PAG over Pastries
A pediatric and adolescent gynecology review podcast. Started by a fellow for residents, fellows, and others to learn more about PAG topics.
PAG over Pastries
11 - Fertility Preservation
Fertility preservation options have dramatically expanded for children and adolescents in recent decades, offering hope to patients undergoing gonadotoxic therapies for cancer and other conditions. Dr. Stephanie DuFour, PAG and REI attending at CHEO in Ottawa, Canada, joins Dr. Susan Kaufman to discuss the latest advances in preserving reproductive potential for young patients facing treatments that may compromise their fertility.
Outline
- Case Presentation: 7-Year-Old with Leukemia
- Introduction to Fertility Preservation
- Who Needs Fertility Preservation
- External Impacts on Fertility
- Fertility Preservation Options
- Assessing and Monitoring Patients
- Barriers and Insurance Coverage
- Case Resolution and Conclusion
References:
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What is PAG?
Pediatric and Adolescent Gynecology is a subspecialty of OBGYN (2 year fellowship) focusing on reproductive healthcare for children and young adults. It fills the overlap between general gynecologists and pediatricians. It is a multi-disciplinary field involving work with pediatric endocrinology, dermatology, hematology, surgery, ect. Go to NASPAG.org for more PAG educational resources.
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We have a seven-year-old pre-pubertal girl that was recently diagnosed with leukemia and she's about to start chemotherapy. Her parents are worried about the possible impact of chemotherapy on her ovaries and wanna know if she has any options to preserve her fertility.
Susan:Hi everybody. My name is Susan Kaufman and I'm a pediatric and adolescent gynecologist in South Jersey, and today I am with
Stephanie:Hi everyone, Dr Stephanie DuFour.
Stephanie:I'm a pediatric and adolescent gynecologist here in Ottawa, Canada, and also a reproductive endocrinologist.
Susan:And we are here today for PAG over pastries, which is a 20 to 30 minute review of everything in PAG. Our topic today is ovarian fertility preservation for children and adolescents, and we take this information, written by Olga Kuk and Stephanie Marie Cizek in Essentials of Pediatric and Adolescent Gynecology that was released by NASPAG
Susan:So, stephanie, what's your favorite pastry?
Stephanie:I know technically not a pastry, but tiramisu I would die for. So I would go with tiramisu anytime. And what?
Stephanie:about you.
Susan:Usually I'd pick something chocolate, but the other day I had some kind of pastry that was filled with blueberry filling, and that was outstanding. So let's get started.
Susan:Well, this is such an important topic. A couple of decades ago, we didn't even have options to offer our patients who were undergoing ovarian toxic or uterine toxic therapy for fertility preservation. And now we do, and that's why we talk about this topic. So, stephanie, who should we discuss fertility preservation with?
Stephanie:So basically, to put it in simple words, anyone who's undergoing gonadotoxic therapies. So that includes the cancer patients, so anyone with a new diagnosis of cancer, recurrence of cancer, about to undergo gonadotoxic therapies. But other patients can also receive treatments not related to cancer. So some diseases are known to be treated with gonadotoxic treatment. So that would include diagnosis like lupus or congenital anemias. And then we also see the patients with higher risk of primary ovarian insufficiency, such as Turner syndrome. So those patients could also be candidates for fertility preservation. So basically, anyone who's at risk of seeing a decline in their fertility should be referred for a discussion about fertility preservation.
Susan:Right, this is endorsed by the ASRM, by ACOG and by the AAP and many, many more. I will say, yeah, that's right. Organizations in Canada, right, exactly. Yeah, you mentioned some examples of patients that should be referred for counseling for fertility preservation. So what are some of the external impacts on fertility?
Susan:First of all, the one that everybody thinks about all the time is chemotherapy, and 6% of cancer survivors will experience acute ovarian insufficiency and long-term 9% will experience either POI or premature menopause, and fortunately, so many of our young patients being treated for cancer and chronic illness are surviving into adulthood, and so that's another reason why this is so important. One of the chemotherapy agents that is particularly toxic to the ovaries is alkylating agents, and we're going to talk about that more in depth in just a moment, but what else can be toxic to the ovaries or the uterus?
