Research Center Takes Lead in Bringing Women Under the Microscope

The fact that men and women are not the same is no longer completely 
overlooked in the medical world. Diseases, such as heart attacks, can 
present differently. Yet, an absence of research that includes women prior 
to the early 1990s has left studies into women’s health largely in “catch-up” 
mode. Our guest is Judy Regensteiner, PhD, director and co-founder of the 
Ludeman Family Center for Women’s Health Research at the University of 
Colorado Anschutz Medical Campus. The center has become a national 
leader in conducting research across the span of women’s lives, especially 
in the areas of cardiovascular disease, diabetes and mental health.

Transcript

Chris Casey:

Welcome to Health Science Radio, where we talk with researchers at the University of Colorado Anschutz Medical Campus about the ways they are innovating and advancing healthcare. My name is Chris Casey, and I'm the Director of Digital Storytelling in the CU Anschutz Office of Communications. It's an honor and a pleasure, as always, to be joined by my co-pilot here, Dr. Thomas Flaig, our Vice Chancellor for Research.

Thomas Flaig:

It's always my pleasure to join you and be your co-pilot. Looking very much forward to our topic today.

Chris Casey:

Me as well. I believe we're at an even dozen episodes that you and I have hosted for the calendar year 2024, so here we are.

Thomas Flaig:

Here we are.

Chris Casey:

An even dozen, and we're finishing strong. This is a great topic today. We'll be talking about women's health and progress being made on women-specific research, especially in the areas of cardiovascular and diabetes treatments.

Our guest today is Dr. Judy Regensteiner, the director of the Ludeman Family Center for Women's Health Research, and Distinguished Professor of Medicine in the Divisions of Internal Medicine and Cardiology at the University of Colorado Anschutz Medical Campus. She holds the Judith and Joseph Wagner Chair in Women's Health Research.

Dr. Regensteiner's research expertise is in the cardiovascular effects of diabetes with a specific focus on women with type 2 diabetes, since they appear to have more significant abnormalities than men with diabetes. Her lab has been funded for over 30 years, and she has authored more than 190 research publications. She is also known for her research on peripheral arterial disease.

Dr. Regensteiner served two full terms on the National Institutes of Health's Advisory Committee on Research on Women's Health, and she is co-founder of the aforementioned Ludeman Center at the CU Anschutz campus. Judy, if we could start off, maybe you could tell us about how the Ludeman Family Center for Women's Health research come about, and what is its overall goal?

Judy Regensteiner:

The Ludeman Family Center for Women's Health Research was officially given Center status in 2004, so this is our 20th anniversary, which is really exciting.

Chris Casey:

That's wonderful.

Judy Regensteiner:

Before that, though, myself and two colleagues worked together to put together the Center, but it really got interesting when we were joined by Judy Wagner, whose name is on the chair that I hold, who was very interested in women's health, so she agreed to take us on. She was a philanthropist and a businesswoman, she still is, but she agreed to work with us to help develop a center. She had the business experience to help me get through those parts of developing a center, so I credit her with being a founder of the Center as well.

Since our founding, it's been really exciting to see what's happened. We started out with cardiovascular disease and diabetes as our main areas. In the last few years, we've added mental health, and so we have three major areas now, and we stay within our bounds, so to speak, but we do stray appropriately when, for instance, a rheumatologist might want to study the effects of rheumatoid arthritis on the heart. That would be a topic we could cover.

Our mission is to do the cutting-edge research in women's health across the lifespan in the areas of cardiovascular disease, diabetes and mental health. Also to train, mentor and retain young scientists, MDs and PhDs, in the area of women's health and sex differences research.

Finally, and no less important, is to educate the public and their healthcare providers about our findings, so that women's health is governed by evidence rather than anything else. Right now, there's a great lack of evidence in many areas of women's health, and so the Ludeman Center is here to fill in the important pieces of evidence and do a lot of really cool discovery, and get young scientists to enter the field.

Thomas Flaig:

Well, I would say that the Ludeman Center is a wonderful resource for the campus, for patients even nationally to recognize the work it's done. The other observation I would make is that, as I look at what's going on in research broadly, there's more and more focus on women's health research. You think about the White House initiative, ARPA-H. It's really wonderful to recognize that Ludeman's been around for 20 years. Do you agree that there is more awareness, funding and so forth for women's health research?

