SESSION II: Treatment considerations
Tomer Singer, MD
Neuropathy and nerve sparing surgery
Endometriosis and oocyte cryopreservation
Advancing the Science and Surgery of Endometriosis
Monday and Tuesday, April 18-19, 2016
The Union Club, New York
Hi, good morning. So we are switching geasr from bladder and rectum to ovaries and from Mac to PC. I will be talking today about the role of oocyte cryopreservation, or egg freezing in patients with endometriosis.
Thank you Tamer for inviting me and putting on this meeting every year. It is a great opportunity and I am happy to see that we have a lot of residents here in the audience. I have nothing to disclose.
The objectives of the presentation is to review the scientific background to review the current technology in egg freezing, to discuss some of the clinical results that we have been seeing in the last several years and to discuss potential future application.
As we know, patients affected with severe endometriosis are at risk for varying tissue damage, infertility, reduced response to ovarian stimulation and in some rare situations, premature ovarian failure, which accounts for about one percent of the general population. The risk for a compromised ovarian reserve in young patients is very high when patients are undergoing multiple surgeries whether it is for endometriosis or recurrent cysts and for patients who have bilateral large endometriomas. The loss of ovarian reserve may also be a result of the damaging effect of the actual pathological process that we see with endometriosis and not just a surgical intervention so we need to keep that in mind as well.
What is the work up? We know that the key is early detection. We have all seen patients going from one doctor to another and not being diagnosed with the right condition and you are the person who finally tells them that they have endometriosis and they are in complete shock. I think that early detection, both of endometriosis and the consequences that can follow surgeries and actual disease is key. We want, as general OBGYNs, we want and expect the community to refer to an endometriosis surgeon and once we decide on the paradigm and how we are going to treat we should refer them to a reproductive endocrinologist to just discuss the option of freezing eggs or embryos depending on the situation the patient is at.
We know that transvaginal ultrasound is as Dr. Isaacson showed in his great talk can detect endometriosis, severe stages and detect adenomyosis. If we do see endometriomas, if we do see that there is some pathological involvement of the ovaries that may have some implication and we may want to speak with the patient and tell her that it may impede her option of getting pregnant in the future. She may need to use gestational carrier, she may need to use a donor egg, so I think that the first two really that we use routinely enough is a pelvic ultrasound.
In terms of ovarian reserve testing we know that AMH has been emerging as the gold standard of ovarian reserve testing. We can test it even when a patient is on birth control pills. At any given time we do not have to bring the patient back when she is on day two of her period or day three of her period. We can get a clear understanding if she has good ovarian reserve right here and there with a simple blood test and there are more and more talks about having AMH testing that are going to be readily available just by going to a pharmacy and picking up a kit. At this point it takes about a week to ten days to get the results. If you are doing the actual ELISA test it takes probably about six hours. I can tell you I have done hundreds of tests as part of the fellowship but it still takes two weeks. Patients will call back and find out that the AMH is low and what does that mean and they have to come back to discuss the AMH results. But I think if it was up to me I would recommend doing it routinely when a patient shows up with severe endometriosis because I think that is always a good number to go back to when you want to repeat it every six months or so to see if the endometriosis is getting worse or if the surgery may lower the AMH. The patient may decide to do something about it like potentially getting pregnant earlier and so forth.
Day three FSH with a background estradiol level has been the mainstay of ovarian reserve. Testing has been around for the last 20 years and elevated FSH as we all know will suggest diminished ovarian reserve. This is probably the only ovarian marker that we have that also gives us some indication about the quality of the eggs. There are multiple studies that show the patient with endometriosis do have elevated FSH at a younger age when compared to patients with no endometriosis.
And antral follicle count and ovarian volume and ruling out endometriomas in a simple bedside ultrasound is also very important when a patient actually sees their ovaries and she sees that she has only two or three follicles in each ovary rather than six or ten or twelve follicles in someone her age without endometriosis. We will help explaining that there are other options and maybe we should be proactive.
Tubal patency – I think it is important to assess tubal patency even though you know that the patient has severe endometriosis and she is complaining of dysmenorrhea and is not really complaining of infertility, knowing that the patient has bilateral hydrosalpinx or blocked fallopian tubes may mean that this patient will need IVF anyway. Maybe getting those eggs out before she is ready to conceive and freezing those eggs will be a wise thing to do because not every patient with endometriosis will obviously need IVF. And egg freezing and IVF are pretty much equivalent just without the sperm component.
We know that primary infertility, dysmenorrhea, uterosacral and cul-de-sac nodularity and by manual exam are significant independent predictors of finding endometriosis when we take these patients to a laparoscopy. Hysterosalpingogram has been shown to show bilateral hydrosalpinx like this image or a distal tubal obstruction. It is another tool to have when you discuss with the patient the extent of the surgery, the involvement, whether or not you are going to remove those fallopian tubes during the same surgery and whether or not this patient will end up needing IVF, which may convince them that they should probably work on doing egg freezing prior to doing the surgery.
