Transcription:
Advances in Fertility Preservation

Melanie Cole (Host):  Welcome. This is Better Edge, a Northwestern Medicine podcast for physicians. I’m Melanie Cole. And today, we’re discussing fertility preservation options available to women at the Northwestern Medicine Center for Fertility and Reproductive Medicine. Joining me is Dr. Mary Ellen Pavone, she’s an Associate Professor in the Division of Reproductive Endocrinology and Infertility and Dr. Kara Goldman, she’s an Assistant Professor in the Division of Reproductive Endocrinology and Infertility and they’re both at Northwestern Medicine. They’re here to discuss options available and what’s next on the horizon for the field.

Dr. Pavone, I’d like to start with you. Give us a brief history if you would of how fertility preservation options for women have evolved over the years.

Mary Ellen Pavone, MD, MSCI (Guest):  Yeah great, thanks. So, it’s really a new and emerging field. Up until the late 1990s, really the only option for fertility preservation in women was embryo freezing. Meaning that women would have to undergo an IVF cycle and then fertilize any of the eggs that were available to fertilize. However, the field has since evolved and things like mature oocyte cryopreservation or egg freezing can now be done very easily as well as embryo freezing. In addition, we’ve gone from doing very conventional, ovarian stimulation protocols that started with menstrual cycles to doing something called random start stimulation protocols where we start kind of regardless of the time of the cycle likely expediting the start of cancer treatment and ovarian tissue cryopreservation has now become a treatment option and actually as of last month, it’s no longer considered experimental.

That first baby born from ovarian tissue cryopreservation was reported in 2004 and since then there have been over 130 babies born using this method. Updates to embryo freezing and egg freezing include vitrification techniques which is a fast freeze which is really why we are able to freeze individual eggs and don’t need to rely on embryos.

Host:  And Dr. Goldman, what are some reasons patients may decide to explore fertility preservation options? Dr. Pavone briefly touched on them. Can you expand a little more for us?

Kara Goldman, MD (Guest):  Absolutely and thank you so much for hosting me this morning. So, women are born with a limited number of eggs and the ovarian reserve decreases progressively over time until menopause. And unfortunately, we know that the loss of eggs is accelerated in women with cancer who require chemotherapy, radiation or fertility threatening surgeries so patients who face these gonadotoxic treatments have the opportunity to preserve fertility and increase the possibility of becoming parents after cancer treatment.

But there are also a number of other medical conditions besides cancer that also may increase a patient’s risk of future subfertility or infertility. And so any treatment that compromises a patient’s fertility regardless of their underlying diagnosis should really warrant referral to discuss fertility preservation options.  We also know that fertility preservation should be discussed with transgender men or adolescents who intend to initiate gender affirming hormone therapy because of the unknown effects of long term testosterone therapy on the ovaries and the preference of patients not to discontinue their testosterone once it has been initiated.

But thinking about fertility preservation in more general terms, we know that infertility is largely a preventable disease and a very common cause of infertility is impaired egg quality and diminished egg quantity due to advanced reproductive age. So, women or couples who are potentially delaying pregnancy may seek to preserve fertility if they know they’ll be delaying pregnancy. And for these individuals or couples, we can freeze eggs or embryos to increase the possibility that they’ll achieve pregnancy with their own eggs in the future.

Host:  Dr. Pavone, tell us about some of the more common types of fertility preservation options for women available at Northwestern Medicine’s Center for Fertility and Reproductive Medicine please.

Dr. Pavone:  Sure. So, the most commonly used is embryo freezing where women undergo and IVF stimulation. That normally takes about two weeks of time. And then they do the actual egg retrieval where we under sedation, we go in under ultrasound guidance and retrieve the eggs and then fertilize them with the partner’s sperm. We also offer egg freezing or oocyte freezing. Which is the same – the first part is the same as the IVF cycle so ovarian stimulation and then after the egg retrieval, the eggs themselves are frozen without being fertilized.

We also offer ovarian tissue cryopreservation. This is a procedure that involves the surgical removal and freezing of a portion or of the entire ovary until it’s desired for future use. There are other things like ovarian transposition where if a woman knows that she’s going to be getting pelvic radiation, the ovaries can be surgically moved out of the field where the radiation would go. And there’s also hormonal therapy. So, there are some medications that may help prevent follicle loss during the time of chemotherapy and that can also be used alone or in conjunction with other fertility preservation methods.

Host:  Dr. Goldman, is oocyte cryopreservation as effective as embryo cryopreservation? What are the differences and what are some things to consider when deciding which one is the best route to take?

Dr. Goldman:  So, oocyte and embryo cryopreservation represents very different options. And the counseling is relatively nuanced. When counseling patients, there are a number of important considerations involved. We consider relationship status, but assumptions should never be made based on relationship status alone. Partnered women often will choose to freeze eggs rather than embryos to maintain reproductive autonomy and alternatively, women who are single or in same sex relationships may choose to freeze embryos using donor sperm. Ultimately, there are a number of complex psychosocial and sometimes legal considerations that go into the decision to freeze eggs or embryos.

