Welcome to Fertility and Sterility Roundtable. This podcast will delve into sections of the journal previously unexplored in the Fertility and Sterility podcast family. Articles that we would consider some of the most timely, cutting edge, thought provoking, and dare I say controversial.
We will be joined by a couple of the authors each month to explore the themes, debate the pros and cons, and generally expand our knowledge in a conversational format. I'm your host and F&S Interactive Associate, Dr. Emily Barnard. And I'm your co-host and producer, Dr. Ben Peipert.
We will be covering articles in the Fertile Battle and Views and Reviews portions of Fertility and Sterility. This podcast is brought to you by the Fertility and Sterility family of journals in conjunction with the American Society for Reproductive Medicine. Welcome everyone to Fertility and Sterility Roundtable.
I'm your host, Dr. Emily Barnard, and I'm joined by my producer and co-host, Dr. Ben Peipert. Today, we will be discussing a challenge that all of us in the field of reproductive medicine face, ovarian aging. We will specifically be discussing the Views and Reviews article from the March 2026 edition of Fertility and Sterility, which is entitled Influencing Ovarian Aging in Reproductive Medicine, Promise, Evidence, and Unresolved Questions.
We are joined by three of the esteemed authors of this publication to dive into this topic, learn about new research, and sort out what treatments are and are not yet ready for primetime use in clinical practice. I would like to start by introducing our guests. First, we have Dr. Kara Goldman.
Dr. Goldman is a reproductive endocrinologist and associate professor of obstetrics and gynecology at Northwestern University, where she serves as director of fertility preservation. Dr. Goldman leads a high-volume clinical program in complex fertility preservation, and her translational research focuses on the role of mTOR signaling in ovarian aging and strategies to preserve ovarian function during cancer treatment and physiologic aging. Her work has led to several landmark publications and prize paper awards from the American Society of Reproductive Medicine, and she also serves on the editorial board of Fertility and Sterility.
Welcome, Dr. Goldman. Thank you so much. It's a pleasure to be here.
We are also joined today by Dr. Francesca Duncan. Dr. Duncan is an associate professor of obstetrics and gynecology at the Feinberg School of Medicine at Northwestern University. She co-directs Northwestern's Center for Reproductive Science and leads a research program focused on cellular mechanisms of reproductive aging, studying how aging affects reproductive potential at the level of the egg and ovary.
Over her career, she has co-authored numerous publications, and her research has been widely featured in several major news outlets, including the Not Limited to National Geographic, the New York Times, and the Wall Street Journal. Thank you so much for joining us, Dr. Duncan. Thank you.
We are also joined by Dr. Allison Eubanks. Dr. Eubanks is an REI fellow at the NIH and Walter Reed Training Program, and she currently serves as the Fertility and Sterility Editorial Board Fellow. Dr. Eubanks is an active duty U.S. Navy physician.
Her work spans research across all aspects of reproductive endocrinology and infertility, from assisted reproductive technology to menopause, along with education and policy initiatives aimed at improving women's health and reproductive care across the military health system. Thanks so much for being here, Dr. Eubanks. Thank you for inviting me.
So I say this a lot about the articles we cover for this podcast, but this was truly one of the most educational. I thought it was a great review of reproductive physiology and reproductive aging. I'm wondering if we could just start by going around with our guests, if each of you could give us a summary of your section and the material you guys covered.
Why don't we go ahead and start with you, Dr. Eubanks? Yeah, my section really focused on the clinical interventions that are currently being discussed more commonly and to address ovarian aging. We're talking like platelet-rich plasma, stem cell therapies, and mitochondrial transfer were the three I focused on. These approaches are all supported by biological hypotheses, and in some studies appear to approve surrogate markers like AMH or antral follicle count, but what I show in the article is that when you look at the clinical evidence more closely, those improvements have not consistently translated into meaningful outcomes like embryo competence, euploidy, or live birth.
So the goal of my section was really to critically evaluate the current evidence and highlight the gap between biologic plausibility and proven clinical benefit. I am Kara Goldman. I wrote the section focusing on nutrient-sensing pathways.
