In the past, young women newly diagnosed with cancer typically received no fertility counseling or were assured they’d be fine if their periods resumed after treatment. Fortunately, as reproductive endocrinologist Mitchell Rosen, MD, explains, it’s a more hopeful world for these patients, with better ways to predict the likelihood of ovarian failure or early menopause, plus highly successful techniques that can allow young women to be future moms.
Thank you for the, the organizing committee, Kristy, for uh inviting me to talk about this uh topic of emergent fertility preservation in a newly diagnosed cancer patient. So, what I'm gonna talk to you about today is how we counsel patients about the impact of chemotherapy treatment, about how chemotherapy treatment, what that impact is on ovarian function, and what the current options are for fertility preservation. And the success and the safety that goes along with it. So let's take this patient. She's 23. She has breast cancer, she's hormone receptor negative, stage 1 disease, and is about to get ACT for her chemotherapy. What's the impact? So, we did a study many years ago with the California Cancer Registry, where we surveyed women across the state of California to understand what the reproductive impact was if they were diagnosed with cancer and they were given chemotherapy, and we looked at 5 of the more common cancers of reproductive age, leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, breast and GI. What we wanted to find out was not only what the impact of acute, what the chance of acute ovarian failure was, which was pretty much well described in the literature at the time, but what was not described in the literature is what the reproductive impact would be if their menses returned. What we found, which was not surprising, but maybe initially surprising to you, is that the incidence of acute ovarian failure ranged from about 3 to 13%. Now, that may seem low to you right now, but it is highly dependent on the age of the individual. As you can see here, the incidence is on the Y axis. This is the incidence of ovarian failure, and here on the X axis is the age of diagnosis, and each color corresponds to the different disease type and associated cancer treatment. And as you would expect, the older you get, the more likely you are to experience acute ovarian failure. So in this case, in our patient that's 23, her incidence of acute ovarian failure is around 5%. And this is in contrast to somebody that is 40 years old, where their incidence of acute ovarian failure after after breast cancer treatment would be well above 50%. Now this data was relatively novel at the time, because when we used to counsel patients prior to this data, the only data we had was if you were less than 40, your likelihood of acute ovarian failure was somewhere around 30 to 40%. And if you were over 40, your incidence of acute ovarian failure was high. Now we have a much better way of counseling patients because we have age-specific stats to at least help us understand a little bit more about what that chance is of each individual experiencing acute ovarian failure. But how about the reproductive impairment? If they have persistent menses, so they're not in acute ovarian failure. They go through their treatment, and ultimately, their menses is either persistent after treatment or returns after treatment. What is the reproductive impact? So, the chance of experiencing infertility, which means trying to conceive and unable after a year of trying, is somewhere around, let's say close to around 30 to 60%, which is significantly high. The problem with counseling patients and their incidence of infertility. It's a little bit challenging because it depends on the age at which they are trying to conceive. So if they get diagnosed at 25, and then they get, uh, and then they try to conceive at age 30, that's different if they're trying to conceive at 35 or 38, because as we all know, even natural fertility declines with advanced. age. So a more concrete way of understanding what that true reproductive impact would be, would be to look at the age of early menopause, because as I'll show you in a couple of slides, the age of menopause is tightly linked to their end of reproductive window. So in this, uh, in this, uh, data, we show that the incidence of early menopause ranges from 9 to 30% depending on the cancer type or the corresponding disease type. Now what was interesting was the relationship to age. As you can see here, the probability of experiencing early menopause, again, they get their periods back, but then they go into menopause prior to the age of 45, is on the Y axis, and on the X axis is age. Again, the colors correspond to the cancer type or the, or the treatment or the corresponding treatment. And as you can see, really, it's women that are younger that are more likely to experience it, you're experiencing early menopause as opposed to those that are younger. If you recall the last slide of acute ovarian failure was the opposite relationship. You're more likely to experience acute ovarian failure if you're older and less likely if you're younger. This was very trick challenging concept to us at first, but then we saw corresponding literature, literature where women that had unilateral oophorectomies where they removed one ovary but kept the other one in. Uh, if they were young, they were more likely to