Judy Regensteiner:

That's a really good question. I do agree that there's more focus because there are centers like ours, People are studying women's health more, but we still don't have a ton of answers at this point to a lot of basic questions.

For instance, if you go in for blood pressure evaluation and you think your blood pressure is high and you're a woman, or you're a man of say the same age and general health status, you'll get the same treatment, whatever they find. We don't really know that the limits to blood pressure that are set for men are the same as those should be for women.

One big trial that was supposed to look at that called the SPRINT trial didn't enroll enough women, so there's a lot of that kind of thing. However, if you look back before 1993, women largely were not included in most research studies at all. They were excluded deliberately, for some mistaken notions of safety I think, about childrearing or childbearing. Sixty-year-old women are unlikely to be in that category, so that was mistaken, and it was completely not a good idea.

In 1993, the NIH had its Reauthorization Act that mandated that women must be included as well as people of color, who were also excluded 'til then. Since then, we have had research that has included women, but there's still a lot of catch-up to do, and a lot of clinical trials still don't include equal numbers of women and men. Lots of questions, but more interest in finding the answers, and not assuming that women's responses will be the same as men.

Chris Casey:

Digging into the specific areas in which you said that Ludeman Center does its research – cardiovascular, diabetes – it seems to be getting better, but usually when people think of a heart attack, they envision a man clutching his chest, falling to the ground kind of thing, but yet, cardiovascular disease is the number one killer of women. As your research has shown, it develops and presents differently in women than in men. Could you explain a little bit about how the symptoms of heart attacks differ in women, and what we've learned about how they differ?

Judy Regensteiner:

That's also a great question. Symptoms of heart attacks can be the same in men and women. Both sexes can get that crushing chest pain that will bring you quickly to the ED. If you think about it at all, why would you stay at home with that, but some people do. There also are symptoms that are less specific, such as jaw pain, neck pain, back pain, arm pain, that might occur more often in women, although they can also co-occur in men.

However, those symptoms ... which can also be like a flu-like symptom, so not very specific ... can be ignored, because people don't think of it as the classic heart symptoms, so then people don't go in. Women are less likely than men to seek help, even for that terrible chest pain. It is hard because the digestive system is also located in the general area, so people don't want to admit that they might be having a heart problem.

Also, there's still bias on the part of physicians even sometimes, who say, "Oh, you're a woman, you're not as likely to have heart disease," and that's just not true. Since we founded the Center, I have had women come to me who wanted to donate to the Center because their mothers died having sought help and been sent away, not even just once. There are people who have sought help and been helped also, but some people have died, and that struck me as really shocking.

I had an experience with an arrhythmia. My mother had an arrhythmia, a nonmalignant arrhythmia called superventricular tachycardia, and she called her doctor. She'd been having this uncomfortable symptom for four hours, and he said, "Oh, you're okay." This was definitely at probably a different time, but he didn't even examine her. She got a different doctor after that. It's like we got her a physician who actually examined her and sent her to a cardiologist, but it is pretty shocking that that type of bias still persists.

Thomas Flaig:

Think about raising awareness for differential presentation in women and men with cardiovascular disease, is the target audience patients, providers, or both, really?

Judy Regensteiner:

Absolutely both. Absolutely both. Patients and their providers have to be really aware that the symptoms that they're talking about can be pretty nonspecific, and that it's better to check it out. That's what I tell patients when I speak to a laypeople audience. I say, "If you're in doubt, check it out. No reputable ED is going to send you away saying you are full of nonsense if you come in saying, `I feel strange.' Check it out." We want everyone to know that.

We have an offering every spring. We have a women's health symposium which is targeted to providers, and the providers learn about the latest and greatest evidence in women's health. We want both the population, the public, and the providers to understand what it is that we need to look for.

Thomas Flaig:

I think it's a great message to get it checked out. Just a general observation I would make, that it seems there's a change in healthcare more recently where there's much more interaction via email, or this is a Zoom call or whatever, a telehealth, we just do this over it. I think the idea of seeing your providers is really an important thing. I feel a shift, which I don't necessarily think is good.

Judy Regensteiner:

You do.

Thomas Flaig:

Yeah, where people aren't coming in. They want to do a long exchange in the health record or do even a video call. Just seeing someone, going back to that fundamental idea to be examined and to look at people, we're maybe losing a little bit of that. It's an important message.

