Ovarian Tissue Transplants Provide New Hope to Women with Ovarian Insufficiency

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Daniel I. Simon, MD (Host): Thank you for listening to another episode. Today, I am happy to be joined by two very special guests, Dr. Rebecca Flyckt and Dr. Kathryn Coyne.

Welcome, Rebecca and Kathryn.

Rebecca Flyckt, MD: Thanks.

Kathryn Coyne, MD: Thanks for having us.

Daniel I. Simon, MD (Host): So, Dr. Flyckt is the division chief of Reproductive Endocrinology and Infertility and Advanced GYN Surgery at University Hospitals Cleveland Medical Center and the Medical Director of the University Hospitals Fertility Center. She is also a Professor of Reproductive Biology at Case Western University.

Dr. Coyne is a faculty member in the Division of Reproductive Endocrinology and Fertility at University Hospital and serves as the Director of Fertility Preservation for UH's Fertility Center. She is also an Assistant Professor in the Department of Reproductive Biology at Case Western University School of Medicine.

Well, it's so great to have both of you here today, but before we begin, we really like to learn a little bit about your personal journey into medicine, into your specialty area, and how you got involved potentially in this topic. So, Rebecca, tell us a little bit about how did you get into it?

Rebecca Flyckt, MD: Yeah, well, Dr. Simon, I know you know a lot of my story, but I don't know if you know this part of it. I'm from Cleveland, and when I was in my teenage years, one of my cousins who was training to be a midwife at the time, went through her first pregnancy and actually had a home birth, which I am not necessarily endorsing on this podcast.

But, you know, as a 15-year-old, I was blown away. I thought it was one of the most beautiful, terrifying, fascinating things I had ever seen, this transformation, pregnancy, birth, and back again. So that's really one of the things that inspired me to devote my career to pregnancy and childbirth and eventually lead me to the area that Dr. Coyne and I both work in, which is, women's reproductive health

Daniel I. Simon, MD (Host): And tell us where did you get educated? Did you travel around? Did you stay local?

Rebecca Flyckt, MD: I grew up here, but like many Clevelanders, I had a desire to see the world. So, after I graduated from high school, I went to University of Michigan. Then I did my medical school out in California, dragged my husband back here, and did residency and fellowship back here in Cleveland

Daniel I. Simon, MD (Host): Oh, good. So, you came for the weather. That's terrific.

Kathryn Coyne, MD: Thank you.

Rebecca Flyckt, MD: Like most.

Daniel I. Simon, MD (Host): So, Kathryn, tell us a little bit about where'd you grow up? How did you get into medicine?

Kathryn Coyne, MD: So, like Dr. Flyckt, I'm also from Cleveland. I can actually pinpoint the moment that I decided this career was for me. It was the summer between my junior and senior year of undergrad, and I came home for the summer, and I was looking for some exposure to medicine. And I found an internship at the Cleveland Clinic Center for Reproductive Medicine, and part of the internship was you had lectures in the morning, and you did research in the afternoon.

So, each of us had a specific project, and I left that summer with my first-ever publication. And the publication was called Creating Standards of Care for Fertility Preservation. The biggest thing I walked away with was this very clear vision that this must be what I do with my career. You know, I was absolutely in love with it.

So, I went into medical school knowing that I wanted to be an REI, and I early on sought out a research mentor there who was very productive, and I helped establish an ovarian tissue freezing program there. I then met Dr. Flyckt during my medical school career and started working on research with her, and then I was so fortunate to come here to UH for both residency and fellowship.

During fellowship, we started our ovarian tissue freezing program here at UH. I feel so lucky to get to stay here and serve as Director of Fertility Preservation… really living out the dream that I established back in 2009, seventeen years ago.

Rebecca Flyckt, MD: It has been amazing knowing Dr. Coyne and, you know, watching her evolve, but this passion was so clear from the very first time that I met her, which has got to be over 10 years ago. It's pretty exciting to see everything she's done in that time.

Daniel I. Simon, MD (Host): Yeah. So, it's great to have mentor and mentee together, on this podcast today. So, we're going to talk about ovarian insufficiency, both on its impact in fertility and also in other aspects of life beyond infertility. So, could you tell us, you know, both of you in sort of layman's terms, what is, ovarian insufficiency?

Rebecca Flyckt, MD: Ovarian insufficiency is essentially when the ovaries have run out of eggs. So, you are in a state of menopause, and it is both a reproductive concern because you don't have eggs, you cannot achieve pregnancy, but also a hormonal concern because the ovaries are what are responsible for producing estrogen.

Estrogen has much broader impacts than just reproduction, and it's surprisingly common. Probably depending on your definition, somewhere between one and 5% of women lose ovarian function at a young age. Rarely this can happen at birth, so somebody never has ovarian function, or sometimes it can happen by age 40 or so, which is just a little bit earlier than natural menopause

Daniel I. Simon, MD (Host): When we think about that and people come to you for infertility issues, what percentage have ovarian insufficiency who get to you - meaning that they've been trying for a while and they don't, they, you know, they can't get pregnant?

