at it as if they're doing it for social reason or elective reason just because they're single and 35. I can tell you that with some companies or with some institution, we're making some progress but this is something that we need to focus on. Patient with endometriosis should have egg freezing, not elective anymore, covered by their insurance policies. The other reasons are genetic condition, Fragile X... Thank you. Thank you so much. Genetic condition, Fragile X, BRCA, B-R-C-A... All those condition promote fertility preservation treatment and those are covered by a lot of the insurances, much more than it is for endometriosis. Failure to obtain sperm on the day of IVF. We basically do stimulation for 10, 12 days and the guy has a bad sperm day, then we can freeze the eggs. Elective or social indication, we know that that's very popular nowadays and patient who are in need of egg donation. That's important also for endometriosis. A lot of the patient, unfortunately, were not offered to freeze their eggs and they're now in their 40s and they wanna have a child and they wanna have a family and they have a partner and they have a uterus. In that situation, what we do is we have an egg bank. We have young women aged 21 to 32 who are doing it and getting reimbursed for stimulating for 10 days and donating their eggs. In that egg bank, our patient with endometriosis can select from and get basically pregnant with their own uterus using an egg donor and their husband or partner's sperm. Next slide. The technique itself, it's called vitrification. The reason egg freezing was not very popular and not very successful in the 90s and in the early 2000s is because we thought that freezing the eggs very slowly would make a lot of sense. 90% of the egg component is water. What happens when you freeze water? It becomes ice. When it becomes ice, it breaks the egg and the eggs did not survive. Only 5% of eggs survived the freezing using the slow technique back in the 90s. It got a little bit better in the 2000s, but we now know that the new technique, which is essentially plunging the eggs straight into liquid nitrogen and preventing it from undergoing this slow freeze saves those eggs and allows us to get a very mature egg with a good pregnancy rate that's equivalent to a fresh egg's. Those studies came from Italy and from Spain and other places that were preventing women from creation of too many embryos. The Vatican says you're gonna try IVF because you have a blocked tube, that's fine, but you can only fertilize three because we don't want human beings in the freezer. So, the Italians were very good at developing techniques to freeze eggs, and now we can use it to other type of scenarios. With vitrification, 95% of the eggs in our lab will survive the freezing and the thawing, meaning if I froze eggs now at age 38 and the patient came in five years later at age 43 and at that point, her FSH is very high, she has a partner, she wants to get pregnant, her chance of getting pregnant are similar to when she was 38. That's the key, you're putting a halt on your biological clock from the time that you froze the eggs. Next. So, this is really the American Society of Reproductive Medicine report that says that essentially, it's no longer experimental. Next slide. We know that we only do it on women who had their periods, so only post-pubertal. There's risk of bleeding, infection, hyperstimulation and the propofol when we give anesthesia, the risks are less than 1 in 1,000 for bleeding, less than 1 in 500 for infection, and very small chance for OHSS. Usually the endometriosis patient will have low ovarian reserve and not high ovarian reserve. Next. This is something that I think all OBGYNs should be discussing in their first appointment. We now do Pap smear every three years and mammogram, there is a push to start it at age 45, so women don't see their OBGYN. They don't get to see them because the insurance is not gonna cover their Pap smear, so no one is talking to them about ovarian reserve and other issues. The A stands for age and AMH, like I spoke to, genetics is G, and E is talk about eggs and embryo freezing and endometriosis because those go hand in hand. Next slide. This is just a slide showing the correlation between AMH. The younger the patient, the higher the AMH. Next slide. This is an average what we should expect. A patient who's in her 30s should have an AMH greater than three, a patient in the 35 should be having an AMH greater than two, and we can see the significant decline above age 42. Next slide. This is all the publication and all the hype in the media regarding egg freezing, whether it's for endometriosis or whether it's for other reason. You know that Google and Facebook are giving free cycle of egg freezing for their employees. There's a lot of debate whether or not that's the right thing. I believe it is, it's another benefit. Patient can choose if she wants to use it. Northwell, this hospital, gives free egg freezing for their resident, medical student, physician. That's a big advantage and I believe that if endometriosis patient had that benefit, that will be an amazing benefit to take advantage of. Next. So, when do we use eggs, when do we use embryo freezing? It all depends on the sperm. If a patient feel comfortable with a partner that she's with, she can decide to freeze embryos. The advantage of egg