My area of research really encompasses thinking about how the mTOR pathway and, more broadly, the mTOR network impacts both ovarian function and the impact of ovarian function on systemic health. It really comes down to the fact that mTOR critically modulates primordial follicle activation, and we understand that there is a limited pool of primordial follicles in the ovary, and activation of this pool to growing follicles results in irreversible follicle loss. So this critical primordial follicle activation stage is a target to preserve primordial follicles and preserve ovarian reserve during both cancer treatment, chemotherapy, as well as in physiologic ovarian aging.
The mTOR pathway is a really critical nutrient-sensing pathway, but there are other nutrient-sensing pathways as well, like AMP kinase. There is this broad literature focusing on nutrient-sensing pathways and healthspan and lifespan. The work I do sits in the umbrella of a larger body of work focusing on mTOR and systemic aging and organ aging throughout the body, and so this section aims to focus on the role of mTOR in the ovary, but also thinking more broadly about the role of mTOR in systemic aging and metabolic function.
So, obviously, the focus of ovarian aging is the egg. We're trying to preserve the eggs, and I, in my section, I bring a slightly different perspective in terms of what is happening in the microenvironment where these eggs are developing, which we refer to as the ovarian stroma, and I like to think about this as the nest where these eggs are developing. And our lab several years ago made this discovery that the ovarian stroma actually undergoes very prominent age-related changes.
It becomes fibrotic, it becomes inflammatory, and this leads to a stiffening of the environment, and this has profound consequences in terms of the physiology of the ovary as well as pathology. And so this section really focuses on how we can use fibrosis in a clinical space both as a biomarker of ovarian aging, but also as a therapeutic target. A lot of work in the basic science side to define that fibrosis is happening is a hallmark of aging in the ovary, and it has profound biological consequences.
So that fibrosis changes how follicles activate, it changes how follicles grow and develop, it influences ovulation because you can imagine if you have this stiff organ, it's going to be harder for these follicles to grow and then to ovulate, but also it has really important implications for pathology, so ovarian cancer. So we know that ovarian cancer is commonly diagnosed in postmenopausal women, and ovarian cancer cells prefer to be on this collagen-rich matrix of which that aging ovary is one. So I always think about fibrosis as sort of a third hit when you think of ovarian cancer.
So we know quite a bit about fibrosis in the ovary in terms of its physiology and pathology, and I think now we have the opportunity to turn this into both a biomarker, so can we make stiffness measurements of the ovary by ultrasound and say, okay, your ovary is this age? So is it a biomarker, but also is it a therapeutic opportunity? So can we make the ovary softer and keep it functioning longer? And I think there's some really exciting preclinical work in mice from our group, but also around the world in Australia, and then a really exciting paper that just came out in Science from Qiuyi Liu's group in China, where they use an antifibrotic in a mouse model of premature ovarian insufficiency, but also in humans, and they show that treatment with an antifibrotic can soften that ovary and lead to follicular development. So while this concept of fibrosis, I think, is newer for the field, I think we are actually seeing a rapid sort of transition from bench to bedside. And so while we need to find therapeutics that are specific to the ovary and safe and effective, I think that this is definitely going to be a therapeutic, hopefully, that we see on the horizon in the next 10 years.
There was an additional section in this views and reviews written by Dr. Babayev, who was not able to join us today. This section focused on epigenetic reprogramming. So Ben, would you be able to summarize this section on partial epigenetic reprogramming and why the world of reproductive medicine is excited about this? Yeah, I'll do my best.
So this approach is based on the Nobel Prize winning discovery of Yamanaka factors, which are a specific set of transcription factors that can reset a mature cell back into an embryonic-like state. And in doing so, you can develop pluripotent stem cells. But the partial reprogramming part is really key to this article.
Instead of completely erasing a cell's identity, scientists supply these factors just long enough to sweep away the epigenetic changes, such as DNA methylation, histone modification, and chromatin reorganization that accumulates with age. We know that oocyte quality declined significantly with age due to these epigenetic changes, and early research suggests that partial reprogramming could potentially reverse the accumulated epigenetic changes in aging oocytes. And this could restore mitochondrial function and chromosomal stability.
In doing so, these methods could restore an older patient's eggs to behave and perform more like a younger patient. Yeah, that's really interesting. I certainly encourage all of our readers to read this whole views and reviews in its entirety.