And these are conversations that unfortunately have to be made over a very short period of time given the urgency with which patients have to move forward with fertility preservation prior to their cancer treatment. Egg freezing offers patients the possibility of future reproductive autonomy as the eggs can be made into embryos with a future partner or with donor sperm depending on her relationship status when ready to achieve pregnancy.

Embryo freezing offers more concrete knowledge about the future reproductive potential of the patient’s frozen material and patients can freeze at various stages of embryo development with the opportunity to even test the embryos to understand which embryos are chromosomally normal and therefore which embryos have the best chance of future pregnancy.  When comparing how eggs and embryos do in the lab, we know the eggs survive the warming process less efficiently than embryos. And frozen eggs also demonstrate somewhat impaired embryo development compared to fresh eggs. That said, an embryo derived from frozen eggs should provide the same chance of future pregnancy as an embryo derived from fresh eggs.

So, this counseling is really important for patients to understand. Frozen eggs absolutely result in pregnancies, but a patient has to understand these limitations and the fact that a larger yield of frozen eggs might be necessary to give her a good chance of achieving future pregnancy. And so, ultimately, all of these limitations and nuances are weighed against the tremendous benefit of maintaining reproductive autonomy and ultimately, we have to use shared decision making with our patients to help them understand their options.

Host:  Such an interesting field you both are in and Dr. Pavone, along those lines, you offer several experimental techniques such as ovarian tissue cryopreservation. Who can benefit from this and how is it different than other types of fertility preservation?

Dr. Pavone:  Well the good news is that as of last month, ovarian tissue cryopreservation is no longer considered experimental in the US. American Society of Reproductive Medicine issued guidelines saying that it was no longer an experimental technique which is very great and exciting news. Ovarian tissue cryopreservation might be the only acceptable method for prepubertal or premenarchal females who need to undergo fertility preservation since in prepubertal or premenarchal girls, their ovaries would not respond to more conventional ovarian stimulation. It involves a surgical procedure that removes either part or an entire ovary and then freezes what’s called the cortex which is the outside part of the ovary where all the eggs are stored with the idea that in the future, this tissue could be either re-transplanted into the patient and we know from studies that it eventually starts to become hormonally active or hopefully in the future, we’ll have ways of being able to isolate the baby eggs in the lab and grow them to the point that they can be fertilized.

This has not been done yet in humans, but we are actively working on research here at Northwestern.

Host:  Dr. Goldman, does a woman’s age play a role in which option might be more successful? Are certain techniques more effective in a woman at a higher reproductive age?

Dr. Goldman:  So, a woman’s age is the most important predictor of success of any fertility treatment including all of our fertility preservation options. And what we see with in vitro fertilization is that success rates begin to decrease among women in their mid to late 30s and there are dramatic impairments in success in women who are 40 and above largely because of both a decrease in egg quantity but also a dramatic impairment in egg competence leading to more chromosomally abnormal or aneuploid embryos.

So, for patients who are thinking about planned egg freezing for purposes of preventing future infertility, who don’t necessarily have a medical condition that could compromise their fertility; it’s proven to consider fertility preservation at a younger reproductive age. For patients with a diagnosis of cancer or other medical conditions threatening their fertility; it’s important that they are counseled about the likelihood of success with frozen eggs or embryos based on the age at the time of freezing. Unfortunately, we know from the literature that patients often overestimate their likelihood of success with frozen eggs and embryos so, we need to provide very clear expectations and timely feedback because in some cases, patients who have completed a cycle of egg or embryo freezing may have an opportunity to complete more than one cycle prior to chemotherapy, radiation or surgery and we know that the number of eggs retrieved either for egg or embryo freezing is really going to be directly related to their future success with those eggs just because of these impairments in egg quality with age.

So, ideally, if possible, we can potentially complete more than one cycle in a very brief window of time to increase the odds of success for that patient.

Host:  Well thank you for that answer and Dr. Pavone, in many cases, treatment obviously can be time sensitive and requires coordination by several teams at Northwestern Medicine. Share for us how your team collaborates with other specialties as we’re discussing the role of the oncologist, in advising patients about fertility preservation options. Tell us about your multidisciplinary approach and who is all involved.

Dr. Pavone:  Yeah, so at Northwestern, we have dedicated patient navigators who help our patients kind of triage the patients and shepherd them through their visits with oncology to fertility and then back to oncology. And so, they are available pretty much every day of the week to help counsel the patients and then coordinate their care between the oncologist or surgeon and then our fertility team and then to quickly get them back over to oncology where they can start their cancer treatments.

Host:  Dr. Goldman, what’s next on the horizon for the field of fertility preservation? Can you share any recent advancements or breakthroughs in surgical techniques or really anything?

