Melanie Cole: Welcome to Better Edge, a Northwestern Medicine podcast for physicians. This episode is part four of our Better Edge Parts and Labor Mini series

Dr Angela Chaudhari (Host): Welcome to Parts and Labor Round Table Discussion with the OB gyn experts here at Northwestern Medicine. My name is Dr. Angela Chaudhari, and I'm a minimally invasive gynecologic surgeon and serve as chief of Gynecology and Gynecologic Surgery here at Northwestern Medicine. I will be your host today discussing Uterine Fibroids and the research that's gotten us to where we are today in our understanding of what causes them and how to treat. So first off, let's meet our very esteemed panel today.

First up, Dr. Bulun, our John J. Sharp, Professor of obstetrics and gynecology and chair of the department of ob gyn here at Northwestern Medicine. He's a professor of both reproductive science and reproductive medicine, and is a member of the National Academy of Medicine. He runs the Bulun Lab here at Northwestern University, which we'll get to hear more about. Dr. Julie Kim, the Susie Yung, Professor of Obstetrics and Gynecology in the division of Reproductive Science and Medicine at Northwestern University is the co-director of the Center for Reproductive Sciences at Northwestern and runs the Kim lab here at the university.

Dr. Milad, the Albert B Kurby, Professor of Obstetrics and Gynecology, and the division Chief of minimally invasive Gynecologic Surgery Here at Northwestern Medicine, Dr. Milad is board certified in reproductive endocrinology and infertility with a focus practice designation and minimally invasive gynecologic surgery, and has done a number of different research work surrounding fertility, fibroids, and patient reported outcomes. Dr. Bob Vogelzang, the Albert Nemec education Professor of Radiology here at the Department of Radiology at Northwestern Medicine with a focus on vascular and interventional radiology.

He's a past president of the Society of Interventional Radiology and has published on uterine artery embolization for many years, including on multimodal therapy for uterine. So let's begin by better understanding the research landscape here at Northwestern. Dr. Bulun, you've spent much of your academic career performing research on steroid hormone production and action, and how it impacts disease, with a focus on uterine fibroids and endometriosis. Now I pulled that off your Fineberg University panel.

What I did really find out was that the Bulun lab is the most highly funded NIH lab in the country doing research on uterine fibroids and endometriosis. Can you share with our audience what kind of work you're doing in the lab?

Dr Serdar Bulun: Thank you, Dr. Chaudhari I will start with endometriosis First, it's important to understand the clinics, clinical aspects of this disease. Endometriosis Is caused by backward menstruation of blood and endometrial material every month that goes to the tubes and lands in abdominal tissues. Although almost all women experience this backward menstruation, only 10% of women develop endometriosis. Which is an inflammatory condition in which these endometrial tissues grow on bowel and other peritoneal surfaces and cause enormous amounts of pain and infertility.

So we asked, what is special about this 10% of women and we found that they're normally located inner lining of the uterus, which is called endometrium, is molecularly abnormal. For example, we discovered this enzyme called aromatase that makes estrogen. And what separates endometriosis from other inflammatory conditions such as rheumatoid arthritis would be its dependence on estrogen for inflammation. We found that endometriosis tissue is very devious. It makes its own estrogen through the use of this armatase enzyme.

When we targeted armatase, we found that these patients pain symptoms were alleviated, Therefore, our basic research, almost like single handedly broad armes inhibitor to the treatment of endometriosis.

Dr Angela Chaudhari (Host): That's amazing, Dr. Bulun, when we talk about endometriosis and that's a whole nother podcast by the way, I'm gonna bring you back for that one. But when we talk about endometriosis and aromatase inhibitors, we think about breast cancer and some of these other things, and the fact that we're now using some of these. Because of the research done in your lab for treatment of endometriosis is really just amazing. I think that we can't highlight enough the importance of the work you're doing in the lab. So now, how did you get interested in uterine fibroids and what sort of work are you doing around that?

Dr Serdar Bulun: Uterine fibroids is another form of uterine disease, in fact is the most common uterine disease as our surgeon, colleagues, and interventional radiologists colleagues will agree. We perform more than 200,000 hysterectomies and some 40,000 interventional radiology procedures every year in the US only for Uterine fibroids. I don't think any other gynecologic disease come close to uterine fibroids for is public health impact.

What we found was, the normal, my endometrial normal muscle cells of the uterus that handles a pregnancy normally response to this hormone, progesterone every month in anticipation that it will handle a pregnancy. This process activates these normal stem cells. But there is a very high rate of mutation among these stem cells. One of these stem cells, if it is hit by a mutation, it just grows and makes its own tumor over the years. And this process is stimulated by progesterone. And I should also point out that interestingly, all though fibroids is not considered a malignant disease.

It's steroid profile is almost identical to br breast cancer. Whatever hormonal treatments we use for breast cancer also do work in fibroids. Therefore, our lab concentrated on these targets over the years.