There are a lot of really interesting things included, and I'm really glad to have these authors here today. I think one thing that none of them said when I was hearing them give their summaries was mentioning the term rejuvenation or ovarian rejuvenation. And I would be curious if any of you had any thoughts on that term, because I did a little Googling last night on some of these things.
And you know, you see in some things on social media, or maybe even some clinics that are sort of touting ovarian rejuvenation. So I'd be curious how our authors feel about that as a term. Is that something that should be used? Sure, I would love to address this because what we are talking about is not ovarian rejuvenation.
There are a limited number of oocytes in the ovary, and there is no opportunity to rejuvenate or create oocytes that are not there. What we are talking about, and specifically when we're talking about mTOR and nutrient sensing pathways, is there is this limited dormant pool of primordial follicles, and this pool can be activated. And so there is a really interesting body of literature on signaling pathways that can activate primordial follicles, like HIPPO signaling and mTOR signaling that activates primordial follicles to grow, but those are activating dormant follicles.
And then we are thinking about the alternative, which is preventing activation and using mTOR inhibitors to prevent activation from primordial to primary. You know, a lot of what we will be talking about in terms of, you know, interventions like PRP or in vitro activation or any of these interventions that mechanically stimulate the ovary, the ovary and these follicles are being activated through mechanical pathways and metabolic pathways. But this is very distinct from the idea of rejuvenating an ovary.
You know, we don't have enough data to consider any of these interventions primetime. And so the, you know, interventions that I will be referring to and that I think about a lot in a research setting are, you know, still in research phases. And, you know, they're preclinical or, you know, require clinical trials before they can be rolled out to patients.
I think, you know, we chose to do the views and reviews on this topic because it's controversial and to attempt to clear up some of the controversy around it or explain some of the concerns, you know, again, as Dr. Goldman said, it really comes down to terminology. The word rejuvenation suggests that you can reverse what's going on. You can reverse ovarian aging.
And that's what's unfortunately being implied in a lot of the social media, regular media publications that are coming out that are speaking about these ways to, you know, reverse this process, which is exactly why we wanted to address this topic. And I know that there's a lot of interest and there's a lot of hope in PRP and mitochondrial transfer, and it would be lovely if those were active, functional ways to reverse this process. But as she explained, you know, the combination of public excitement, patient interest, and then still so much science to come, I think, is really what makes this article so interesting.
Yeah, I really feel like our field is very susceptible to the marketing of some of these clinical interventions outpacing the actual state of science. I mean, I think it's important to also sort of put this in the context that the ovary is really one of the first organs to age in the human body. And this is happening in an otherwise chronologically sort of young individual.
But that aging process is a deterioration of tissue function, and it's very difficult to reverse an aged tissue or rejuvenate. So I think when we think about therapeutics, I strongly believe that our best approach is going to be preventing the aging process from happening rather than actually rejuvenating. And in the context of fibrosis or the accumulation of scar tissue in an organ, it's much easier to prevent that from happening than to make it go away.
And I think the rejuvenation is, you know, like you said, sounds really appealing. But when we're thinking about an aging process that basically starts going, it's very hard to turn that back. You know, when we see patients for infertility, they are potentially presenting with their first symptom of significant endocrine dysfunction.
And so infertility, you know, might be the canary in the coal mine that is kind of opening up the door to all of the systemic dysfunction that is to come. And so when we see a 35-year-old who has diminished ovarian reserve who's looking for all of these different treatments to try to activate follicles and promote follicle growth and get pregnant, this same person in 10 years is going to have significant hypoestrogenemia symptoms and all of the impacts, you know, all of the systemic sequelae that come with that, cardiac dysfunction, you know, potentially cognitive decline, dryness, all of the other kind of impacts, osteoporosis, osteopenia. And so I think what we are focusing on is not just how can we, you know, how can we improve the fertility function of the ovary, but how can we improve systemic health via the ovary, like using the ovary as the door to improving health of all these other organ systems that rely on the ovary.
One of the things that connected both the nutrient sensing pathway section and the ovarian fibrosis section was the potential for calorie restriction as a means of reducing inflammation and preventing some of the markers of aging that we see, especially in ovarian tissue. Could both of you talk about the role of calorie restriction in the research in each of your areas? Certainly. So caloric restriction has been applied for decades in the aging literature as a geroprotective, and it is really one of the most effective geroprotective strategies, but this is a very challenging intervention to apply to humans.
