Advancing Ovarian Health from Fertility to Lifespan with Francesca Duncan, PhD

[00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show.More women are living longer, healthier lives, maintaining better physical health than the generations that came before them. But despite these advances that have led to longer, healthier lifespans, women's ovaries are aging as they always have. By their mid 30s, most women will experience a decline in fertility and hormone production. This can not only impact reproductive ability, but also cardiovascular, bone, cognitive, and immune health. My guest today, Dr. Francesca Duncan, is investigating novel ways to improve maintenance of the ovaries and prevent key age related changes in ovarian function. She is the Thomas J. Watkins Memorial Professor of Reproductive Science at Feinberg and an Associate Professor of Obstetrics and Gynecology. I am thrilled to have her on the show today to discuss this topic. Welcome Dr. Duncan. 

[00:01:13] Francesca Duncan, PhD: Thanks so much, Erin. I'm really excited to be here today. 

[00:01:16] Erin Spain, MS: Well, let's start this off by talking about female reproductive aging. It is an interesting thing that the ovaries are one of the organs that age first. Tell me about that. 

[00:01:27] Francesca Duncan, PhD: I've really always been fascinated with female reproductive aging. The female reproductive system is actually one of the first to show overt signs of aging in the body. So when we think about aging, we think about tissues deteriorating in function. But typically we think about this in people in their sixties, seventies, eighties, and nineties. And here you have an organ system that really starts showing signs of deterioration much earlier and more drastically relative to these other organ systems. So for example, women's fertility will begin to decline in women in their mid thirties. So that's chronologically a very young individual. And that reproductive function ceases completely at the time of menopause, which is only around age 50. And aging, reproductive aging is gonna affect every single female irrespective of race, geography, so it really is something that's gonna impact half of the population. 

[00:02:19] Erin Spain, MS: And reproductive aging isn't just about fertility and reproduction. As you lose these female hormones, they cease to produce as much as they used to, it impacts organ systems. Tell me more about that. 

[00:02:31] Francesca Duncan, PhD: You know, when we think about female reproductive aging, we tend to think about fertility. And in the ovary, this is really characterized by two main things. First, there's a loss in the number of eggs that are in the ovary and there's also a decrease in the quality of the eggs in the ovary. That's going to directly impact fertility, which is what we hear about, think about and experience, especially as women globally are delaying childbearing. But you bring up the really good point that it's not just about fertility, because as these eggs grow, they develop in a structure known as a follicle. And these follicles produce hormones like estrogen and progesterone, which are really important for maintaining a menstrual cycle. But also are important for regulating downstream organ systems. So for example, we know estrogen's really important for sexual health, cardiovascular health, immune health, bone health, and cognitive function. So with aging, when you lose these follicles and the estrogen that they're producing, this is gonna have much broader effects on the general health of women. And so what I like to also point out is that it's really important that we don't sort of think about menopause as a disease, right? Like menopause is part of our normal physiology. But what's happening is we've really sort of changed the way we're living. So due to medical advances and health advances, women are living well past menopause and the age of menopause has stayed relatively constant, so around age 50 for centuries, whereas our lifespan has gone from about 50, now in the US women are living into their eighties. So women are living three decades longer and so they're living in this altered endocrine environment and experiencing potential negative consequences of reduced hormones. So it's a pretty complex phenomenon where you're dealing with not only fertility, but also just general overall health. 

[00:04:21] Erin Spain, MS: And so one of the goals here is to figure out, well, how can we, bring up the woman's ovarian health span to reach their biological chronological health span. Is that right? 

[00:04:31] Francesca Duncan, PhD: Absolutely. I think one of the misconceptions when people hear about the research that we do is the immediate response is, oh, are you trying to make women in their sixties, seventies, eighties pregnant or fertile. And that's certainly not the goal. The goal is exactly what you said, which is to make the function of our organ match the way that we're living. And I think what's really important is that, in the aging community and longevity community, we wanna live longer and we wanna live longer in a healthier state. And when you're dealing with women's health, you have to consider reproductive span in the context of healthspan and lifespan. And I think that's really what we're trying to do here. And, our work is focused really on making the whole organ, that whole ovary functioning longer so that we can preserve both the eggs, but also the hormones that they produce. 