experience early menopause than if they were older. These women where you remove one ovary. They don't go into early menopause at half the age. It's not like they're they accelerate to where their, if their normal genetic potential was 50, that they would go into menopause at all, all of a sudden it's 25. The other ovary, um, compensates for a given period of time. It's just harder for that ovary to compensate for a long. Long period of time. And that's why women in their younger age have a much higher chance of going into early, uh, menopause, menopause, because these women's remaining ovary or remaining ovarian reserve has to last for over 20 years as opposed to the 40 year old where it might only have to last for 5 years. So in our patient that we talked about with regarding our story, Um, at the beginning of this presentation, her likelihood of experiencing early menopause is well over 50%, something that was very much missed in her initial counseling regarding her fertility. Now, I mentioned that the age onset of menopause is linked to their end of their reproductive window. So this is a study that was done back in 2002 on a population, on a heartrate population. So these are non-contracepting populations, and as you can see here that the age onset of menopause is roughly around 51 with a normal distribution, and the age onset of the last birth is around 41. So we feel that the relationship is pretty much fixed at 10 years. It's not rigid at 10 years, but it's pretty much fixed. So if we assume this relationship, and then you have women going into menopause prior to the age of 45, then their age at last birth would be around 35 or maybe even younger, and that has profound effects in our population as our population is getting older when they're start as they, as they start their family. So let's go back to this patient. So we have a 23 year old that has breast cancer, and In one scenario, she experiences ovarian failure and doesn't have any, uh, and doesn't have any periods after her treatment. And then we have another 23-year-old that has two children post chemotherapy. What is the difference between these two patients? Well, there's probably a couple of reasons, a couple thoughts, um, that are related to this, but two that we do know about are one called the ovarian reserve, the number of eggs that they have left remaining in the ovary, and the other is their genetics. So as it relates to their ovarian reserve, we can actually quantitate or see how many eggs that they have left remaining in their ovary. So here's an ultrasound of an ovary. You can see right here and you can see the black circles that are within the ovary. If you can't see them very clearly, you can see them on this picture right here, and you can see all these red dots, and these red dots correspond to what we call anral follicles. These are the number of follicles or, or eggs. That we can visually see it at the last stage of their development, OK. Now, all of these eggs or all of these follicles have the capability of being released. They have the capability of responding to what's called follicle stimulating hormone and ovulating, but in any given uh cycle, only one gets picked and the rest die off, and then the next month, another crop comes in. In the infertility world, we call that the antral follicle count. In this particular situation, they have good ovarian reserve. In this particular situation. They have Low ovarian syrup. Here you can see, hold on one second, please. S So, in this picture, you could see there's only two circles. And if you can't see them, here are the two red dots. So you can see here, there's good ovarian reserve, lots of follicles, and you can see here, there's a very low number of follicles, so we say not so good. These two patients are the same age. We know that there's this range that exists. We did a study, uh, several years ago where we see the follicle count on the Y axis here. We see the age groups on the X axis here, and you can see the wide range for any given age for this anral follicle count. This rofugal count corresponds to the number of eggs that are left remaining in the ovary. So as you can imagine, if a woman's coming in at age 25 and has a lot of eggs, they have. A potential that if they lost half their volume of number of eggs, they would still have a given volume left to have menses after treatment, and maybe for a given period of time. But if they start out with a really, really low number, then they have much less, much less to lose. So we take this data, plus their age and their history, and then make a composite. The, uh, estimate of what their actual impact is of experiencing either immediate menopause, acute ovarian failure, or early menopause, and a corresponding narrow reproductive window. So after we go through and counsel patients about their reproductive impact, or as it relates to their treatment, we talk about the options for fertility preservation. The 3 main options are embryo and egg freezing, which we can do either do before treatment, which is ideal, or potentially after, if there is ovarian reserve left. Ovarian tissue freezing, which could be done before, during, or after treatment. Or there's the potential to use fertile, what we call fertileprotective agents such as GNRH analogs. You may have heard of them, which are called Lupron or Zoladex. They're also called ovarian suppression agents, and these