Dr. Goldman:  Absolutely. So, we have a tremendous opportunity to improve fertility preservation techniques and also to improve access to care. And our current standard of care allows women and couples to freeze really only a finite number of eggs or embryos and unfortunately we know that egg and embryo freezing may not be appropriate options for patients due to their medical condition, maybe the amount of time they are allotted to pursue fertility treatment prior to their required cancer treatment, cost, access to fertility center and particularly as Dr. Pavone mentioned, these are not options for pediatric patients. And so, from a medical perspective, we’re also thinking that when we freeze eggs and embryos, we’re not addressing the very many other important functions of the ovary that can be compromised by chemotherapy and radiation. And so, we’re thinking about things like the hormones the ovary produces that are important for bone health, cardiovascular health, sexual health, mental health and more and so in addition to thinking about fertility preservation; we also need to be thinking about protecting ovarian function in general.

And so as Dr. Pavone mentioned, there’s one drug available that can be injected prior to chemotherapy with the goal of potentially protecting the ovaries during treatment. These are called GNRH agonists but despite decades of research, they have really not be shown to preserve fertility. They may offer some degree of protection to decrease the risk of ovarian insufficiency following chemotherapy but ultimately, they are considered experimental and we have not made a tremendous amount of strides in identifying pharmacologic agents to preserve fertility. So, really the focus needs to be on identifying pharmacologic agents.

In my research, I focus on a pathway called the mTOR pathway that’s important in activation of primordial follicles. These are the most immature follicles in the ovary that contain the ovary’s total egg supply. In a mouse model we show that mTOR inhibitors can protect the primordial follicle pool in mice and preserve fertility in mice undergoing chemotherapy. So, the hope is that we can maybe translate this work to humans and eventually identify a target to preserve ovarian function and fertility in women undergoing chemo and radiation.

And so, my work is among many other researchers’ work as well who are trying to identify pharmacologic targets, and this will be particularly important for our pediatric patients who have very limited options. And then as discussed previously, ovarian tissue freezing is rapidly evolving. And there’s a tremendous amount of work being done in this area. The work primarily focuses on pediatric patients because this is the only technique currently available to kids and we’re fortunate at Northwestern to have a number of very prominent researchers working on these techniques. So, the labs of Dr. Woodruff, Dr. Larhonda and Dr. Duncan are optimizing techniques for processing ovarian tissue, optimizing how follicles are grown in the lab using innovative techniques like creating 3-D printed ovaries and in the coming years, we will certainly see advances in the way ovarian tissue is frozen and in the way it’s re-transplanted as well as some techniques on the male side looking at testicular tissue freezing.

And then last and I would say arguably one the most critical advances on the horizon is improving access to care for patients who need fertility preservation. Prior to just a few years ago, prior to 2017, no states mandated insurance companies to cover fertility preservation and since then, eight states have passed legislation mandating coverage. Illinois became the fifth state to pass legislation and importantly, we are the only state that also provides coverage for patients with Medicaid. So, this has dramatically improved access for patients who need this critical medical care but there’s really so much work still to be done nationally and globally to increase access for these patients who currently don’t have the opportunity to preserve their fertility.

Host:  Before we wrap up, I’d like you each to have a chance to kind of say a final word. So, Dr. Pavone, tell us what’s unique about Northwestern Medicine and why referring physicians should consider your program.

Dr. Pavone:  So, we offer fast access to all of our fertility specialists with very coordinated care between the fertility doctors and the referring be it oncologist or surgeon. We also offer psychological support for all of our patients. So, we know that this is a very stressful time not only because of the cancer but also now the patients are having to face difficulties with potential difficulties with future family building and so we do have three dedicated psychologists who also see all of our patients who are undergoing fertility preservation.

Host:  And Dr. Goldman, last word to you, what’s the most important advice you’d like to give physicians who are treating patients who may be appropriate for fertility preservation, when you feel it’s important that this discussion start with their patients and when you feel it’s important that they refer to the experts at Northwestern Medicine?

Dr. Goldman:  Absolutely. I’ll start by saying that our physicians at Northwestern do an excellent job of referring patients in a timely fashion. It is a really tremendous institution where the oncologists are clearly very motivated to help their patients preserve fertility. We have a tremendous relationship with our referring oncologists. And so, they are already doing an exceptional job of referring patients. But I think the important advice is that if there’s ever a question about a patient’s fertility to always send them our way. We are absolutely happy to counsel any patient and I think what’s really important to note is that regardless of whether a patient pursues fertility preservation or not; there is a lot of data showing that even having the conversation about fertility preservation decreases the patient’s future risk of regret. If they did or did not pursue the treatment, having had that opportunity to make that decision on their own decreased their future regret.

And so, the decision to refer really should be based not on the bias of whether the patient might be done with family planning or based on the patient’s age; but really if there’s any potential of the treatment to impair that person’s fertility regardless of whether we assume that patient may be done with family building or not, we are always happy to see those patients and have that conversation.

Dr. Pavone:  I’d just like to add too that the actual time delay in time to cancer treatments from fertility preservation is minimal. We’ve actually done research that shows that it’s about two weeks and that these minimal delays do not increase chances of cancer recurrence or mortality. So, please refer our way whenever there’s a patient who is interested.

Host:  That’s a very good point. Thank you so much both doctors for joining us today and sharing your expertise for other providers. And that concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. To refer your patient, please visit our website at www.fertility.nm.org to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. I’m Melanie Cole.