Dr Angela Chaudhari (Host): So hearing that and hearing some of the work you did, aromatase with endometriosis, and now this current work you're doing around progesterone, what can we expect to see coming out of the lab in the future? Dr. Bulun, what are we gonna learn about how we can use progestin to begin to treat fibroids? Because right now progestins work to can maybe control bleeding, but certainly don't have an impact in shrinking fibroids as far as I know.

Dr Serdar Bulun: In Fact, Progestins aggravate fibroid growth. They make fibroids grow, whereas anti proin shrink fibroids and one anti progestin that was approved in the EU has been pulled from the market unfortunately because of a very rare complication of liver disease. What we would like to work on is targeting more anti progestin pathways and developed drugs that do not have such bad side effects.

Dr Angela Chaudhari (Host): We are really looking forward to that, as a gynecologic surgeon and a patient who counsels patients all about the different options for uterine fibroids. Our patients are looking for nonsurgical non procedural options to really begin to impact the growth of fibroids as well as the symptoms associated with fibroids. So we can't wait to hear more about what's coming out from your. I'm gonna shift over next to Dr. Kim. Dr. Kim, your lab from, again, what I read on our website really, focuses on progestin media, mediators of different gynecologic diseases. As Dr. Bulun was mentioning, and in your role in the lab, as well as the co-director of the Center for Reproductive Science. I'd love to hear about some of the work that your lab is doing.

Dr Julie Kim: Thank you and thank you for inviting me. This is so exciting. My lab is interested in identifying the molecular mechanisms that cause growth, as well as development of uterine fibroids. We wanna answer the question of why black women are so disproportionately affected by fibroids. And we also wanna potentially identify targets that we can develop new treatment therapies for that are non-surgical.

And so over the years, as you mentioned, I worked with Progestins in the role of hormones in the growth of fibroids as well as signaling molecules. But I'd love to talk to you about some of the most recent study that we've done in the lab that deals with Oxidative stress. So we've found that in uterine fibroids, the oxidative state of stress pathway is overactive and it is involved in potentially causing fibroids to grow as well as the development of fibroids.

And oxidative state of stress is basically a phenomena where there's an imbalance of reactive oxygen species and mechanisms that detoxify. The reactive oxygen species. I'm gonna call it Ross from now on. And so this is really important because in fibroids what we found was that the Ross pathway is overactive. Oh and by the way, Ross, where does it come from? Ross is actually a byproduct of a metabolism of oxygen that occurs in every cell of our body. And it's a byproduct and it's fine because there are mechanisms that detoxify that. But when there's an over preponderance of Ross it can cause proliferation of that cell.

Or it can actually cause DNA mutations and so it's bad. And so we need those detoxifying enzymes. And what we've found in fibroids is that some of these detoxifying enzymes are not working properly. And so we have this cell where there's a high level of Ross. And so what we find is that these grow in response to Ross. And, but we also found that because those detoxifying enzymes aren't working very well, if we were to overburden them or challenge them with exogenous Ross or triggers of Ross in the cell, then these cells can actually die or undergo senescence. And so this was a really remarkable finding.

With this knowledge we can now consider something like targeting senescence cells. For example, we have drugs on the market right now called Senelitics that actually targets senescence cells. So if Ross promotes cells to go undergo Ines, we can then use another drug call senelitics to target them. And so this is the kind of information that we're gathering. The second thing that we're really excited about is that we find that Ross can actually cause mutations in the Med 12 gene. And so why is that important? Studies have shown that Med 12 is mutated in up to 70% of all fibroids. What does it actually do?

We don't really know yet, but that mutation is associated with fibroid development potentially. And so we've been able to show in the lab that if we treat normal, myendometrial cells with the high levels of Ross for a long time, we can actually cause mutations in the Med 12 gene, which is pretty exciting I think. And then finally we've been able to show that members of that oxidative state of stress pathway are overexpressed in fibroid tumors from black women compared to white women. And so this is very intriguing. It's the first time we've ever shown a difference between black and white women in terms of their fibroid tumors.

And so now we can start leveraging this information in terms of Given the tumor characteristics, does that really dictate how we should treat these fibroids and whether we can treat fibroids in a more personalized manner? And so that's some of the research that we do in the lab.

Dr Angela Chaudhari (Host): It's amazing, Dr. Kim bringing personalized medicine to Uterine Fibroids. You were like speaking our like gyny surgeon language over here. Just to follow up on some questions. Cause I'm really fascinated by the work that you're doing and specifically around our black patients. We see 70% of black women have fibroids and as a clinician, I blame it on the genes, right? I say it runs in the family, right? What does that mean? Thank you to you guys actually doing the work to find out what those mutations are, what, what really is happening in the fibroids that maybe are genetic. Makeup are our family history is really bringing to the problem.