Stephanie:So we know that radiation is also not great for both the ovaries and the uterus. The effect of radiation are dependent on the location, the dose of the radiation. It can either be when it's pelvic radiation or total body radiation. But we also have to think it's pelvic radiation or total body radiation. But we also have to think that cranial radiation could affect future fertility, affecting the hypothalamic glottal axis. Other things would be things like pelvic surgeries. There's a direct impact. If you're going to remove the ovaries, remove the tubes and or the uterus, that could definitely impact future fertility and chances of carrying a pregnancy. But there's also indirect impacts. When patients have surgery there's higher risk of having pelvic indigens that can then lead to tubal factor infertility.
Susan:And another category of patients that we should always counsel about fertility preservation is our transgender patients who are going to undergo hormonal therapy, especially transgender men, because we don't have enough research yet to tell us long-term what testosterone therapy will do to the ovaries and whether the ovaries will be able to recover and ovulate if somebody stops their testosterone and wants to get pregnant. So we should always have that discussion with our trans patients.
Stephanie:That's a field that's evolving very quickly so people should keep up to date with the literature. But very interesting section of the fertility preservation, for sure there's a figure in the chapter for people to look at. So table 23.1,. Could you go over what organs can be affected by the treatment and how they're affected?
Susan:So, first of all, the uterus can be affected by chemotherapy and radiation and that may stunt uterine growth, which then can cause preterm birth or low birth weight. It's possible for some scar tissue to develop within the cavity of the uterus or to affect blood supply to the uterus due to fibrosis, and then that's going to impact whether a pregnancy can implant and grow successfully within the uterus. We should remember that, because we always talk about ovarian effects, but we sometimes forget to talk about uterine effects. Another organ we sometimes forget to talk about uterine effects, another organ we sometimes forget to talk about is the vagina, and the vagina can definitely be impacted by chemotherapy or radiation, and stenosis and adhesions can develop which will impact somebody's ability to be sexually active and thus get pregnant. What about the ovaries?
Stephanie:So ovaries, as we said, can be affected by all those treatments. So whether it's chemotherapy, radiation, different mechanisms, but they can both affect the ovaries. And then we touched upon that just briefly. But testosterone also, we know, affects the function of the ovaries while the patients are on it. But we don't quite know what are the effects long-term of being on testosterone and what happens once you stop testosterone. So there's definitely an effect on the ovaries there. And then we talked about the brain briefly, so we did mention radiation. So it does affect secretion of the hormones of the brain. Hormones including FSH, lh, but also the thyroid function can be affected by the radiation. Chemotherapy might have some effects, but definitely not as much as the radiation to the brain.
Susan:Yeah, absolutely. I have treated teenagers and young adults who had cranial radiation for something such as a craniofaringioma, which then severely impacted their fertility and other endocrine organs. So how do we assess a patient who's coming in to talk to us about fertility preservation?
Stephanie:First thing we should do is see if the patient is pubertal. We need to know what the options are, and options will depend on the patient having their periods or not and having their puberty or not. Then we always need to remember and that's something that we need to stress with the oncologists or the providers that are referring patients, but also the patients and the families themselves that even when we say that therapies are low risk of premature ovarian insufficiency or affecting the fertility, low risk is still a risk and there might still be a potential of harm. There are different ways of assessing the gonadotoxic risk. There is a table you can refer to, the table 23.2, so the risk stratification system. Different tables exist.
Stephanie:That's the one that we use the most often and this one is giving you an overview of the usage of the cyclophosphamide equivalent dose. So, cyclophosphamide equivalent dose. There are different calculators that you can find online and then you can put in the chemo agents that the patients are getting, the number of rounds they're getting, the dosage of the medication and based on that, the medications are converted to cyclophosphamide, which we know is one of the major chemotherapy that will affect the ovaries, and then we can average out the cyclophosphamide equivalent dose to decide how risky is the treatment for the patient and their future fertility. So they are then stratified on minimally increased risk, significantly increased risk and high level or significantly increased risk. If you go back and look at other tables, it used to be a different classification. Now the terms have changed. Just to highlight how important it is to mention that even if it is low risk, it is still a risk for the patients.
Susan:And I just want to note. So, if the patient is being referred to us, these conversations are difficult because, whether it is chemotherapy that this patient is looking at, or radiation or surgery, they're focused on what's going on at the moment. And now we want to intervene and talk about a topic that is not related to their treatment but is a sequela of their treatment, and explain all of this to them and help them with shared decision-making about whether they're going to elect fertility preservation. And I think the younger the patient is, the harder the conversation.