And, you know, in animal models where the setting is highly controlled, you know, certainly there is a significant extension of life in animals that are calorically restricted. In humans, this is much harder because it requires adherence. People do not want to restrict calories.
It is just less effective. And so these dietary mimetics have been identified, so mTOR inhibitors, and we can have a whole discussion on the kind of identification and early study of mTOR inhibitors, and they're such fascinating drugs, but essentially rapamycin was the first identified mTOR inhibitor, and there are a number of other classes, but these essentially mimic calorie restriction. The difference is that calorie restriction works farther upstream, and mTOR inhibitors specifically act on mTOR complex.
And so calorie restriction results in a slightly different phenotype and is slightly more effective than specifically targeting mTOR, but both results in extension of lifespan in animal models and preservation of primordial follicles and important endpoints for ovarian aging. There's also an important relationship between mTOR inhibition and fibrosis. And so similarly, if you suppress and inhibit mTOR early, there may be a diminishing of fibrosis.
And so as Dr. Duncan mentioned that, you know, these are strategies that could be preventative, and I think they work very closely. So I think it's amazing to me because I have been thinking about mTOR for a long time, and Dr. Duncan has been thinking about fibrosis for a long time, and we've collaborated for a long time. And the further I go with my work and the further she goes with hers, the more it appears that our work will eventually converge.
And I think the story is going to be kind of all very highly connected. I would just add, Dr. Goldman is absolutely correct about the sort of interplay between caloric restriction and mTOR fibrosis. In the context of the ovary, the ovarian stroma or microenvironment has largely been understudied.
And so this is a compartment where in various models, it tends to be overlooked, but I can tell you that we had the opportunity to collaborate with Dr. Mary Zielinski, who works at the Oregon Primate Center, and look at secondary analysis of stored biospecimens from a non-human primate, so a rhesus macaque model of caloric restriction. And looking at the ovaries and caloric restricted models, we see more follicles and less fibrosis. So there is, in fact, that connection, but I think more work really needs to be done in that area.
And I will add to that that I am working on kind of a sister study to that, and I have some of those ovaries that Dr. Zielinski shared with me as well, and I'm looking at staining some of those ovaries for markers of mTOR to really better understand that relationship between caloric restriction, fibrosis, mTOR in these rhesus macaque ovaries. Yeah, this is such fascinating research. And one thing I was thinking when I was reading this, and you can let me know, I don't know if this is the right kind of thought process to go down, but you know, we have this research on caloric restriction.
Does the inverse hold true at all? If you have a more nutrient-dense diet, does that have a negative impact on the primordial pool as well or fibrosis? Yes, absolutely, with primordial follicle activation. And this is where we see essentially mTOR, which would be helpful just to briefly define it. So mTOR is a serine threonine kinase.
It's a kinase is a protein that phosphorylates other kinases. When activated, it phosphorylates other proteins and results in activation of this pathway. And it's upregulated by nutrients, growth factors.
Importantly, it's upregulated in about 70 to 80% of human cancers. And then when activated and phosphorylated, it results in growth, proliferation, translation. And so it's essentially this metabolic hub.
And so when it's activated, it activates, you know, kind of creates this cascade of activation and growth. And it is very much upregulated by nutrients and insulin. And so a nutrient-dense diet, excessive caloric intake would then activate mTOR.
You know, that's really where, you know, the idea of caloric restriction and intermittent fasting and the relationship between those things and mTOR are really attractive because essentially you're modulating insulin signaling, which then modulates mTOR and all of these growth pathways. You know, obesity, diabetes is associated with a highly fibroinflammatory environment in the ovary. We know that those conditions are associated with poor egg quality, whether or not the mechanisms of ovarian aging, so just physiologic aging, getting older are analogous to what happens in sort of metabolic disorders that remains to be investigated.
But certainly the changes to the environment are quite similar. This is also why we, you know, we think drugs like Metformin are really interesting because as an insulin sensitizer, you know, it would increase AMP kinase, which is also going to act as an mTOR inhibitor and potentially preserve the primordial follicle pool. There's also a very close relationship with fibrosis as Francesca nods her head.