Judy Regensteiner:

Oh, that's so important. I think the role of the physician is absolutely instrumental in making sure that people get good health. Doing that by telehealth is not always the way to go, although it does have a valuable function.

Thomas Flaig:

There's a role, but it's not everything.

Chris Casey:

Judy, can you talk about what scientists have found likely contributes to this discrepancy ... poor health markers, more fat, less treatment, et cetera ... and define sex differences versus gender differences?

Judy Regensteiner:

Really excellent questions. Sex differences we define as biological or hormonal or genetic differences. XX versus XY is a sex difference. In contrast, gender differences relate to socio-cultural, psychological differences. We're just starting to learn really how to study sex and gender differences. It's really hard to disentangle the differences, but it's important to do so.

For instance, women are thought still to die more of breast cancer, for instance, than they do of heart disease. Breast cancer is a terrible disease. However, I think it's 10 times as many women die of heart disease, so there's that information that needs to come out. The reason for that, though, is related most likely to both the sex and gender differences.

For instance, sex differences could be that their plaque may develop differently in women and men – the plaque that causes the heart attack. My colleague Noel Bairey Merz from Cedars-Sinai says that the plaque develops in a lumpy-bumpy deposition along the artery and causes heart attacks (in women), whereas men may have a more central, large clot that forms.

Gender would argue, would tell you, that women often typically receive less care in terms of the medications and interventional procedures that would be used in men. They’re less likely to prescribe the same medications to prevent risk in women and they’re less likely to have interventional procedures, even though those medicines and procedures typically work as well in women as in men. Because of the bias of women not having heart disease, which isn’t true, women receive less care of that sort, and that’s gendered. Those are gendered variables rather than sex differences.

They conspire, the sex and gender variables together, to have women getting less treatment and potentially having worse outcomes. One of the reasons people think women may have less good outcomes is smaller blood vessels, for instance. That’s one factor that is undoubtedly a sex factor, a sex difference factor. Gender factors could include that your doctor doesn’t think you have heart disease, so you don’t get sent to the doctor or you don’t go to a cardiologist. Most of the time, I would say that sex and gender are both involved. Differences in sex and gender are both interwoven into what happens to people’s health.

Chris Casey:

In their overall healthcare, yeah.

Judy Regensteiner:

Right.

Thomas Flaig:

I think that's a really helpful example of the difference between sex- and gender-related. I think the word uses conspire sometimes to affect health.

Chris Casey:

Yeah. Poor cardiovascular disease outcomes are particularly true for women with diabetes, as I understand, which is also one of your focuses. Can you tell us about that area?

Judy Regensteiner: 

Sure. I've been working with my colleague, Dr. Jane Reusch, who's an endocrinologist, for the last many years, looking at the causes of why exercise performance is impaired in type 2 diabetes in both men and women, but more in women than in men. Why it's important to know about this is we measure performance at the maximal level and at submaximal level.

Most of us don't live at the max level. Much of the time we're not at max, in fact, almost all of the time. You say, ‘What difference does it make, for instance, if somebody can't exercise to a level 20% less than what people without diabetes can do?’ The difference is that maximal oxygen consumption, fitness, is very strongly correlated with mortality. The fact that you can't exercise as well leads to (effects on) your lifespan.

In addition, at submax, if you're unable to exercise at normal activities, you may end up not being able to live independently also, because functional range narrows with age. You may end up being less likely to live independently. I find that most people are actually even more concerned with living independently and having a good quality of life than quantity of life, although a lot of people would like both. That's why the work we're doing matters, and we're looking at the cardiac performance and the skeletal muscle performance.

What we discovered in one of our early studies is that women are more impaired with exercise than men. Why that's important, again, is that you might not live as long and you might not live as well if your exercise is more impaired, and women have a disadvantage in that area. People with type 2 diabetes die much more often of heart disease than people who don't have type 2 diabetes, and that's linked undoubtedly to the metabolic differences that occur with diabetes where your insulin isn't functioning right, your glucose isn't functioning right, and your insulin resistance isn't working right either. There's a lot of metabolic abnormalities, and they are very closely linked to cardiometabolic illness.