[00:05:19] Erin Spain, MS: So the mechanisms that drive reproductive aging in women are fairly poorly understood. Why is this? 

[00:05:26] Francesca Duncan, PhD: I would say, I think the field of reproductive science in general is quite small relative to other disciplines. It's a very sort of focused but really critical discipline, but it's a small field in general. And then you have a topic of ovarian biology and then an even more narrow topic on reproductive aging. So I think it has been not studied as extensively as, you know, one would hope, but I think really a tide is turning in the sense that there's a lot of societal awareness and we're at a fulcrum where people are really starting to pay attention about this topic in the quest to live longer in a healthier state. 

[00:06:05] Erin Spain, MS: And this is something, again, that is happening in your lab. You've actually made some significant discoveries about what's exactly happening to the ovaries as they age. Explain this aging process to me in some of your earlier studies and what you've found. 

[00:06:18] Francesca Duncan, PhD: I'm an egg biologist by training, and so what that means is I'm studying sort of the egg cell. We know that when women age, the quality of the eggs decreases. And one of the really common outputs of this is something called aneuploidy, which refers to the chromosomes in the egg and they do not separate correctly. And so you end up with the incorrect number of chromosomes that can lead to conditions that you might be familiar with, like down syndrome which increases exponentially as women age. And so I was really interested in understanding why was this egg changing in terms of its quality with age, and why were these chromosome abnormalities increasing? And so I spent a lot of my early career actually taking the eggs outside of the context of the ovary and studying them. But in this process I can tell you we use a mouse as a model system. This is a really powerful model system that we use in the research lab. But the way we take these eggs out is we actually take these ovaries and we use needles to actually poke the ovaries and the eggs come out, and then we can study them in isolation. And there were several people in the lab who were doing this and they realized that the old ovary was tougher. It was just physically harder to get these eggs out of the tissue. That sort of derailed my lab in a really positive way because it changed the trajectory of our research because it made us start thinking, it's not just about what's happening to the egg cell itself, but maybe where this egg is developing something is really changing in that environment. And that could have really significant implications for the quality of the egg. And I always bring up this concept of tissue microenvironments. So in the field of cancer, we know that the tumor microenvironment is actually really critical to inform how these cancer cells behave, how aggressive they are, where they hone in, where they metastasize. But this concept of the environment of the ovary had really been overlooked because researchers were much more interested in the egg cell since that's, again, the important cell that gives rise to the next generation. So this really changed our trajectory and we started trying to understand what is happening to that environment where that egg develops with age. 

[00:08:23] Erin Spain, MS: So it actually is a scarring that's happening. Is that what you found? 

[00:08:27] Francesca Duncan, PhD: Yeah, so our study, we published this many years ago. So back in 2016, the ovary is a very dynamic organ. So normal development in the ovary, you have follicles that develop, but only a few follicles make it to ultimately produce an egg that's gonna ovulate. And all of the other follicles, they go through waves of growing and dying. So there's actually quite a bit of debris and death of cells in the ovary that have to be cleared. And you also have a process of ovulation that's happening repeatedly, and this is a basically cycle of wound healing and repair that can lead to scarring. And so you can imagine that in women as they get older, they've been exposed to more cycles of follicles growing and dying, but also more ovulation and wound healing. And so the ovary becomes less adept at clearing this debris or clearing this scar tissue. And so you have this accumulation that actually leads to a physical toughening of the ovary. Now, I will tell you that. there's also accompanied by inflammation. So there's inflammatory response, there's fibrotic response, and the organ actually gets quantifiably stiffer. So we can actually measure this both in mice, but also now in humans, we can measure the stiffness of the ovary and that increases with age. 

[00:09:46] Erin Spain, MS: Well, since 2016, you've done quite a bit to understand what's causing the scarring. Tell me more about that.  