Kathryn Coyne, MD: You know, I do think it's a smaller percentage of our patients, but we do discover it. I don't know, maybe 5%. What do you think, Dr. Flyckt?

Rebecca Flyckt, MD: Yeah, I would say about 5% of our practice. It's rare that we're making the initial diagnosis. A lot of times the general OB-GYN, you know, someone comes in, they're not having periods, they're having hot flashes, you know, so they do the evaluation and then they're sent to us for subspecialty care.

And there's lots of roads that lead to it. You know, it can have genetic influences. Sometimes it's the result of cancer treatments that are life-saving that we do so well here at UH, but as an unintended consequence, a woman may go into menopause. Sometimes it's autoimmune, sometimes it's infectious.

So, part of our job is helping them understand the "why." And for the patients that we treat, even though it's an irreversible condition, it's so important to them to know why this happened because the psychological impact of this diagnosis is just as profound as the medical impact. And so, the first step is trying to understand why, if we can.  And then the second part is, like anything in women's health, talking about what our options are.

Daniel I. Simon, MD (Host): So, we're going to switch here now into this exciting, only FDA-approved transplant protocol in the US related to ovarian tissue. So, Dr. Flykt, your work has obviously explored groundbreaking transplant approaches, uterine transplant that we've talked about before. What makes ovarian tissue transplantation, especially between non-identical siblings, such an exciting step forward in reproductive medicine?

Rebecca Flyckt, MD: Yeah, and I was thinking back to your previous question of what inspired me to do the kind of research that I'm the most excited about. And I did forget to mention, you know, along the way in my travels around the United States, I spent about three years working at the NIH in what was like the heyday of the NIH.

You know, funding had doubled, collaboration and creativity were everywhere. You know that was the era of the Human Genome Project. So, we were solving unsolvable problems. And in relation to this question that is what I'm really excited about, is finding novel, innovative solutions where women have been told in the past, "You've been dealt this terrible hand and there's literally nothing that we can do."

So, my earlier work with uterus transplant was mostly women who've been born without a uterus. You know, they had been told usually by fifteen, sixteen years old, "You're never going to be a mother."  Flash forward a few decades and we're able to take a uterus. We had a deceased donor program, so similar to when someone dies and gives a liver or kidney, you can take a uterus and actually implant it into a woman that was born without a uterus, and that uterus comes to life and can give life.  And there's actually now been dozens of births, including from our trial and around the world. So, in a similar way, this is an unsolvable problem and that's what makes it so interesting. You know, we have some workarounds. We can give them hormones. If you can't make eggs, Dr. Coyne and I do IVF every day. We can have a sister donate eggs to a sister through IVF, but as Dr. Coyne can mention, IVF is not for everyone, you know, and it often results in lots of extra embryos that then you have to make decisions about. And so, I think that it's a very similar thing to uterus transplant where, you know, currently there's really no real solution, no real cure, and that's what gets me really excited about this clinical trial we're about to start.

Daniel I. Simon, MD (Host): So, Dr. Coyne, can you walk us through how the clinical trial will work from selecting donor recipient pairs to the use of immunosuppression and what success looks like for the participants? Obviously, a live birth, we would say, but, but tell us a little bit more about this process

Kathryn Coyne, MD: Sure. Well, our trial will start as a pilot with 10 sister pairs. So, the sisters, there'll be a donor who has normal reproductive function, and then a recipient who has been diagnosed with premature ovarian insufficiency or POI. We do have pretty strict inclusion and exclusion criteria.

We want to make sure we're being really safe and also want to set our patients up for success as we start this trial. So, we do require that the donor sister be between ages 21 and 35, with a BMI less than 30 and no other, you know, comorbidities, no hypertension, history of cancer, things like that and of course, have normal ovarian reserve or a normal ovarian function.

For the recipient, we of course want documented POI, meaning that their ovarian reserve is depleted. They must be between the age of 21 and 40, and also healthy, BMI less than thirty, no other comorbidities. They must have a documented open tube. We want to make sure they can attempt natural conception and no history of any radiation to the pelvis. You know, we want a healthy uterus as well. Then we also want that recipient to have a committed partner so that they're ready to attempt conception as soon as they have resumption of their menses. So, once we have, you know, gone through the inclusion/exclusion criteria, we determine this is a good candidate pair.