The other thing is that people with type 2 diabetes tend to be overweight and tend to be inactive, very inactive, as it turns out. You think about identifying problems in people's health, you also want to think about how to make it better. We propose exercise training and try to get people to exercise more, working through their physician, just because people sometimes listen to their physician. A lot of times they don't listen to anybody, but sometimes the physician can make a difference. We work in a lot of directions, with technology to try to get people to exercise more. It's not easy, but it's really important.

Sometimes you get people who do it and they're really happy when they do it. I was involved in an NIH multicenter trial years ago, the Diabetes Prevention Program, and I gave talks to patients now and again. One older lady said to me, "Well, I called my grandson and said, `Do you want to take a walk with Nana?'" He, to her shock and surprise, an eight-year-old boy, said, "Yes," so they started walking and kept walking, so that helped them both.

Thomas Flaig:

When we think about cardiometabolic changes and diabetes, I hear questions about pregnancy and the impact of those. Does pregnancy unmask underlying issues, or does it actually contribute to some of the potential comorbidity of these metabolic changes?

Judy Regensteiner:

Both. Pregnancy is a stress test, in a lot of ways for a lot of health issues. For instance, there's gestational diabetes, which happens in some pregnant women, which is strongly linked to the development of type 2 diabetes. It's not a benign thing that happens during pregnancy. It's something that can suggest that there are metabolic abnormalities, and the abnormalities can affect the baby as well.

Pregnancy itself is considered a stress test, and it's one of the least well-understood conditions because people are still very reluctant to study pregnant women, and yet if we don't have answers for pregnant women, it really compromises safety at some level. That's an area that's still very difficult to approach, and for understandable reasons. Nobody wants to do harm to a pregnant woman or her baby, but still, how do we figure out the answers so that pregnant women are treated with evidence as well?

Thomas Flaig:

That's such an important point, right? There's an area of medical need, but because of the other concerns, people may shy away from that, when it actually becomes an even a bigger area of need because people have done that over time. It's an important point.

Chris Casey:

Another stress test area for women, I guess, could be said is menopause, right, because it's an inevitability and also an understudied condition or time phase of a woman's life. What could be said about what's been learned as far as heart disease risk and menopause, and maybe the risks of heart disease associated with menopause may be starting earlier than once thought, or maybe there's something to do with the hot flashes, et cetera?

Judy Regensteiner:

Well, menopause is a time where, either because of age or hormonal change – and it's not exactly clear what's driving what yet in those areas – that women start having more heart attacks. Normally, if you're a woman who does not have diabetes, you will have fewer heart attacks than men up until the time of the menopause, where women then catch up. Except if you have type 2 diabetes, you start having heart attacks younger, even if you're a woman. Normally there does appear to be some protection against cardiovascular disease before the menopause, and then after the menopause, heart disease starts making its mark more. Again, in diabetes that happens earlier.

Thomas Flaig:

There is a prevalence of seeing diabetes rise in patients who are younger and younger these days. Is that not correct?

Judy Regensteiner:

That is correct, and that's a really interesting point. The Center studies diabetes across the lifespan, as we also study cardiovascular disease and mental health across the lifespan. We work with pediatricians, some of our Ludeman Center scientists who are pediatricians, and they have found that there's an increase in type 2 diabetes in youth. By youth I mean teenagers, 15 years old.

We've done some collaborative work with colleagues such as Dr. Kristen Nadeau, pediatric endocrinologist, and found that the same abnormalities and exercise capacity that we see in adults, who are 30 to 50 years old in our studies, we see in teenagers. That's kind of scary, because we have found associated heart disease in adults that's associated with the type 2 diabetes, and are teenagers going to start having heart attacks? The thinking is they will have them younger, but we of course want to prevent this.

Chris Casey:

We could shift gears a bit to talk about some of the research that's being done in this area, and specifically at the Ludeman Center. Do you want to comment on maybe some of the major research initiatives or areas of focus that you have right now?

Judy Regensteiner:

Well, we do work on diabetes and cardiovascular disease. We have a cadre of researchers who are in the field of endocrinology or in study exercise, and a large number of us are doing that type of research. We also have a large group studying PCOS, polycystic ovary syndrome, which Dr. Melanie Cree, who's a pediatrician at Children's Hospital, she's put together a group which includes several Ludeman Center scientists. Dr. Noy Phimphasone-Brady, who's a psychologist, is in that group. I love the way mental health is finally being woven into research, because it wasn't for a long time. That group, though, is trying to deliver multidisciplinary care and look at possible treatments for PCOS, which affects 10 to 12% of women but is pretty much not well treated.