[00:09:52] Francesca Duncan, PhD: in the last 10 years, we and others have shown that there's actually quite significant consequences in terms of biology. So I can sort of give you three examples of why we should care about this. One is we've been able to model that stiffening environment in vitro, so in a dish, and we can show that if you grow follicles in stiffer environment that mimics the aged ovary, you actually have poor follicle development and you also have reduced quality of the eggs within those follicles. So we think that that stiffening environment is actually impacting the quality of the eggs that are produced. So you can imagine if you have this stiff ovary, it's gonna be harder for that egg to be released. And in fact, we see that with age there are defects with the ovulatory process. And finally, the sort of third thing that we've investigated is really the interface between reproductive aging and ovarian cancer. So, as I mentioned, cancer cells, their behavior changes depending on the environment. And we know that in the context of ovarian cancer, this is typically diagnosed in postmenopausal women. And we know that the postmenopausal ovary is really fibrotic. It's almost like a rock. It has tons of this collagen that causes the scar tissue, and it turns out that ovarian cancer cells really prefer to hone in on a collagen rich, stiff matrix. So obviously not every post-menopausal woman gets ovarian cancer. We think that this is sort of a double hit where it provides an important niche for these ovarian cancer cells. So, that's what we've been doing in the last 10 years is figuring out, what are the causes and what are the consequences biologically? And really now we're trying to shift into therapeutic. Can we therapeutically target it, but also can we think about using ovarian stiffness as a biomarker of ovarian age and ovarian function? 

[00:11:41] Erin Spain, MS: Well, that leads us to your most recent study, which was published in GeroScience, where you actually discovered a potential solution to help mitigate this ovarian scarring or fibrosis, and generally improve the ovarian environment. So tell me about this most recent study and what you found. 

[00:11:57] Francesca Duncan, PhD: Yeah, so again, our goal is to push our work translationally. And several years ago we actually developed a tool to be able to measure the stiffness of the ovary. But what we also did at that time was we treated the ovaries, this was in a mouse model. We treated the ovaries with an enzyme called collagenase. And so, actually I should mention that fibrosis is caused by an increase in collagen I and III. So these are proteins that make a matrix and they tend to accumulate with fibrotic tissue. And so we treated these ovaries with a collagenase, which is an enzyme that breaks down collagen. And what we showed is that we could change the stiffness of the old ovary and rejuvenate it so that it looked like the stiffness of a young ovary so we could soften that ovary. And that observation gave us the clue that perhaps we could therapeutically target the stiffness of the ovary, if we could find ways or drugs that could target the fibrosis that was happening. And so in our most recent study, this was a proof of concept study that we did in a mouse model, where we used an FDA approved drug called Pirfenidone. This is FDA approved for the treatment of idiopathic pulmonary fibrosis. So lung fibrosis in humans. And we use this because it was shown to be effective in mice, but also importantly, it was shown to target molecules that we know increase with age in the ovary in mice. I will mention though, that this drug has, in humans, it does have side effects, so it has liver toxicity and clearly it's used in the setting of idiopathic pulmonary fibrosis because these patients are quite sick. And so there's a risk benefit there for those particular patients, but you could never really translate this directly into healthy women to take it sort of prophylactically to prevent ovarian fibrosis. So this study was really more of a proof of concept to say, if we could change the stiffness of the ovary, can we actually improve reproductive outcomes? And so in this study, that's exactly what we did. We delivered this drug Pirfenidone systemically, so throughout the body of mice for a period of six weeks at a point where they would normally have ovarian fibrosis just starting to form. And our question was, can we prevent this inflammation and fibrosis from happening? That was question number one. And question number two is, if we could do that, what was the outcome on the reproductive parameters. And so what we found is that by treating these mice with a very low dose of this drug. In mice, it turns out that the drug is not toxic. But what we were able to show is that the ovary has reduced inflammation and fibrosis. And what's really exciting about this is that we were able to give the drug for a relatively short period of time, then stop the drug treatment. And even three months later we were still seeing positive effects, which is really exciting. And then what was really exciting is that we were able to increase the number of follicles. So, decrease the loss of follicles that normally happens with age in these mice. We also were able to show that they had better ovulation, that they had increased hormones and they had what's called estrous cycling, which is more akin to a menstrual cycle in women. So we were able to prolong that. So that was really exciting for us because it says we're preserving eggs, but also hormone function. And so this really lays the foundation to again, to be able to push this work forward clinically. 