And so I think, you know, we're both interested in, you know, our own areas of interest in how Metformin could play an important role, but I think it's also that Metformin acts via mTOR inhibition. So I think, you know, again, it's a network that's all very closely related. I love how close to the longevity space we're getting here, which makes complete sense.
Given how hard it is to get humans to adhere to calorie restriction, is there any evidence or at least mechanistic plausibility that GLP-1 medications could exert similar effects? So certainly, I think GLP-1 agonists are attractive targets for downregulating insulin, which would then potentially downregulate mTOR and potentially have a similar impact as the other drugs we've been speaking about. So I think all plausible, but we need more data. I think one thing that's really fascinating is that several anti-diabetic drugs, so Metformin and several others have been used in preclinical studies in mice.
And that treatment has actually been shown to change the transcriptome of fibroblasts in the ovary and what they're producing and secreting. So they become less sort of fibrotic in nature, and that translates into a less fibrotic ovary and then better outcomes in terms of reproductive potential. And women who have been on Metformin have less collagen in their ovaries.
So that's really interesting. Again, mechanistically, we need to dig deeper. I think there's a few points that I want to stress here, which is that while it's really attractive with these GLP-1 agonists, we really need more basic research on this before we start making claims that we extend clinically.
And this comes back to sort of how rapid do we translate information. So I think much more controlled studies need to be done here to understand the impact and the mechanism. The other thing that I wanted to bring up in this concept is, you know, what is the interplay between the ovary and the systemic environment? So is it possible that, you know, GLP-1s are having a broader systemic effect and having a healthier individual is actually what's resulting in better outcomes in the ovary.
So is it a direct or indirect effect? And I think that's a really interesting question. Again, needs more research behind it, but lots of things to explore. Dr. Anneke Vandenbroek Yes, and I'm glad that you brought that up, Francesca, because I think that is one of the key questions that I've struggled with in evaluating mTOR inhibitors in mice, that we administer them via oral gabage.
These are systemically absorbed. And so if we have a healthier mouse who otherwise might live longer, does that healthier environment just promote a healthier ovary, or is it really driven by the ovary itself? And so I think it's the chicken or the egg question, but I think it's a key question. Absolutely.
Dr. Anneke Vandenbroek You know, we know when patients are on oral contraceptives, for example, it does not preserve the follicular pool. But I was curious if it does help at all with sort of minimizing fibrosis if they aren't ovulating? Because I know in your article, you were talking about, of course, how women have about 400 ovulations in their lifetime. And that is part of the damage that happens as their ovary is kind of repairing itself after ovulation.
So is there any research on that? That again, while it doesn't preserve your egg count, does it help at all with the fibrosis aspect of things? Dr. Francesca We actually think we're trying to figure out what are the drivers of fibrosis in the ovary. And what I think is underappreciated, especially if we look at sort of medical textbooks about the ovary, we see this beautiful structure with follicles sort of at different stages of development. It looks like this beautiful orderly organ.
But what we don't appreciate is that in a normal, healthy ovary, there's a ton of dynamic remodeling and a lot of cellular death and debris. So follicles, as they're growing, only a few will make it to the ovulatory stage. Many of them will die and have to be cleared from the ovary.
And also same thing, like after you ovulate, there's a wound and a heal, but there's also the production of the transient endocrine structure of the corpus luteum. And so there's a tremendous amount of debris that has to be removed from the ovary to keep it functioning. And we actually think that this whole cycle basically becomes defective with age.
The ability to remove sort of the garbage from the ovary becomes less effective, and that's what's causing this inflammatory and fibrotic response. And so the idea would be, or the sort of the corollary would be, that if you were on oral contraception, if you were pregnant for extended times, if you were breastfeeding, where you are stopping that cycle and that ovulatory cycle, that that actually would improve the microenvironment of the ovary, preventing fibrosis from occurring in this inflammation. And, you know, I think there is some epidemiologic evidence to suggest that birth control, pregnancy and breastfeeding might have a slight increase in ovarian longevity, but certainly it might lead to a better environment and better quality eggs.
But this needs to be actively examined, which is something that we're currently doing. Perhaps another sort of angle to think about this, you know, a procedure that a lot of us do many times in a day and sometimes many times for a single patient is an egg retrieval. And, you know, when I think about there's all of these follicles we're stimulating to grow, then they're all sort of having this perhaps sort of ovulation event or, you know, where they're being punctured with a needle.