Patients who complain of pain and endometriosis symptoms usually do not try to get pregnant at the same time. It is really something that comes back down the line, five, seven years down the line saying, “Yeah, I do have endometriosis. Now I’m married and I’ve been trying for a year or two and nothing is working”. I think that we know now that maintaining fertility and discussing future parenthood those are really important lifestyle issues that are desired by most of our endometriosis’ patients given that most of our patients are in their 20s and 30s and definitely into the productive age.
However, studies have been showing, just like in the fertility preservation, when it comes to cancer patients a very small portion of patients are actually counselled regarding fertility preservation and prior to requiring surgical intervention, prior to actually taking them to surgery, even fewer are actually referred to reproductive endocrinologists. I think we have a very unique situation here with the relationship we have established at Lenox Hill that a lot of the endometriosis surgeons in the audience are referring to reproductive endocrinologists just for a talk, a chat, reviewing the options and then deciding how we should approach; do we do egg freezing before surgery or surgery before endometriosis. I think that is a good model to follow outside of New York.
What are the hurdles? Obviously there are a lack of RCTs that show that doing elective egg freezing prior to doing surgery for endometriosis stage three or four is beneficial and as we know it is true for a lot of the field of medicine, especially in an emerging field like egg freezing. There is a limited access to care outside large academic centers and large cities so if you are not in Manhattan it is going to be very difficult to find a very good endometriosis surgeon and a good reproductive endocrinologist who is going to be willing to take you for egg retrieval when you have bilateral endometriomas and trying to harvest those eggs going in between the chocolate cysts. There is a concern about iatrogenic estrogen elevation from the IVF. We have ways to go around it just like we do with breast cancer patients by supplementing with letrozole for instance, an aromatase inhibitor that is going to keep the estrogen level at the lowest possible level. Some patients do not have a partner to create and freeze embryos. Therefore they are probably not thinking about whether they should freeze their eggs. All of these hurdles really could be overcome.
Just a little bit of history about cryopreservation. We know that the first live birth from frozen sperm was in 1953. Thirty years later the first live birth from frozen embryo is being reported and just two years later the first live birth from frozen egg. Over the past decade we had switched from the slow freeze technique to vitrification, which has shown a significant improvement in the survival rate and the pregnancy rate.
This is a nice timeline that shows the process from the early 30s into recently that we now do elective egg freezing in a very, very good manner with 90 percent survival of these eggs that are being frozen.
What are some of the clinical applications? We know that most of the studies with egg freezing started with patients with either breast cancer or Hodgkin’s disease lymphoma and so forth. So patients prior to receiving chemotherapy that will have a detrimental effect in more than 50 percent of the patients are going through egg freezing. It is covered by some of the insurance providers and if not most of the academic institutions will have some kind of policy that they offer a discounted price. The patients who are receiving ABVD for instance are told that you know following their chemotherapy and resolution they may look at probably about 50 percent decline in their chances of conception. Patients with significant genetic conditions that can cause premature ovarian failure like Turner’s syndrome for instance or fragile eggs do consider freezing eggs or embryos before they are ready to actually have a baby.
Patients who undergo IVF and a husband is not available or does not give a good sample or cannot ejaculate on that day, those patients will be freezing their eggs routinely. There is obviously an emerging indication which is the elective/social indication. We probably freeze hundreds of patients’ eggs a year just for elective reasons. They are in their early 30s they are planning to go onto a Master’s degree or conquer the world and then they will get those eggs five or ten years later and use them with a future partner.
And of course, the egg donation program; we have a very large egg bank now, egg banks I should say that offer frozen eggs. You can purchase six eggs from Atlanta and get them in two days with a cryoport, you can choose the donor, have some frozen eggs for the future. There are several egg banks now in the country that are FDA approved for usage and we use them on a weekly basis. I have a patient tomorrow who is going to be thawing her six eggs, her husband is going to produce fresh sperm we are going to create embryos and transfer them to her on Saturday. Those are things that are happening on a daily basis.
The slow freezing has been developed in 1972 but we now know that this technique is not really the way to go. That technique involved slow cooling of those eggs into -5c and -7c over several minutes and then the solution was seeded in a cooler media which got them to -30c to -65c and then those straws were plunged into liquid nitrogen for storage. I saw a lot of patients who did that ten years ago, 12 years ago when they were very smart about exploring this option under our R&B protocol and most of these eggs really did not survive unfortunately. By good studies it is about one in five that survived, so 20 percent.
The new technology, the vitrification is the way to go. We know that 95 percent of the eggs survive so if you freeze six eggs you usually get five or six eggs that will survive the freezing and thawing process and 70 percent will fertilize. There are multiple studies coming from the US, from Spain and Italy. In Italy it is an interesting concept. You are not allowed to fertilize more than three eggs at a time so by default all the extra eggs were frozen and then if the patient did not get pregnant and they went back to the frozen eggs and thawed another batch of three and fertilized it with the husband. We learned a lot from the Italian experience given the Vatican influence over there.