could be given before or during the treatment. Let's first talk about embryo and egg freezing. So how we do embryo and egg freezing is we take advantage of those follicles. As I mentioned before, a given woman has a given number of those follicles that are always present. In a natural cycle, the natural cycle will only utilize one at a time. So one will grow and release and have the opportunity to be fertilized while the remaining die off. When we do egg or embryo freezing, we stimulate the ovaries prior to uh collecting the eggs, and that stimulation actually overrides the physiologic process and gets the other follicles to grow as well. How we do that stimulation is we basically give gonadotropins, which are the hormones that come from the pituitary to stimulate the ovary naturally, and then we give what's called a GNRH antagonist, which blocks the ovulation at that time. So, we're just continuing to give the stimulation, and then we're monitoring their ovaries, and we're blocking the ovulation. What this would look like would be shown here. This is a diagram of, of an ovarian stimulation. You can see on the Y axis are the sizes. This is the size of the follicles, and on the X axis is the days of stimulation. It normally takes about 2 weeks to perform a stimulation. The blue line is the estrogen levels. Red line is progesterone levels. But as you can see here, this woman had this number of baseline follicles and had one that was popping up that happened naturally. So we were pretty much mid-cycle for her. And we started the stimulation, and by giving her those gonadotropins, we were able to make a number of follicles develop and then ultimately go in to collect the eggs. An ultrasound, it looks like this. Here are follicles, and again, normally one of these would grow in a natural cycle, but when we give these gonadotropins and we block the Ovulation, we get all of the follicles to grow, and then what we do is we go in with a needle through the vagina and we aspirate out the follicle contents, and inside the follicle contents is a floating egg for which we would be able to collect. We would then Look at that egg, and this is what it would look like coming out of the ovary. And we would either clean off these cells, visualize it, make sure that it was mature, and freeze it, or we would fertilize it. Here's a sperm, look at the difference in size. The egg is the largest cell in the body, by the way, and we would put the sperm inside the egg, create an embryo, and then correspondingly freeze it. Now, egg and embryo carreservation is a very established treatment. Millions of babies have been born worldwide. In the past, this was a major limitation, or a major challenge, I should say, in treating patients with cancer because it took up to, uh, ultimately 2 to 6 weeks to perform this treatment. The reason why it took that long is because we always thought that Just like we do traditionally with fertility, infertility patients, is we would have to wait for their menses in order to start for their, start their stimulation. So if a patient came in day 7, we would have to wait potentially 3 or 4 weeks for them to have their period, and then it would take approximately 2 weeks to perform that stimulation. So that would be a 5 to 6 week process, which potentially would delay their treatment. And that delay causes increased anxiety and stress amongst the patients and the oncology team, and it would potentially lead to uh preventing many patients from undergoing this uh fertility preservation treatment. Well, no longer is it an issue because now we perform what's called a random start, and we're able to stimulate these patients at any time in their cycle. So they would come in and no matter where they were in their cycle, we can just start and we can be done in 2 weeks. So it's a very rare situation that we would not be able to perform this treatment as long as we had an early referral that, and we would definitely avoid delays in their treatment. How it works is like this. So let's say we have a patient, in this case, let's just say it's a breast cancer patient. She has surgery, and after her surgery, she has chemotherapy. So now, in addition to basically being very efficient with the treatment, we can actually work around their treatment, and we can just say, OK, you, the, the cancer treatment, you line up. We're gonna work around your treatment because we don't care where you are in your cycle. So, if the patient presents before treatment, we can just start and go ahead and give our gonadotropins and our Antagonist to prevent the ovulation before the surgery. Or alternatively, we can do it after surgery. And it doesn't, again, it doesn't matter where they are in their cycle. We can just say, OK, how stressed are you? What's the situation? What time is it, when is your surgery? And we just work around that process in order to do the egg or embryo cryopreservation. This is basically revolutionized how we actually perform, uh, fertility preservation treatment in the cancer, uh, patient. If the patient's just getting chemotherapy, as long as we have that initial consultation, they have to go through a whole bunch of workup. Before they get their chemotherapy. So as long as we have this, still this two-week process should minimize any delays in their chemotherapy. We know that there wouldn't be any delays because we actually performed a study at UCSF where