Chris Casey:

Are there some research areas that you think, nationally and globally, of as areas where there's additional work needed, perhaps by the Ludeman Center, other groups in the country, in terms of women's health?

Judy Regensteiner:

Well, menopause is a big topic of focus. We have Dr. Wendy Kohrt, Dr. Kerrie Moreau and many others, who are studying the menopause and actually making good inroads.

I participated as a co-chair of an NSF-NIH conference where we brought together informaticists and those who study the menopause, you could just see fertile grounds for networking and working together and developing more studies, which we'll use AI to examine questions that arise with the menopause. There are also good questions in mental health.

In cardiovascular disease, we're looking at why women have heart attacks earlier and what are the risk factors. A whole new set of risk factors is emerging which you may have heard about, including endometriosis, including early menarche, early menopause, just a lot of questions, and a lot of frightening new risk factors that we have so much to learn about. Ludeman Center is excited and interested in many of these.

Thomas Flaig:

One area that I hear more about is implementation science and taking these findings. I think those of us in universities are focused very much on the discovery, but it's implementing that to patients, providers and so forth. Is that an area that you think is fruitful in this, and are you or others working in that area?

Judy Regensteiner:

Dr. Amy Huebschmann, who is one of our senior scientists, who is an amazing scientist, is working avidly and successfully in that field, and she is mentoring people who are interested in that field as well, so some Ludeman center scientists. We all love the mentoring piece of what we do. That's a huge part of it. It's the second part of our mission, is we all do a lot of mentoring, and the mentoring leads to development in the field. Amy's one of the best mentors I know, and so we're growing in all our areas.

Thomas Flaig:

Yeah, I think as we talked about this at the beginning, making sure the providers have the latest information, patients who can actually influence those providers to their own care or pick the right provider is really critical. Integrating that new knowledge into the practice of medicine, which I'm always shocked at how difficult that is, for me personally and just the field. When we have new discoveries, we've got a certain way of practicing. It's really a critical area.

Judy Regensteiner:

It really is. Getting the word out to the public is a key part of what we do, and we have programs. The Let's Talk series that we partner with UCHealth in doing, where we have UCHealth physicians who are also mostly scientists giving talks to the public in a particular area, like sleep. Sleep was our most recent one, and that's really interesting. It's such a problem for everybody, but women more than men.

Thomas Flaig:

It's great too to hear about the multidisciplinary approach that much of this work is taking, informaticists, clinicians, basic scientists. I've watched the work at the Ludeman Center, and I think you're really a shining example of bringing together groups of people that solve problems.

Judy Regensteiner:

It's really fun, and the team science approach is so collegial, so collaborative, and also extremely productive.

Chris Casey:

Talking about that collegial and collaborative approach, you mentioned it at the beginning, Judy, about a lifespan approach. Could you expand on what you mean by a lifespan approach for women's health?

Judy Regensteiner:

Absolutely. Well, women don't start out as women. They start out as girls. Just so you know, because we do a lot of sex difference research, we also study boys and men. We start with even OB-GYN. We have some researchers who are studying, like Dr. (Nanette) Santoro, some of her scientists or our scientists, and they study what happens in the womb, which can affect you for your whole life, looking at that properly. What happens in the womb is very important, and behavior by the pregnant mother and by the whole family is really important.

We start in the womb and even before, and go through the pediatrician's focus on boys and girls and some of the differences. The girls develop type 2 diabetes more than boys – teenage girls. Why that is, we're not sure of yet. There's lots of questions, as you can imagine. Then going through to women, premenopausal – the menopausal transition is the premenopause – the menopause, and the postmenopause, and then through to old age. We're covering the whole lifespan and we're learning so much. I mean, we have researchers that focus on Alzheimer's disease, since we do focus on mental and brain health.

Chris Casey:

You've touched on this already, but are we starting to see some women-specific research that's resulting in some breakthrough treatments in the cardiovascular, diabetes realm?