[00:15:17] Erin Spain, MS: This really opens a door to understanding the possibility of a more targeted intervention. So what are the next steps for possibly applying this to humans clinically? 

[00:15:26] Francesca Duncan, PhD: I think there's several ways to go forward. One way is to identify specific targets in the ovary that are causing fibrosis in the ovary. Ideally this would be specific proteins that are causing fibrosis in the ovary or ones that could be general to fibrosis outside, across organ systems, but that could be targeted safely. So you could actually imagine since the ovaries aging much earlier if you did identify something that was safe, you could be on a low dose antifibrotic that could potentially prevent not only ovarian fibrosis, but fibrosis in other organs as well.. So I think we really need to focus on understanding, are there specific mechanisms that are causing fibrosis in the ovary or are there more common mechanisms across tissues that could be targeted in a safe fashion. So that's really in the preclinical space where we need to go. In the clinical space. There are, I think, developing pipelines to be able to do clinical trials in women to say, can we actually develop therapeutics and be able to evaluate them in women. What's super exciting is that there's a technology called ShearWave Elastography, which is an ultrasound based method to measure stiffness of human organs. And this is commonly used to measure liver fibrosis by ultrasound method. And we've recently applied this technology to measure stiffness of the human ovary. So I think that's gonna be really critical because as we develop therapeutics, we can now test to see are we actually, are they effective? I think that's gonna be super critical. 

[00:17:01] Erin Spain, MS: I know you mentioned that the goal of your research is not to improve fertility in women as they age, but there could be some benefits here for women who are in their twenties or thirties, forties who are experiencing infertility and this could possibly help improve their fertility and chances of pregnancy. Could you talk about that a little bit? 

[00:17:22] Francesca Duncan, PhD: I mean, there's several ways to think about it. One is, if you think about measuring the stiffness as a biomarker, for example, there's not really great readouts of what is your reproductive potential at any given moment. And so if we can decode and really connect the relationship between the stiffness of the ovary and reproductive function, that could be a really important biomarker that could be addressed relatively non-invasively by an ultrasound based method to say, here's a predictor of your reproductive status. So that's one way. The other way is, as I mentioned, if follicles are developing in a stiff environment, they're not gonna grow as well. Their eggs aren't gonna be as healthy. So you can imagine that if there was a therapeutic that targeted that environment and made a softer environment, that actually, that could improve the quality of the eggs and extend reproductive function. So I definitely think you're talking about here a scenario, it's a win-win where you could extend the function of the entire organ, but also extend that reproductive or fertile window of that individual. 

[00:18:25] Erin Spain, MS: If one day therapeutics would be available based on this research that you're doing, what kind of impact could that have on the health of women? 

[00:18:33] Francesca Duncan, PhD: My hope or my vision would be that if you are sustaining ovarian function and hormones that are happening in a cyclical fashion rather than like hormone replacement therapy where it's single dose of and not recapitulating the entire hormone profile of the ovary, that you would actually be able to sustain the function of the ovary, but also these downstream organ systems so that you would have an overall health benefit. That being said, we do not know what is the long-term consequence of having an organ that's functioning for decades longer than it otherwise would. And so I do think that because we are on the cusp of these types of discoveries, and I don't think that these therapeutics are that far off, I do think we need to think about what are the consequences and really think through that deeply.The other question is, how long could the organ actually function? So, one thing to remember is that females are born with a fixed number of eggs. So once you're born, that's all you have, you don't make more. And so I think eventually you would exhaust the pool. And there are also other mechanisms that are leading to the deterioration of the function of the ovary. So, I just talked about was what I call the nest. It's like everything, the nest in which these eggs are developing, it's that environment of the tissue. But you can imagine that if eggs are made in fetal development and then they have to stick around for decades, they're gonna accumulate damage over time. And that's actually also gonna contribute to poor growth outcomes, poor quality, fertility, and so forth.  

[00:20:09] Erin Spain, MS): This research is so fascinating and it does raise a lot of questions about what does the future look like for female reproductive health? 