Then the way this would look is that there would be two surgeries back-to-back. First, the donor would undergo a minimally invasive laparoscopy where we remove one ovary. The other ovary would remain in place. So, she should not have an impact on her, you know, ovarian health. Right after the recipient has her surgery, we do some quick processing in the OR to kind of divide out the medulla from the cortical tissue, and then we take just about a third or a quarter of the cortical tissue and transplant that directly into essentially the ovarian bed or where, you know, an atrophic ovary may be and immunosuppression would be started. We are modeling this after, you know, other solid organ transplant immunosuppression protocols, which have proven safety and efficacy. And of course, we're getting help from our transplant medicine team, to make sure that there's good, you know, oversight and monitoring the immunosuppression.

And then, you know, we let the body start functioning again, and we'll be monitoring very closely to assess hormone levels. That should be our first sign that the graft is working. We should start to see the ovarian reserve going up, the normal gonadotropins start going down out of the menopausal range, and then after that is when the patient should have resumption of menses. And with that, that's when they can start trying to conceive. And again, the endpoint, of course, our goal is for a full-term healthy live birth.

Rebecca Flyckt, MD: And just to add to that, if I might, just in case some listeners think this sounds like total science fiction, you know, like all good research, this builds on a really strong legacy of transplant surgery, ovarian tissue work, immunosuppression and so it really marries all of those things together, which is very much in my wheelhouse and Dr. Coyne's wheelhouse. But I think the key thing that sparked…Dr. Coyne and I were actually at a meeting together and I texted her..that sparked this is that there is a surgeon who has done this. His name is Dr. Sherman Silber. He's in St. Louis. The difference for us is that this is going to be under a clinical trial and in clinicaltrials.gov.

And, you know, we've engaged a multidisciplinary team sport, you know, in doing it, but it has actually already happened, and there is a live birth that was presented at our national fertility meeting in 2023. And when Dr. Coyne was talking about how we take the ovary from one sister, remove it and give it to the other sister, the coolest thing about that case report is that they actually both became pregnant at the same time.

So, the donor became pregnant showing that there's no reduced fertility for the donor and then the recipient also became pregnant showing that this is proof of concept; that this can work with the addition of immunosuppression, and that really was the missing link previously.

Daniel I. Simon, MD (Host): So, I have a, a question obviously for-- I mean, it's, it's incredibly exciting, and you see the power of being able to return the mother into carrying her child to full term and then delivering that and having that experience. I guess the question is, though, if you don't have a sister. So, I understand that obviously, you know, there's sharing DNA from your parents, and so perhaps immunoseppression is less robust, but what if they came to you and they said, "I have a first cousin." Why did you limit it only to sisters?

Kathryn Coyne, MD: We decided to start with sisters, but it doesn't need to end there. And you know, in fact, Dr. Flyckt has mentioned Dr. Sherman Silber, and he is moving on beyond sisters. So, I do think that's definitely where this could go, but of course, we do get the benefit of HLA compatibility with sisters, so we want to start there.

And there is something meaningful to have the genetic relatedness. I think that that is part of what patients desire as well. But if they don't have a sister, then absolutely this could be expanded once we've determined safety and feasibility with this pilot trial.

Rebecca Flyckt, MD: And that's really the key. I mean, and I think with any pioneering tissue transplant is you want to control as many variables as you can initially establish that we can do this and do it well. And then I think as this pivots to clinical uptake, you know, that is the point at which I think we can really start to broaden it.

And that's where, you know, it becomes really exciting to see what this could do to make a huge mark in the field of reproductive medicine, not just for sisters, but for anybody who goes through premature menopause.

Daniel I. Simon, MD (Host): We have this in living-related, you know, kidney donors, the impact that you have on who you're donating to is so incredible, and I think, I mean, it chokes you up to think that you would be giving this gift, you know, to your sister. It's really incredible. So, Dr. Flyckt and Dr. Coyne, obviously you do a lot in fertility preservation, and you have a lot of tools. You mentioned one, of course, that you can get the sister could donate an egg, and you can have IVF, but how does this fit into the broader picture of things that you're doing?

Rebecca Flyckt, MD: Yeah. I mean all of this falls under, in our field, what we call a third-party reproduction. You know, sometimes you need someone else's sperm, like a sperm donor, sometimes you need someone else's eggs, sometimes you need a uterus to carry. and again, there's a very large precedent of work that has happened to establish not just clinical norms, but legal, psychological, ethical. And that's the beauty of a clinical trial - is that we can weave all those elements in at the beginning and build on that third party foundation that exists nationally today but add these novel elements. And I think keeping those conversations going as surgically innovative reproductive procedures evolve is really, really important and was one of the key lessons that we learned from the uterus transplant trial.

But I think thinking bigger, which is what's fun to do and, and what I think we're good at, at UH is, okay, ultimately this is a reproductive transplant…we want to help women have babies, but you know, as a cardiologist, like the impact of the lack of estrogen on receptors all over the body, and increased risks of heart disease and lipid issues, increased risk of bone loss and osteoporosis fracture.