Stephanie:Yeah, it is difficult, but I will say it is much easier to have the discussions before the treatments than after the treatments, when they didn't get the counseling and now they're in POI and unable to have a pregnancy or just not having periods after the treatments, right?
Susan:Yeah, absolutely, and I saw an 18-year-old the other day with her mom for secondary amenorrhea and this was a follow-up to her testing, and I made the diagnosis of idiopathic premature ovarian insufficiency and, as part of their treatment plan, I began to discuss fertility preservation, and that was not anything that they had thought about or that anybody else had mentioned, and so they were both extremely upset more upset about that conversation at the moment than talking about their POI and treatment for their POI yeah, at the moment than talking about their POI and treatment for their POI. Oh, and the other things we have to keep in mind too are, when we're discussing fertility preservation is is the patient physically a candidate for fertility preservation? So can they undergo surgery safely for egg or tissue retrieval? So we have to consider that and we also have to consider tell me about the differences between children and teenagers and how we approach the discussion.
Stephanie:So our discussion will be based on what we can offer. So if patients already have periods, they have cycles. They then have the option of undergoing egg freezing. So egg freezing is the Optional, has the strongest evidence. We've been doing it for a lot longer than any other options and it's been clear that it results in a good pregnancy rate and life birth rate. Egg freezing is the same egg freezing that we would do for any other patient that wish to go egg freezing or even IVF. So very similar Patients usually do injections for 10 to 14 days and then we monitor the follicular growth by ultrasound and then, when their follicles are ready, they get a trigger medication and then they get the procedure, so the egg retrieval to get the eggs out, and then, once we have the eggs, the lab will have a look and we'll be able to freeze the eggs to be able to use in the future.
Stephanie:Another option that we don't discuss as often in the younger patient population would be to do embryo cryopreservation. So not as often done, because we need to use sperm to make embryos and then the genetic material of that sperm will be part of the embryo. So the patient wishes to use those embryos in the future, they would have to know that their partner's DNA won't be part of that embryo, and for some patients that's not an option. So we typically don't go ahead with embryo cryopreservation, except in certain populations or restricted to some areas, right.
Stephanie:Maybe an older person who already has a partner Exactly so typically people that are actually trying to conceive and then have a new diagnosis of cancer. That would be a good case to freeze embryos rather than eggs.
Susan:Right, and I have sent young adults who are married but not thinking about pregnancy at that time. But they develop breast cancer or thyroid cancer and I have sent them for consults for fertility preservation. What about children?
Stephanie:Yeah, I was going to say those children, especially the younger patients who are not yet pubertal, but also patients who cannot undergo egg freezing for different reasons. So either for a preference, where they cannot undergo the procedure, or we don't have time, or we can't afford to do a stimulation for some reasons. So in those patients the main option now has become ovarian tissue cryopreservation. So there's different protocols that exist, but the good news is since 2019, it's no longer experimental. So it is standard of care and should be offered to patients at higher risk of ovarian insufficiency due to treatments. So for that what we do is a laparoscopic unilateral ophrectomy. So we basically go in, we take one ovary and then the ovary is sent to the lab and then the lab will process the ovary and we only keep the cortex, so what's around the ovary, where the primordial follicles are, and then that gets frozen.
Stephanie:And then in the future the patients could put back the tissue. There's different ways of going about it. It is evolving, but we're basically putting back the tissue and then the patient would have cycles again and would start ovulating and hopefully we're hoping for a spontaneous pregnancy. So the rates are really, really good. The reports are showing between 37, 40% of live birth rate with that technique.
Susan:Where do you put the tissue when you're putting it back in?
Stephanie:So there are different options. Mostly we're putting the tissue back on the ovary, so the other ovary that's left behind, so we would put the tissue on there. We can also use the ovarian fossa so we can create a window in the peritoneum and then just put the tissue there. If that's not an option, we can consider other locations. It's been described mostly in the arm, but the success rates are not as good with that because you have to undergo IVF, so you have to undergo medical procedures as opposed to getting pregnant on your own, and the advantage to tissue preservation is that it can be accomplished within 24 hours.
Susan:So if somebody is a surgical candidate and doesn't have any other contra indications at the moment meaning they're not too sick to undergo a laparoscopy they can have an ovary removed and then cryopreserved, as opposed to people who will undergo oocyte harvest, where it takes 10 to 14 days. The other comment to make is that if somebody has an ovary removed, they can start chemotherapy or radiation within 24 hours of their surgical procedure. So there's no delay.