a where breast cancer patients were going, undergoing neoadjuvant chemotherapy. So that means they would do chemotherapy followed by surgery instead of the conventional surgery followed by chemotherapy. And what we did is, in this group of 54 patients, We evaluated the time to chemotherapy. On average, from their medical oncology consult to their time of starting chemotherapy, it was around 27 days. But whether they had a fertility preservation consult or not, or whether they underwent treatment with us or not. The average time that they would go, that they would uh start chemotherapy would be around 27, 28 days. So this means that even in this setting, where we're emergently starting chemotherapy. There is no delays in their cancer treatment if they were to be offered a fertility preservation consult or if they were to undergo the treatment. So the success rates of embryo cryopreservation, uh, we don't actually really know very well in the cancer patients specifically. There's really only about 80 live births that are reported. But in other populations, which are, which we use every day in our infertile population, we know that the frozen embryo transfer rate. And the fresh transfer rate is exactly the same. In an approximate, approximates somewhere around 40 to 50% chance of getting pregnant per embryo transfer. Now, obviously, this is age and embryo-dependent, but that's our average. And based on the limited data that we have with those that have Had transfers and had had cancer in the past, it appears, at least by that limited data, that the pregnancy rates are very similar to the other populations that we treat. So it's a very, very successful treatment. Egg cryopreservation even has more limited data as it relates to uh cancer treatment. What we have found in our other populations is that egg cryopreservation is rather efficient. If you have an embryo. That uh is beautiful, whether you froze the egg, and then thawed the egg and fertilized it and then transfer it, or whether you had a fresh egg that you fertilized and transferred it. Those pregnancy rates are the same. What we find is that in the, those that have done egg cryopreservation, that there's just a little less efficiency on the number of embryos that you have to use to get transferred, but the embryo itself has similar implantation and pregnancy rates. Now, what is the safety of egg and embryo cryopreservation? Well, there's short-term safety that we gotta talk about, and then there's long-term safety. So regarding short-term safety, we have the usual, which is the main risk of performing an ovarian stimulation, which is called ovarian hyperstimulation syndrome. If there's a number of eggs. What can happen is, is that some of these eggs can release what's called vascular endothelial growth factor. That vascular endothelial growth factor can cause third spacing of fluids, and then fluid can accumulate around the heart or in the lungs and create a significant sickness and cause significant, uh, long-term morbidity, not long-term, but short-term morbidity. In a cancer patient, this is even more likely because they have a propensity to have fluid shifts. So we really, really have to watch out for that. The other thing is the risk of anesthesia. So in some of these patients, they have big solid tumors in their chest. So they're at, they're at major risks for their anesthesia. So we have all these patients go through extensive repair appointments being evaluated by anesthesia or other uh uh. Uh, physicians to help us understand what the risks are, what to watch out for as we take these patients through the treatment. And then some of these patients have very low platelets, and they have a propensity to have bleeding disorders and bleeding and so on, or other sorts of injury. So this is not your standard infertility patient. These patients have additional risks cause they're sick to begin with. Then you have those that have estrogen receptor positive disease. With these with these treatments, there's a propensity for the uh estrogen to rise, because we're stimulating the ovary and each follicle produces a given amount of estrogen. So in a natural cycle, you have one follicle and it's producing an excellent amount of estrogen, but in a stimulated, you might have 20 follicles, so it can have almost potentially 20 times the amount of estrogen, and they have, if they have estrogen receptor positive disease, we don't want to progress. We don't want to increase the risk or change the prognosis of the patient. So what we do is we add what's called an aromatase inhibitor or an estrogen receptor blocker while we're giving the stimulation. Here we show another stimulation. Again, we have the follicle size on the y axis. We have the number of days on the x axis. These all these little dots are follicles, and here are the estrogen levels. But what you can see here. Is that this, these numbers here, down here, you can see peak at around 377. This is the estradiol level. That's the estrogen level that we would expect to see in a natural cycle. How we control that estrogen level is by giving an aromatase inhibitor called letrozole. So you can see right now we're giving 5 mg, and as it goes up, we're giving 7.5 mg, and we're controlling this level to make it to where it doesn't exceed. What you would see in a natural environment. If we go ahead and give these medications, the letrozole or the