So, I think it has the possibility to really expand options available to women who want to grow their families and it probably won't replace IVF but will could be one of the options that's available. And then also start to think about how we can address the other effects of primary ovarian insufficiency or premature menopause, which can really be ravaging for women over the subsequent decades.

Anything else, Dr. Coyne?

Kathryn Coyne, MD: Yeah, I think one other point I would make is that really this is a paradigm shift, right? Everything that we've offered patients before this, we've been circumventing or going around ovarian failure and giving them options with ART, you know, donor egg IVF. This doesn't circumvent that, that this addresses and reverses something that we thought was irreversible.

So, we're actually providing a true treatment for a condition that had very few options. And then the option that we're providing is it could potentially restore fertility, endocrine function, but also reproductive normalcy, right? It gives them the option for natural conception.

Daniel I. Simon, MD (Host): It's really mind-boggling because obviously as a cardiologist, we do face this problem, which is that physiologic estrogen replacement is very different than hormonal replacement. And so, you're getting right into this cardiovascular protection, which we're, you know, very interested in. I guess the question is, and I think, you know, probably some of the listeners are wondering, there are risks of immunosuppression.

And so, I guess what I would say to you is, you've mentioned health benefits beyond reproduction so that you would say, "Okay, we're going to have the full course of ovarian function through some defined period that will then leads to menopause when you stop potentially immunosuppression." But have you thought about that? Does the trial, after you give birth, do you continue immunosuppression until natural menopause time period or is it undefined? Are you concerned about the risks? You know - those questions

Rebecca Flyckt, MD: So, right now, all reproductive tissue transplantation that is non-native to the individual, meaning coming from somewhere else, needing immunosuppression, all of it is meant to be, we call it an ephemeral transplant, meaning that it's there for purposes of reproduction and then once those goals are achieved, usually within a couple of years to maybe four or five years, the tissue is removed, because of as you said, the well-known risks of immunosuppression.

And we saw that in the uterus transplant trials. These are young, healthy women, normal kidney function. You put them on immunosuppression for a few years, and you start to see an increase in their creatinine. So, there are particularly renal consequences, but probably others, you know, to the mother for being on this.

So, one of the key questions that we don't know the answer to, and I'm interested as this evolves, is, you know, is the ovary somewhat immunoprotected? And can, you know, tolerance starts to occur at the level of the ovary? Do they really need to be on immunosuppression for the longevity of the graft?

Honestly, that's something we don't know, and I'll be fascinated to see where that leads because I think if you can get to a point where either you're on really just like a tiny dose of tacrolimus or, you know, maybe you don't need any immunosuppression at all, and then we could leave it in for non-reproductive purposes.

Daniel I. Simon, MD (Host): So, Dr. Coyne, I'm going to give you the close. So, tell us, if the trial is successful what happens? So, you got your 10 patients, and then do you go to a randomized trial? Do you expand the numbers? Do you extend to non-sisters? What's your goal?

Kathryn Coyne, MD: That's exactly right. We are starting with sisters. That's a natural starting point. But absolutely, we would hope to expand to a larger population of patients. So, it's not limited to those who have the availability of a sister who's willing to donate an ovary. So absolutely could be other related cousins. It could be just friends, or it could be a non-identified donors, which is what we call them with gamete donation. So absolutely, we would hope to expand, but I think one of the other things is, as Dr. Flyckt already mentioned, there are so many unanswered questions.

So, we're hopeful this trial will be successful in terms of achieving live births for our patients, but we also really aim to learn a lot. You know, we want to answer the questions of what is the optimal immunosuppression protocol? We want to look at graft longevity. We know with auto transplantation of ovarian tissue there's this concept of graft burnout, so we don't know how long it would last anyways.

We want to look at long-term obstetric and neonatal outcomes. So really a goal of this is to start answering these questions that really no one else is positioned to start looking at yet.

Rebecca Flyckt, MD: And one more closing thought, and I know this is again bringing some science fiction into it, but I can imagine a world, because this has happened with egg donation, where instead of at the local level, there are national repositories. And I think once we can crack the code on some of this, I could see a world where just like with organ donation, you know, people decide to donate their ovaries. It goes nationally, gets frozen in strips that can be reimplanted, and then when there's a need, you know, it just goes to whoever that woman is. So, I think that there's really broad national applications, but we've got some work to do between now and then.

Daniel I. Simon, MD (Host): Thank you so much for joining us today. I certainly learned a lot here, and I think that it's great that you're doing this in a FDA-approved manner in a trial that's been submitted, and you're going to learn a lot, and hopefully will help women not only, here in Cleveland, but globally eventually one day.

To learn more about research at University Hospitals, please visit UHhospitals.org/UHResearch.

Thank you, Dr. Flyckt and Dr. Cohen

Rebecca Flyckt, MD and Kathryn Coyne,MD: Thanks so much for having us. This was great.

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