That's another repair sort of thing that has to happen. We have good data that we're not depleting the egg count by doing an egg retrieval, but are we hastening fibrosis, I guess? And do you have any studies on that? You're talking about the actual process of retrieving the egg and making the hole in the ovary and whether or not that sort of causes a wound and repair. And especially in women who have sort of repeated cycles, what is the impact there? We don't.
I mean, we have not sort of systematically modeled that to see if that could potentially add to the fibrotic response. I do think something that's really interesting that we have not followed up on, but we can hyperstimulate mice just like you would hyperstimulate women in terms of a hormonal regimen. And we looked at proliferation marker in the ovary and what we found was that after stimulation, which makes a lot of sense, is that the cells in the microenvironment become highly proliferative.
And so I think that's super interesting to think about, like, what is the stimulation protocol doing to everything but the egg? You know, like we understand what it's doing to the egg, but what is it doing to all the other cells? And could that hyperproliferation actually be contributing to some of these endpoints of fibrosis and inflammation? So I think it's very, very interesting. And, you know, we have the tools in the lab to study it. So I think this would be really interesting.
I think just to kind of bring it back to a plausible mechanism for why mTOR inhibitors could be beneficial at the level of the ovary as well, it's, you know, I've always kind of assumed that it was just related to primordial follicle activation, but I think based on what I've seen in our mouse studies and others, that's not enough to explain the phenotype that we're seeing in terms of prolongation of reproductive potential. And I think that there is a significant immune modulating effect that is likely related to mTOR inhibitors increasing autophagy, which is allowing debris to be cleared, the debris that Francesca, you know, is seeing leads to fibrosis. And so I think, you know, when I'm looking at these young mouse ovaries that have been treated and then thinking about how are we seeing a phenotype six months down the road from four weeks of treatment in a young mouse, I think there is probably some significant immune modulation that happens early and that's changing, you know, how fibrosis is occurring long-term.
So Dr. Goldman, you already brought up some of these potential drugs such as rapamycin that could be candidates for clinical applications. Could you talk a little bit about how these therapeutics are currently being used, what the state of the science is and where we could potentially go? Sure. So rapamycin is kind of the original mTOR inhibitor and it's, you know, it was initially identified as an antifungal, was then found to be a potent immunosuppressant and is still used in that way.
And in fact, this morning I saw a patient who had a prior transplant and is on sirolimus, rapamycin for transplant rejection. So these are drugs that are used frequently in that space. They're used in some cardiovascular treatments and there are a number of mTOR inhibitors that are used in oncology.
Everolimus is one of those and there's temsoralimus. There are a number of kind of newer derivatives of these rapalogs. And so I think they are attractive agents for pharmacologic fertile protection because they are clinically used.
They are, you know, a number of them are FDA approved. And, you know, I think one of the struggles will be that rapamycin is off patent. And so there are very few incentives for people to go do expensive trials to identify these as bringing them to clinic because they may not make money for whoever is doing that trial.
And so there's not that incentive from a pharmaceutical company. So I think, you know, there are newer derivatives of these drugs that are being looked at. The ones I studied were everolimus, which is RAD001.
It's an mTOR1 inhibitor and then INC-128, which is a dual mTOR1 and mTOR2 inhibitor. So it's both an allosteric and catalytic inhibitor, which have different effects on the pathway and different levels of suppression and inhibition. So there are a number of directions that this could go.
I think it's really a matter of, you know, doing the right trials. And there is a trial going on right now out of Columbia with Yuxin Su and Zeb Williams, and they are looking at rapamycin. The trial is called Vibrant and essentially looking at could these be used in advanced reproductive age population to preserve ovarian reserve? I think one of the struggles is, you know, the endpoints are the same endpoints that we would all look at, AMH, antral follicle count.
And what's really going to be interesting is what happens over long periods of time, because we're really interested, of course, in not just ovarian function in the immediate, but long-term function. And are we seeing prolongation of ovarian function past the age of what would have otherwise been physiologic menopause? And are we going to see the benefits of prolonged ovarian function? And so I think that is going to be the key question. Yeah, that sounds like a really fascinating study.