We know that the specialized freezing technique that rapidly freezes the eggs and prevents ice crystallization is the way to go. The vitrification process takes minutes and the temperature is going down by thousands of degrees by really just a few minutes. That is the way to go. We know that this is used routinely in most academic institutions. The only down side with that is that once the egg is thawed you have to fertilize the sperm with ICSI because you are peeling off the egg from the granulosa cell and take the cell around it and you really have a naked egg that would not fertilize if you just put some sperm around it and pray for 24 hours. We really have to impose fertilization by injecting the best local sperm.
In 2012 the American Society of Reproductive Medicine essentially released a notion that egg freezing is no longer experimental and it actually had a recommendation for women facing infertility due to chemotherapy or other gonadotoxic therapies and encouraged them to freeze their eggs. I would argue that a patient with endometriosis is no different. A patient with endometriosis, stage three, stage four have debilitating pain, they have psychological impact just like our patients who suffer from different types of cancer. This recommendation I hope in the next year or two will include also endometriosis patients and this is a part of what we should be looking at in our research.
What are the benefits? Obviously it is a safe, well controlled procedure that is done every year by 196,000 women who undergo retrievals in the US and over 25 million people went through IVF since 1978. We know that it is a safe procedure. We use the same well tested IVF stimulation protocol with a caveat that we usually use a GnRH agonist trigger, which is essentially a safer trigger than the HCG and prevents hyper-stimulation. So I can tell you that the rate of severe hyper-stimulation has gone down significantly and it is well below 1 percent when done in trained hands.
The risks are bleeding, infection and obviously if a patient is facing a surgery that will delay her treatment by a couple of weeks given it takes about two weeks to stimulate the ovaries.
Once the patient has already decided that she is going for endometriosis surgery we usually recommend doing a consult with a reproductive endocrinologist doing the stimulation with a Lupron trigger again, doing the retrieval 14 days later and then essentially moving forward with surgery. There are obviously some special situations and we have discussed the limitation of OHSS by giving GnRH agonists and ideally giving Letrozole to lower the absolute level of estrogen. Ovarian stimulation, we know that this is how ovaries look like before and after stimulation all the way on the left hand side. You can see that this is on day of retrieval. The retrieval is done trans-vaginally. The eggs are harvested and within four hours we freeze those eggs and they can be used all the way through age 51 if it is in our academic institution. Different centers will have different cut offs.
We have very good evidence now that fertilization rate and pregnancy rate are very similar to IVF/ICSI when compared with fresh eggs. We know these studies coming from Italy and Spain show that the pregnancy rate is very similar with frozen eggs and fresh eggs. That gives us good reassurance that this should become a mainstay of treatment.
There is one study coming out from NYU looking at the outcome of these babies after. Nine hundred cases have been reviewed and we see that the rate of birth anomalies were very similar to the general population, about 1.3 percent looking at 936 live born. There is good evidence that there are no increase in chromosomal abnormalities. I have just had a case last week that a couple essentially did IVF and they did not want too many embryos to be frozen. So we froze some eggs and on the day of retrieval then thawed them, fertilized them and checked them for chromosomal abnormalities with a technique called PGS and the frozen eggs have shown the same rate of aneuploidy rate as the fresh eggs. That means that the freezing and the thawing did not cause an increased risk for chromosomal abnormalities.
This was a good study or a good article that came out in the New York Times right after the ASRM meeting saying that essentially “we should allow women to store their unfertilized eggs for a future partner and we must go one step further and expect OB-GYNs to bring up family planning at every annual visit so that women have the information they need to choose to take charge of their fertility”. I could not have said it better and this definitely follows when we speak about endometriosis patients.
We all remember the Faddy study from the 1990s, 1992 showing the decline of the quality of the eggs and the quantity of the ovarian pool past age 35. We know that the chances of conception past age 42 is less than five percent in IVF patients. We should really be pro-active before a patient gets to the late 30s early 40s, especially if to begin with the reserve is lower, diminished by the endometriosis process and we know that there are increasing chromosomal abnormalities with age.
This is essentially a summary slide that shows you what the egg freezing process entails. You will meet with a reproductive endocrinologist, there will be a physical exam, a pelvic ultrasound with some blood tests, AMH, ___ blood if she is on the right time, then ovarian stimulation for about ten days which requires about four or five visits for ultrasounds and new blood tests. Then a trigger shot and retrieval about 36 hours later. The egg freezing process again takes about 14 days and a patient will be seen four or five times. This is the way that we actually make sure that the eggs are frozen without the formation of crystallization. We freeze it in liquid nitrogen and we noted a viability in the pregnancy rate is greater than 50 percent in patients younger than 30. There is very similar outcome with fresh eggs. So egg freezing, the ultimate reproductive emancipation of women.
In summary, women with severe endometriosis designated for extensive ovarian surgical intervention are frequently not planning to conceive. With advances in oocyte freezing and increasing success rate we should evaluate the option of fertility preservation in these endometriosis patients. Personalized counseling should be offered to all endometriosis patients taking into account their age, extent of ovarian involvement, current ovarian reserve, previous and pending surgeries for endometriosis along with the current success rates and possible risks. Thank you.