Judy Regensteiner:

Well, I will tell you that most care is still delivered non-sex-specifically. The guidelines are not there, but we are working now on the guidelines. For instance, Amy Huebschmann and I, along with an early career physician scientist, Dr. Stacey Trent, who's at Denver Health, and Dr. Larry Allen in cardiology, did a study looking at troponins, which is a protein that's measured when you go in the hospital. To see if you're having a heart attack, they measure that, and the values by which you would say, "Yes, I think it's likely there's a heart attack," were the same in women and men. Turns out they shouldn't have been, that the values should be lower in women than in men. We published on that, and now the guidelines, I think at UCHealth, have changed to reflect that. That's exciting.

We just worked on a paper with Dr. Dave Kao, because there are men who study women's health and sex differences research such as Dr. David Kao, who's a cardiologist and informaticist. He wrote a paper, and 17 million people – which believe me, I had never studied 17 million people before. Most of my studies are 30 per group, big groups in physiology research. Dr. Kao and I just published a paper which he led looking at the fact that in 17 million people that women receiving statins – certain statins, we don't know if it's all statins – are more likely to develop diabetes than men. That's scary, because statins are a major, major drug, one of the most common drugs prescribed to prevent high cholesterol.

Chris Casey:

As you think about making additional advances in this area, one of the key things is the next generation of researchers and providers. I think you mentioned earlier that for the Ludeman Center, mentorship is one of your key principles. Do you want to talk more about the work and how important you think that might be for what we're talking about here?

Judy Regensteiner:

Well, in any field, if you don't have people to do the research, it's not going to do so well. Also, you have to have physicians, who bring the viewpoint of a physician and clinical care as well. It's really critical to have physician-scientists as well as PhD scientists. We have mentored, I believe, 104 early-career scientists, MDs and PhDs, over the life of the Center. We've provided funding through peer review, C-grant funding, and then we follow the careers of many of these scientists, and hopefully getting them into the field of women's health, sex differences research. I think we've been pretty successful. We're always looking at metrics to see that we're doing things right.

I'm also the principal investigator of a grant called the Building Interdisciplinary Research Careers in Women's Health Grant, which is an NIH training grant for young faculty, early-career faculty. That program has been very successful as well. The Ludeman Center has developed its own partner program called Women's Health Innovation Scholars, because we are really interested in bringing our findings to innovation, to point of care for patients. We have a lot of mechanisms of mentoring, and we have seven senior scientists and then many other scientists. Everyone loves mentoring and are good mentors, so it's very rewarding.

Thomas Flaig:

It must be rewarding, because of how expansive and open-ended and under-researched this whole area has been over these years. I mean, it must be like opening a door to just all sorts of possibilities.

Judy Regensteiner:

Yeah. It's both exhausting and exhilarating, because there isn't much known. The more you get into the field, you realize we haven't even identified all the sex differences by any means. We have to not only identify them, but understand why they are doing what they're doing, and understand the sex and gender differences. There's so much work, but it's exhilarating because we have the opportunity to do this exciting work, and that's just thrilling.

Chris Casey:

Do you have any further questions?

Thomas Flaig:

Yeah. Your passion for this field is remarkable, I think. The impact of the Ludeman Center for 20 years – mentorship, research applications – it's really remarkable, and it's great to be able to celebrate the 20th anniversary. Thanks for mentioning that. What are your personal hopes for women's health research? If we look ahead to five years, what are your hopes for where we'll be?

Judy Regensteiner:

Well, that more risk factors are treated. I mean, my field is cardiovascular and diabetes, but the risk factors for cardiovascular disease, I feel like if there is good research that's ongoing – and some of that has to be epidemiologic research, and it can't all be small lab studies – but I'd like to see that more of the risk factors are treated based on evidence, and that evidence needs to be sex-specific in a lot of cases. Probably not in every case, but in many cases. There's the whole issue of medications. Are they the same, are they different? Does it make sense to have one dose when men are bigger than women? I mean, it's just so many questions. I'd like to see some of those questions answered.

Chris Casey:

Well, terrific, Judy. Thank you so much for sharing your insights and doing the work that you're doing with your team at the Ludeman Center. I think it's incredible, and as we've touched on, barely touched on, there's so much here yet to explore. Thank you very much for joining us today.

Judy Regensteiner:

Thank you. It's really been my pleasure.

Chris Casey:

Ours as well. Thank you.

Thomas Flaig:

Thank you.