Stephanie:For sure. And it can be combined with other things such as port placement, which is very convenient for patients, so they only undergo anesthesia once and then they get both procedures.
Susan:That's a good point.
Stephanie:What about patients undergoing radiation? What can we do for their fertility presentation?
Susan:Something that's old-fashioned, that we've done for decades, especially if somebody's having pelvic radiation. To move the ovaries out of the field of radiation, this does require a laparoscopic procedure. It is not super guaranteed to work because sometimes, no matter how high up we try to move the ovaries, they're still might be impacted by radiation. But for somebody who doesn't want to go oocyte stimulation, who is not a candidate for a nephrectomy or doesn't want a nephrectomy, at least we have something to offer them. Anything else in terms of preservation.
Stephanie:Well, if patients are not candidate to any of those or if they choose not to undergo any of those, there's always the option of the GnRH analog therapy. There is some good data showing that maybe with breast cancer we do see more life births and more recovery of the ovarian function not as clear with the other type of cancers, but definitely something that we offer quite frequently to patients, and it also helps with other things. So it helps with menstrual suppression and decreasing the blood loss that patients undergoing chemotherapy are at higher risk of bleeding, so that's also a benefit of those treatments.
Susan:And we can use this not only in cancer patients but in patients with complex medical illnesses that are receiving medications that may be ovariotoxic. And I actually treated a patient with Bechette's many decades ago and she was going to start chemotherapy and was not a candidate for surgery, and we gave her GNRH to try to offer her something to help protect her ovaries. So, aside from all of this, are there other things that we should be counseling our patients about if they are not interested in fertility preservation in the ways we've already discussed.
Stephanie:Yeah, so we can always broach the topic and then talk about it later when they're ready to have a family. But there are definitely other ways of having a family right. So we know that donor eggs or embryos are an option. Psyrgacy is also an option. And then some patients they have a partner who already has children and they don't feel like having more children or they would choose to go ahead with adoption. And then some people will decide not to have children and that's totally fine as well.
Susan:Right, and I find that when we're discussing these subjects with teenagers, we're asking them to project years into the future about whether they may or may not want to have children, and that's challenging for them.
Stephanie:They often have no clue. I mean, some of them know for sure. They'll tell you I want to be a mom. I know I want to be a mom and those patients are more keen to undergo treatments. But for the other patients where family building is not even a thought they ever had, it's a bit more tricky to go over.
Susan:Right, and especially when it may require surgery and additional medications. So after somebody is treated, how do we follow them and how do we evaluate them for the possibility of POI?
Stephanie:So we should see those patients frequently. It varies a bit if they're pre-pubertal or pubertal, obviously, so patients that are pre-pubertal, we cannot rely on menses to make sure that things are still going well. The kids should be assessed on a regular basis for their growth, for the evolution of their Tanner, staging based on their age, and see if the progression of puberty happens as expected. We can also ask for hypoestrogen symptoms, but that would be very unlikely in someone who never had estrogen before that they would feel those symptoms and then we can repeat hormones. So we just broached over that. But part of the investigations that we do before treatments are doing hormones, so FSH, lh, estradiol and AMH and then that allows us to track it over time so it can be repeated every few years until the age of typical puberty and then if we see that the AMH is slowly declining, that might be a sign of impending POI, even in pre-pubertal patients.
Susan:We can always offer fertility preservation after treatment if we find declining hormonal levels for somebody who wasn't able to accomplish it prior to their treatment starting. What about in post-pubertal girls?
Stephanie:So in teenagers we do have a good marker of their health and their ovarian health and that's the menstrual calendar, so we can ask them to track their period and see if they're still having regular cycles. The other things is that if you've been exposed to estrogen when your body's not making estrogen anymore, you might start having symptoms. So all those menopausal symptoms. Some patients will experience it, and I do have patients quite frequently that will tell me I'm having hot flashes and then we start them on hormones and then eventually we see that their ovaries are recuperating. And then we start them on hormones and then eventually we see that their ovaries are recuperating and then they start having periods again on their own. So that's something that we see quite often after gonadotoxic treatments. It does take a bit of time for the ovaries to start kicking back in and functioning normally again.
Susan:So when should we start evaluating these patients?