I guess my question for you, And I would love your opinions, both of you about this because you guys are really getting to the heart of what causes fibroid growth, working both forward and backward to try to figure out how we're gonna treat these fibroids. And so many times we have patients that come in who have fibroids and we'll take out 10 fibroids and they're 30. And it's a black patient wants to have a baby in the next few years and she said,my whole family had their uterus out at 35 because they, we just grow fibroids right back. What can I do to prevent these fibroids from growing back? And our answer right now is we don't know.

We don't know if we can do anything right to prevent those fibroids from growing back. I'd love to hear from both of you guys about whether the research that you're currently doing, looking at both the development of fibroids and how to combat the growth of those fibroids, is there gonna be something that comes down the line in my lifetime as a clinician that I'm gonna be able to share with my patients that they can change?

Dr Julie Kim: I always think optimistically and I think yes, if we understand the biology of how a tumor is formed, I think we can really start targeting that mechanism. We have so many advancing technologies now and there's so much that we can do and so many ways that we can look at things that I think the important thing is bringing different people together to solve a question. Bring engineers together with the biologists, with the molecular badge, with the clinicians. And I think as a group, as a team to answer your question, I think so I think the biology is really giving us real interesting clues as to where to look, what to look for, potentially identifying biomarkers risk, etcetera.

Dr Serdar Bulun: And from a practical perspective, fibroids occur because of repeated cycles of ovulation because uterus is exposed to both estrogen and progesterone. If he can break the cycle, probably that will really help. The current medications mostly contain estrogen and progestins. But new generation antagonists are coming on the market. I am somewhat hopeful that new technologies such as these generation antagonists, which do not stimulate fibroid growth, might be preventive. However, we have to figure out how to do this without significant side effects that needs to be worked out.

Dr Angela Chaudhari (Host): Sounds like you're pulling us into a clinical research study, Dr. Bulun. I heard that in your tone. I completely agree and I just really wanna highlight that, really around the country, everyone talks about how uterine fibroids are not studied enough. We don't know enough information. It's one of the most common diseases out there, as Dr. Bulun mentioned. And we just don't have the information to give our patients to really find targeted therapies and people blame gender bias in our NIH funding. People blame the fact that this is a disease that is a that affects so many black women. And maybe is that racially biased in the terms for funding for our research?

So I really just wanna thank the both of. All of your teams at the Center for Reproductive Science for really focusing on this disease that clearly is very near and dear to my heart as a gynecologic surgeon and really for my patients as well. So thank you for all that work that you do. I'd love to shift the conversation and talk a little bit more about some clinical research that we have happening here at Northwestern Medicine. Dr. Milad, I'd love to start with you. I know you are an avid researcher looking at clinical outcomes, Patient reported outcomes. Studied fibroids for much of your career. Can you discuss some of the work that you've done?

Dr Madgy Milad: The Center for Complex Gynecology is uniquely poised to be able to do clinical trials and clinical studies for patients that suffer from fibroids. We see thousands of patients every year. We do nearly a thousand surgeries between the four of us minimally invasive surgeons. And and we have a full-time research coordinator to help us with these types of studies. We've tried to use the highest level of research studies in clinical trials using randomized clinical trials as the as the study design. And we've studied things that improve outcomes and reduce blood loss. So we've done randomized trial looking at trans medic acid at the time of hysterectomy for fibroids.

We've done a randomized clinical trial of misoprostol for myomectomy for looking at blood loss. We've we have a current trial looking at low pressure hysteroscopy pumps versus traditional pressures to see if we can improve outcomes and lower the risk of having to do a second procedure. We also have a systematic review looking at mini laparotomy, which is a sweet spot for patients that are undergoing myomectomy patients. It's not really an it doesn't really follow the same pattern as patients that have an abdominal myomectomy.

We can do it as a outpatient procedure in a couple of hours, send them home same day, and they have similar outcomes as if they had it done laparoscopic. And then lastly, we have a study right now looking at the use of low-dose Ca rboprost to promote the migration of fibroids intraoperatively during his hysteroscopic resection for those types of fibroids that partially in the cavity, but mostly in the wall in order to reduce the need to do a second procedure. So there's a lot going on as far as clinical research at the center, and I think we're uniquely poised nationally to be able to pull these studies off.

Dr Angela Chaudhari (Host): I think, when I hear about the cadre of research that's coming out of Northwestern, first the basic science and now thinking about all these different clinical outcomes, ways to make procedures for fibroid surgery safer. It really is an opportunity for our patients to come in, be. Of the solution and so many of them want to be part of that solution because they've suffered with uterine fibroids for so long. Anything they can do, can we give fibroid tissue to Dr. Bulun or Dr. Kim's lab? Can we be a part of this hysteroscopic memectomy study if we're making surgeries safer for other people? That's what they really wanna do and I think our clinicians are uniquely poised.