freezing is that single women can do that if there's a severe male factor, if there's any medical indications such as endometriosis, and if they have any ethical or social culture issues basically with having frozen embryos in the freezer. Eggs can be discarded just like sperm can be discarded. Embryo freezing, the advantage is that usually, embryo freezing is a part of IVF and that may be covered by insurance, unlike egg freezing. The vitrification technique requires a specialty lab. You cannot just go to any place and say I wanna freeze my eggs. Embryos are much easier to freeze and thaw. Genetic screening of embryos... When you have an embryo, you can find out if it's a boy, if it's a girl, if it's chromosomally abnormal, if it's Down Syndrome. With eggs, you don't know that. You still need the guy. We need the guys for something to find out if the embryo is normal. And embryo freezing has been around for over 30 years. Next. This is really what we need to promote. You see the OBGYN, you've been referred to the REI, it takes about 10 to 14 days of stimulation, you do an egg retrieval which is about 20 minute procedure, we usually give propofol, and then you go home the same day. Next. We'll skip this slide. This is a summary of what I just said. This is how the stimulation will look like. Usually, a patient will be on birth control pills for two to three weeks with endometriosis then stop the birth control, have a little bit of spotting, stimulate for about 10 to 12 days, get a trigger shot, and the retrieval will take place 35 to 36 hours after that trigger shot. Next. This is how the ultrasound is basically showing us when is the right time to trigger the patient. The patient will be doing injection every night between 6 to 10 PM and will come to see the reproductive endocrinologist every two to three days to measure the hormone levels and measure the follicle size. Next slide. Once they're ready, they'll go in for egg retrieval, which is done transvaginally. There is no scar, there is no incision. Patient will be doing the injection as you see there on the slide on the left in their belly usually, subcutaneous injection. There are about four or five medication that are being used throughout this stimulation and then the procedure itself is done under anesthesia with propofol. The patient is not intubated, there is no... Besides the nasal cannula with oxygen, there is nothing going on and in some places in the world, they do it even without anesthesia. Next. There is no impact on egg freezing when they looked at neonatal outcome and the chances of having an abnormal embryo. The statistics tells us that about 1 to 2% in the general population is what fetal abnormalities are found on ultrasound and it's very similar when over 900 women used frozen eggs to conceive. Next. This is, we spoke about it, next slide. How many eggs to freeze? So, this is really important because it depends on the patient age, depending on the patient willingness to go through this process. With five frozen eggs, there's about 15% chance of getting pregnant and with 15%, there's a much higher chances of getting pregnant, almost 85%, when a woman is younger than 35 years of age. Next slide. In conclusion, the diagnostic evaluation of infertility should include a comprehensive history and physical exam to rule out endometriosis. The diagnostic evaluation of infertile patient should have also evaluation of the semen analysis. Women younger than 35 should really try on their own if they don't have endometriosis, but if they're over 35 and they tried for six months, that's enough of a reason to rule out endometriosis and to rule out infertility because we know that mild and minimal disease may not be seen on ultrasound or physical exam. There's really no age cutoff for endometriosis patient. Once you've been diagnosed, you know that this will have some impact on your fertility and you should be using early intervention, just like any other type of medical condition that have an effect, and the patient really should be advised that egg freezing is now no longer experimental and this is a good option for our patient. Next slide. The diagnostic evaluation essentially needs to assess the fallopian tube, the ovaries, and the uterus. Ovarian reserve testing, like we spoke to, is very simple to be performed. It's a simple blood test and ultrasound. Routine laparoscopy should not be performed unless there is a strong suspicion and the patient has pelvic pain, but obviously we see them after they've been diagnosed and if we change that paradigm, we'll be able to intervene earlier. Next slide, I think it's the last one. In summary, major advancements in the past few years made egg freezing a new, developing area in artificial reproductive technique and the demand of egg freezing for non-oncologic indication dramatically increased and reached social media. I think that this is where we as promoters of endometriosis should be talking to insurance companies and lobbyists in D.C. to promote this important topic. Next slide. And at least six to eight mature eggs will be a good statistics in terms of achieving a viable pregnancy. The main stumbling block is still the price. Women who are not covered for egg freezing spend anywhere from 5,000 and 15,000 per cycle, so that's still an expensive process. Next slide. That's it, next slide. Thank you so much.