I'll be really curious to see how those results turn out. I think I want to take a chance to turn this back to Dr. Eubanks. When we think about the clinical applications of some of these experimental modalities, there appear to be some evidence that you do see gains in antemullarian hormone or other surrogate markers.
Why do you think that this frequently fails to translate into meaningful differences in egg yields, embryo development, or live birth rates? Well, I think it's consistent with the same problem we see with patients every day, you know, taking a real stronghold of their AMH or AFC value and hoping that that translates directly to clinical outcomes. The main issue here is that AMH and AFC are surrogate markers of follicle activity. They're not direct markers of egg quality or reproductive competence.
So you transiently stimulate follicles that were already present. You may see a bump in that AMH follicle count, but it doesn't necessarily mean that you've actually reversed the underlying biology of ovarian aging as it's sometimes being advertised as. The core age-related problems, as we've discussed, the meiotic instability, mitochondrial dysfunction, chromosomal error, changes in the ovarian microenvironment, they're all still going to be there.
That's why our paper emphasizes that distinction between transient follicular activation and true modification of reproductive aging. So you're seeing across PRP, stem cell therapy, and mitochondrial transfer that these reported improvements are going to be these surrogate outcome measures. But again, that's not translating to the outcomes we're all hoping for, live birth.
And I think that's where you're getting some of this, you know, fake news. We have so many patients who are so motivated to do whatever they can do and really would be thrilled to start treatment with something if there was potential benefit. I think we have to be cautious and be kind of even more cautious than we would be with other types of treatments that what we are doing is safe and that we have studied it well.
And so I think it's just a call to do the studies and get the data because I think it's challenging. A lot of the preclinical work is done in, you know, rats and mice, and obviously those are not humans. And there's some work done in non-human primate models.
But even then, I think how things are going to actually translate to human is a different story. And I think that's also why it makes it so much more attractive to think about drugs that are already used safely in humans. And so some of these antifibrotics and the mTOR inhibitors that are clinically used, there is an opportunity to look at ovarian reserve parameters in patients who are already on these drugs for other indications.
And so I'm working with a community of patients who have lymphangioliomyomatosis, which is a really difficult disease that is mTOR mediated, and looking to see if we can find proxies, ovarian reserve parameters, in women who are currently taking these drugs and who are of reproductive age. So I think trying to find creative ways to do these studies, especially in the funding environment that we're in right now, is going to be important. Yeah.
And just to build on that, I think in our field, patients are often so desperate for the outcome that we're trying to help them achieve, building their family. And especially among poor prognosis patients, they're particularly susceptible to some of the technologies that we're talking about today, especially those that Dr. Eubanks brought up that are already being marketed to patients. And so I think when you have validated alternatives like donor egg, it can be challenging for patients to see that as an option for them that may not feel like the right one at first and be attracted to some of these more experimental modalities.
And I think that that's a risk we face as we develop new technology, that we have to make sure we're striking that balance between safety and hope for our patients. I also think it's like our responsibility to understand if and when there are benefits and if and when there are not benefits. And I think sometimes the easy thing to do is to say, well, it can't hurt.
But I also think that's in some ways because we haven't read all the papers on this topic or it's hard to keep up. There's a lot going on. And so, again, intended for the discussion after this paper with different groups should be a better understanding of what is out there.
So when your patient does come to ask, hey, I read this article about this option, what is this the right option for me? I think it's our responsibility to understand the risks and benefits and there are benefits for these things instead of just kind of relying on the probably can't hurt because patients are going to ask about it. And they certainly do. I think PRP and stem cell therapy are asked about, I would say, at least daily for our patients.
So we need to understand what's out there and what they're seeing and then how to respond. I want to thank all of our guests for participating in our in our podcast recording today. I know I learned a lot.
This is really such a challenging topic, a heartbreaking topic for our patients. And it's so wonderful to hear about this groundbreaking research. I really have a lot of hope for the future.
I would encourage everyone listening to this podcast really, though, to go to the journal and read the article. There's so much more information there that these authors have included. So we encourage you to do that.
But thank you so much for listening. And we hope you join us for our next podcast. Fertility and sterility roundtable was developed by fertility and sterility and ASRM as an educational resource and service to its members, other practicing clinicians and members of the public.
The opinions expressed are those of the discussants and do not reflect the views of fertility and sterility or ASRM.