[00:20:17] Francesca Duncan, PhD: Right. I was writing an article for Scientific American and I did sort of this thought exercise of what are these issues like,let's say you had this organ where the quality of the eggs are going down, but they're still there and they can still produce the hormones. Like then all of a sudden, are you going to have to... 

[00:20:32] Erin Spain, MS: be on contraceptives...  

[00:20:34] Francesca Duncan, PhD: Exactly, like contraceptives much longer? Or would women even want to have the risk of pregnancy much later? The other big question is, we're assuming that if you have ovarian function in hormones, that you're generally going to be healthier, but the question is if you're someone who's older, having a pregnancy in an older individual has risks of pregnancy complications, and so is extending ovarian function significant enough to actually have a healthier pregnancy in older ages or would you still have those impacts? Again, I don't think we've thought deeply enough about these questions because it has seemed too far in the future to even think about that. I think within 10 years we're talking about seeing therapeutics that are hopefully widely available but safe and effective. And so I think having these conversations and thinking through the tough questions is really forward thinking and something that we need to do. 

[00:21:27] Erin Spain, MS: Well, it seems like this is a very exciting time for women's health research, longevity research. There's so much going on, but what does it mean for you as a female scientist as well, paving the way for not only future research, but for the future of female reproductive health generally. 

[00:21:43] Francesca Duncan, PhD: I think it's really exciting time. Like, as I said I think there's a lot of societal and clinical ramifications of this topic that we're all becoming very well versed in. You know, I think 10 years ago, this wasn't on the radar of everyone, but now we're really, as a society, much more open to these types of dialogues. I also didn't really mention this earlier, but I think we also have a really unique opportunity right now because there's a big partnership between aging researchers and reproductive scientists that didn't exist before. and it's really only in the last about five years that the aging community has really partnered with women's health researchers and reproductive scientists to really take a look closer look at this and what's really cool is that we are really having more and more researchers who are coming into this space. And I think when you have people from diverse disciplines, tackling a topic, that's really where you gain traction in new ideas. So that's really exciting that the field has broadened, but I will say what we're learning is that there are many similarities in the aging process, in the mechanisms that drive aging in the ovary relative to somatic tissues or other organs in the body. And so that's interesting because again, the ovaries aging earlier, relative to these other organ systems. So we could potentially use the ovary as a canary in the gold mine to really tell us, what is driving aging in the other organ systems and are there similar mechanisms at play? But we also are learning that there are mechanisms that may be unique to this organ system, and again, that those could be targeted in a very specific way to improve reproductive outcomes. So I think we're in an exciting time, again because of increased awareness, but also because of the interdisciplinary nature of this work, bringing a lot of diverse perspectives into the field. And I have to say that I think it's very rare for disciplines to potentially adopt each other in such a synergistic way. And it's been really exciting and very welcoming to be included in the paper space with aging researchers as well. 

[00:23:45] Erin Spain, MS: there's so many possibilities ahead. And you said you could see a lot of things happening in the next five to 10 years, but what about in your lab? What can we expect next from your team? 

[00:23:54] Francesca Duncan, PhD: Really where I'm headed next is the translation. So I think that's one of the benefits of being at a place like Feinberg School of Medicine and Northwestern, where you can in under a decade go from a bench discovery into clinical realm. And so, as I said, we're already measuring human ovarian stiffness clinically in women. We're working towards identifying these antifibrotic agents. So one thing that I didn't mention is that we've actually developed a model, an organoid based model where we can actually create in a dish, the ovarian microenvironment, so that nest, and so we can use that as a screening tool to identify therapeutics that can target fibrosis. And so we're really going to be pushing hard to find these safe and effective ovarian, anti-fibrotic agents and then putting those into the clinic through clinical trials. So that's where I see the next 10 years going from bench to bedside. 

[00:24:49] Erin Spain, MS: Thank you so much for coming on the show and really shining a light on this area of research that is emerging and evolving right here at Northwestern. I appreciate your time. 

[00:24:57] Francesca Duncan, PhD: Thank you so much, Erin. 

[00:24:59] Erin Spain, MS: Thanks for listening, and be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts, and rate and review us. Also for medical professionals, this episode of Breakthroughs is available for CME Credit. Go to our website, feinberg northwestern edu, and search CME.