tamoxifen or some type of blocker. Um, there should be no difference in their disease-free survival. Here's a study that was done in 2016, where it's looking at survival on the Y axis and the time on the X axis, and as you can see for those that have breast cancer, if they underwent fertility preservation or if they didn't, the disease-free survival was no different. We recently published the largest study to date, which is in 2019. Where we were looking at disease-free survival on the Y axis, and this is the month's follow-up as well, and found no difference. And most recently there was a meta-analysis where they took all the data together and they showed that as long as we have these. Medications on board that while we're, while they're undergoing this treatment, there is no increased risk for the patient. There's no change in their recurrence or disease-free survival. And this is whether they have a BRCA mutation or they're estrogen receptor positive. So now, what about ovarian tissue freezing? Ovarian tissue freezing, how we do this is we go ahead and we perform a laparoscopy, and we go in and we either take, classically, we would take one ovary or part of one ovary. And we have options. We can either go ahead and attempt to do what's called in vitro growth. So we would freeze the tissue. And then when we're ready to use it, we would thaw it, and then we would try to culture this tissue in the laboratory, all the way until it made those antral follicles, and then once it made those an follicles, we would then go into the ovary that we were growing in the culture, grab out the egg, fertilize the egg, make the embryo, and then transfer it back to the patient. This has been successful in a mouse model. It has not been successful in humans. So highly experimental, pretty, we're relatively far away from this producing live births in humans at this time. The other thing we can do, we can thaw the tissue and we can transplant it back. We can either transplant it back orthopically, that's back near the ovary, or we can transplant it heterotopically somewhere else in the body, either on the abdominal wall or in the arm as you see here. If we transplant it back orthotopically, then they have the option of getting pregnant naturally or through IVF. If we transfer it back heterotopically, then obviously the only way that they would be able to get pregnant is potentially through IVF. IVF is by giving those gonadotropins, having the tissue be stimulated, and going in there to collect the egg, fertilizing the egg outside the body, creating the embryos, and transferring it back into the uterus. So what are the success rates with ovarian tissue cryopreservation? Well, there's been over 200 reported transplants, uh, worldwide. Uh, the majority of this tissue has been cryopreserved. The reason why I say that is because there's probably been around 20 or 30 cases where fresh ovarian tissue has been transferred from one patient to the other, identical twins and resulted in live births, but the majority has been, uh, cryopreserved tissue. And after thaw and transplanting it back orthotopically, cause that's the only way that we've had live births. There's been about 100 maybe 30 live births worldwide since the first live birth of 2004. In the majority of cases, these patients have conceived naturally. The youngest is those that were that had ovarian tissue cryo at age 9, transplanted back at age 23, and she conceived through IVF. And then there was another that was uh Uh, cryopreserved, had brain tissue preserved at age 10, transplanted it back at age 20, and then following the transplant, uh, conceived naturally. Now, the problem with ovarian tissue cryopreservation is that the success rates, one of them, is that it's very, very difficult to ascertain. The transplants that have been done across the world have been grossly underreported. People don't like to report negative results. So we don't know about all the transplants that are, are done across the world and what that corresponding success rate is. We only know about case series and those that want to, uh, those that want to publish. So we don't really know the denominator, and we don't really know the true numerator. And we also, another issue is that it's possible that when you transplant the tissue back into the ovary, that you can create injury within that ovary that was not working and create some sort of inflammatory process and wake that ovary, that residual ovary up. And then that native ovary could be producing the egg rather than the tissue that we transplanted. So, we know that it works, OK? And in general, we've had situations where women have been in menopause for 5 years and then transplanted this ovarian tissue back and we've, we've seen live births, but it's success and how to counsel about the success is very, very challenging. The other challenges are that when you put the ovarian tissue back in, Is that the tissue has a relatively short half-life. So what you do is you take the ovarian tissue, you cut the tissue in pieces, and then you freeze it in pieces. And the reason why you freeze it in pieces is because it's a lot easier for our cryoprotectants, the, the, the materials that we use to freeze the tissue, to penetrate into the tissue. So if it's a whole ovary, it's very hard for that, those cryoprotectants to get into the ovary. And what happens is, and how these cryoprotectants work, is