And I'm gonna turn it over to Dr. Vogelzang because he's been doing fibroid procedures for 20 plus years and spent his academic career really researching so many of these topics. Both, fibroid therapies with uterine artery embolization, as well as multimodal therapy. Dr. Vogelzang, can you share how you've really had that focus on quality and safety for our patients undergoing these procedures?

Dr Robert Vogelzang: Yeah, absolutely. I would highlight that most of the work we've done has been in conjunction with surgeons, especially Dr. Milad At the Center for Complex Gynecology. I'll highlight one area that I think has made a huge impact, which is, I think still not fully recognized in America, which is the use of MRI to evaluate fibroids. In most of America, ultrasound is still a method that decision making is based upon, and it's a bad one. It does not tell us what we need, where they are, location intramural, incavitary and so on. And we did some early research looking at the impact of preoperative MRI in decision making, and it influenced decision making a tremendous amount in terms of a decision for or against myemectomy.

Decision for or against embolization. That's an example where I think we've really impacted the practice of gynecology and it has yet to be fully realized. And then some of the other areas have been for Dr. Milad and I have been in things like looking at our own data on this vexing issue of infertility or fertility preservation. What do you do Myomectomy or embolization? It's really an open question and the data is very poor. Internally, our data suggests that it's at least equivalent and we can say confidently to our patients as a result what we're suggesting to you. We have the basis on which to say that and recommend it, and I think our patients are the better for it.

Dr Angela Chaudhari (Host): I completely agree. I think we hear so much in the community. You can have an embolization if you wanna go on and have children in your future. And certainly we all know the FDA guidelines, but we're talking about a procedure that's been FDA approved for over 25 years. We have so much data regarding fertility and pregnancy that is out there just with a large number of patients that have been treated. And I think it's sometimes shortsighted that we can't continue to grow. I love what you said about MRI as well, Dr. Vogelzang saying, because I completely agree.

We have so many colleagues, Dr. Milad and I around the country who are focused in on different types of ultrasound and getting really focused. And I would say probably one of the number one second opinions I get is from patients who failed a hysteroscopic mymectomy, or patients who failed laparoscopic myomectomy because. When they were there, they only took out one fibroid and they had another 10 that were bothering them, but they didn't really see them on ultrasound because of shadowing and all those other things.

And MRI, we get an MRI and I show them exactly why they're still having the symptoms and it's pretty amazing what patients come back to us with so well. I really just wanna thank all of you for really all the research that you're doing for our patients. Like I mentioned, this is one of those areas that I think is horribly under researched around the country and around the world. And I'm really proud to work at an institution where fibroid research is really forefront of mind and really we have some of the top researchers in the country working here, so I'd love to open it up for any final thoughts for our referring colleagues about what's out there for research. How can they get their patients involved?

Dr Madgy Milad: All of our studies are posted online on clinicaltrials.gov. And so we have patients that are finding us on their own. But certainly we would recommend patients being referred in to the center as far as being managed for their complex issues. And, then of course we'll refer them back, it's a very unique. That's mission driven to be a one stop shopping for patients that suffer from fibroids or endometriosis. And there's not another center in the country that is that's like this, maybe even in the world, to have interventional radiology side by side with minimally invasive surgeons, with pain psychologists, with a PMNR doctor, with physical therapists, with sex therapists, with ultrasound and lab available. It's really quite a unique situation and patients realize it. And that's why our patient satisfaction is so high.

Dr Robert Vogelzang: I would echo that. I think that we are a distinctive entity that I would hope is replicated elsewhere, but for right now, we will take great care of your patients. They will have cutting edge research. They'll have the fast physicians. Best surgeons, best interventional radiologists, and have the best research team on it.

Dr Angela Chaudhari (Host): Fabulous. And I know Dr. Bulun and Dr. Kim that my patients always ask, Can I donate my uterus to research? I don't need it anymore.

Dr Julie Kim: Absolutely. We will take it . We're sending 'em your way.

Dr Serdar Bulun: Okay. And I would like to advocate for funding for basic research for both fibroids and endometriosis. These are severely understudied diseases compared with other illnesses out there. And we should all advocate for them because all new treatments will come from both basic and clinical research studies.

Dr Angela Chaudhari (Host): 100% agree. I 100% agree. I want to thank everyone for being a part of the podcast today. I know that our colleagues that are out there listening really learned a lot about what the research landscape is around Uterine Fibroids here at Northwestern Medicine. And I'm very lucky to work with each and every one of you sitting at this table today. And all the amazing research that you do. So thank you so much. Thank you.

Melanie Cole: To refer your patient or for more information, please visit our website at Breakthroughsforphysicians.nm.org/obgyn. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. Please always remember to subscribe, rate, and review this podcast and all the other Northwestern Medicine podcasts.