Stephanie:I would say that's up for debate. Typically, six months to a year after the end of chemotherapy is sort of the window where we want to assess their fertility. The egg count can recover for up to two years after the end of treatment, so we want to make sure that we're tracking that. But obviously if you have a patient who's not having periods, after three months of not having periods, we can definitely start doing investigations and if they're symptomatic we could also start treating earlier rather than waiting for a full year.
Susan:And I also find that teenagers who are making estrogen, who are having periods and then their ovaries became dysfunctional because of their treatment, they have a lot of mood swings. I find more mood swings than hot flashes. If they happen to be sexually active, they may notice some vaginal dryness too. So, in addition to monitoring these patients, what else do we need to counsel them about, especially the teenagers?
Stephanie:Yeah, so Even if patients are not having periods and if we tell them that they're in POI, there's still up to 10% of them that will have a spontaneous pregnancy. So POI in that patient population definitely does not mean that they do not need birth control. So it's a discussion we should always have with our patients and obviously those that are not in POI. We should always discuss birth control during treatments and after treatments, just like with any other patients we're seeing.
Susan:We talked about monitoring ovarian function and hormonal production after any sort of fertility impacting treatment. Do we need to do anything to monitor the uterus?
Stephanie:So the uterus is a tricky one. We don't typically follow it. What we know, though, is patients having radiation. We know that they'll typically have a smaller uterus. The lining also doesn't get thicker as much, but even when we give them hormones, it tends to not go back to what it was before or not grow as much. It's something that I would say is more optional, but definitely not something that we do on a regular basis.
Susan:All right, We've covered a lot of ground today how to counsel our patients, what to counsel them about, what we can offer them, how to monitor them after their treatments. But how can we get these patients into our office? Because you and I know how important this is, but if you're not a gynecologist or an REI or a PAG provider, this may not be on your radar.
Stephanie:That's a tricky one. It is difficult to raise the awareness and the importance of discussing fertility preservation. There is a lot of pushback, I feel, because I mean when you have a new diagnosis of a life-changing disease, whether it's cancer or another systemic disease, the priority is on getting better right. So it is often postponed or the discussions are pushed by the wayside. So we definitely need to reach out to those providers who will be the ones referring our patients. So we have the knowledge, but we have to spread that knowledge to other providers. There are probably also system barriers, right, things that are bigger than us. Our reality is very different than Canada, but how is it for you in the US?
Susan:Not everybody's insurance covers fertility treatment, whether it's fertility preservation for medical illnesses or fertility treatment when somebody can't get pregnant later on. So that's one issue. Some states have mandated coverage, but only a handful of states. Insurance is a barrier, Cost is a barrier if the patient doesn't have any coverage. And then, of course, after we either harvest eggs or ovarian tissue, then the cryopreservation process, which could be 10 years for some folks, is a barrier because they have to pay for that on a regular basis and insurance may not cover that.
Susan:So that's another issue to be worked on is raising awareness in the political system to help put pressure on insurance companies to get coverage for these procedures and to impress upon people that this is almost as important as what we're treating them for that's causing the fertility issue. Our national organizations can do more in terms of education and we can do more on our own institutions by offering to give talks to the oncologists and to the radiation therapists and to the surgeons and so on, so that we can, in our own small little world, raise awareness about the need for fertility preservation. Is this covered in?
Stephanie:Canada it depends. It's really by province, so similar to the mandates that you get in the States. But we're getting there. We're raising awareness for fertility treatments in general and with IVF funding comes egg freezing funding. So we're slowly getting there and then medications also varies by province as well.
Susan:Well, we have a lot of work to do in that area. All right, so let's review our case For sure.
Stephanie:Remember we had a seven-year-old, pre-pubertal girl that was recently diagnosed with leukemia and about to start chemotherapy, so her parents were worried about the impact of chemo and asking if there's any option for her. So now that we've reviewed everything, she's pre-pubertal, undergoing treatments that is known to be gonadotoxic, so there's definitely options. In that case, she would be a candidate for a vent tissue cryopreservation and then possibly in the future, a vent tissue transplant if required.
Susan:All right. Well, thank you for doing this podcast with me today on this really important topic. And again, this is PAG over pastry, and you can find the podcast on the NASPAG website, along with an outline, and you can also find it where you like to listen to your podcasts.
Stephanie:Hi, Camille here with a quick reminder to take our survey on our website so we can get to know who our listeners are for research purposes. Otherwise, thank you for listening to PAG Over Pastries. Thanks for having me. Bye.