that we first suck out all the water, and then we put this cryoprotectant in, and then when we thaw, we take the cryoprotectant out and we put the water back in, OK? So this exchange needs to happen very close. The, the, the materials and the cell walls. So if the ovarian tissue is a hole, it becomes much more challenging to do. So because we have it in pieces, we return it back in pieces. So we don't necessarily return back all the pieces, we return back some of them, and that's one of the reasons why it has a short lifespan. The other is that it has to give time for revascularization. So during that period of time while it's sitting there, and it's, we just put it in, it's thought, cells are dying until there's new vasculature that develops around this tissue to replenish it and keep it alive. The other limitation is that it takes general anesthesia. So we have to have general anesthesia to go in to get the tissue to begin with, and then every time we transfer back the tissue, it requires general anesthesia. So there's this need for also possible multiple procedures. And then one thing we can't. Fully, um, do is identify if any metastases from cancer actually gets into the tissue. So if that does, there's always the theoretical risk that if we put this tissue back into the body, that we can reintroduce the cancer. We know that the risk of metastases into the ovary is highest in bloodborne cancers, such as leukemia. So with women with leukemia, we, we would not recommend doing ovarian tissue cryopreservation. But solid tumors such as breast, breast, or lymphoma, depending on the stage, there's probably a very relatively low chance that there's metastasis, but we just don't know, and there's always a theoretical possibility that we could be reintroducing, uh, the tumor. No cases to date have we found that we have reintroduced the tumor and recreated or there has been a subsequent cancer because of that. What about FerD protective agents or GRH analogs? There's a lot, a lot, a lot of controversy regarding this treatment. Basically, what you do is you take what's called Lupron or ovarian suppression, Lupron or Zoladex, which is an intramuscular injection, which can last 1 month or 3 months at a time. And what it does is it turns off the gonadotropins from the pituitary. It turns off the FSH and LH, so there's no stimulation to the ovary, and the ovary kind of shrinks like grapes and doesn't produce estrogen. It's a very, very common treatment for adjuvant hormone treatment in women of reproductive age that have gotten diagnosed with breast cancer and have estrogen receptor positive disease. These women are commonly on these treatments for 5 to 10 years. With the and shown to be very protective and help with decreased recurrence. What we're talking about here is using these agents to try to protect the ovary. We all know chemotherapy attacks actively dividing cells. So the thought process here is if we can decrease the activity of the ovary, then we can decrease the toxicity of the chemotherapy to the ovary. So, if you look at the 5 or 6 randomized 5 randomized studies that have been done, it suggests that at least with respect to acute ovarian failure, that there's an overriding benefit if patients are on a GNRH agonist such as Lupron or Zoladex, versus if they got chemotherapy alone. And if you look at pregnancy, It also suggests that if they're on a GNRH agonist, that they're more likely to conceive after chemotherapy than if they, uh, if they were not on a GNRH agonist and got chemotherapy alone. The problem is the controversy, and the reason why this controversy exists is because the outcomes of these studies are all different. They'll have their incidence, uh, they'll, they'll say periods at 6 months versus not post-treatment periods at 12 months versus not post-treatment, period, versus at 2 years, yes or no, or they might use serum markers instead of menses. Pregnancy is never a primary endpoint. There's often a lack of power in these studies, and the true mechanism of this treatment is not known. But because of the meta-analysis that I showed you with those uh studies. The idea here is, is that every patient that is diagnosed with reproductive age that is getting chemotherapy be offered a GNRH agonist, Lupron or Zoladex, as an adjunct, not as a replacement for fertility preservation, but as an option to help protect the ovary, so there may be longer life of the ovary after chemotherapy. So in summary, fertility preservation is definitely a significant desire. The impact of reproductive compromise has previously been underestimated. I showed you the incidence of acute ovarian failure, and prior to this data set that we just showed you, the idea that women were had a had a significant reproductive impact, even in the presence of menses was not previously described. We talked about the fertility preservation options. Egg and embryo cryopreservation should always be first line. It's the if we have that as an option. We know that it's quite successful. We have the most amount of data with it. It has minimal delays, and it's considered safe. As a second line, especially if there's no other options, so they have a bloodborne disease where they need treatment right away, or they're pre-pubertal, then ovarian tissue is the, is the next best option. And as I mentioned, we can use these GNRH agonists as an adjunct. It likely has some benefit.
