The PCOS and Inflammation Link- the Latest Research [Podcast]

Millions of women around the world struggle with PCOS.  That number would make you think that PCOS research would be popular and well funded.  For many reasons, this is not the case.  The good news is that research physician Dr. Frank González and many who share his passion are undertaking research right now that will change the lives of women with PCOS.

Dr. Gonzalez is studying the link between PCOS and inflammation. We know that inflammation is the underpinning of most major diseases and health problems (cancer, diabetes, heart attack, stroke). Now we can add PCOS to the list. Listen in as Dr. Gonzalez explains

• the “epigenetic phenomenon” that leads an overweight mother to predispose her fetus to obesity for their lifetime
• the effect of inflammation on ovarian dysfunction
• how to reverse the damage inflammation has caused already and prevent new damage
• his research on asprin-like drugs on PCOS and inflammation
• the usefulness of natural anti-inflammatories (like ginger)

A complete transcript follows.

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Dr. Frank González, MD, is an Associate Professor of Obstetrics and Gynecology in the Division of Reproductive Endocrinology and Infertility at Indiana University School of Medicine. He received his bachelor’s degree in Biochemistry and Molecular Biology from Harvard University and MD degree from Temple University School of Medicine. He trained in Obstetrics and Gynecology at the University of Rochester and the Rochester General Hospital, and in Reproductive Endocrinology at University Hospitals of Cleveland. Dr. González is a physician scientist who received formal research training as a U.S. National Institutes of Health (NIH)-sponsored Women’s Reproductive Health Research scholar. He previously held faculty appointments at Case Western Reserve University, State University of New York at Buffalo and Mayo Clinic.

Dr. González’s laboratory investigates the mechanisms by which dietary components such as carbohydrates and saturated fat trigger inflammation, and male hormones alter the immune system, which ultimately leads to ovarian malfunction, insulin resistance, reduced pancreatic function and blood vessel cholesterol accumulation in women with PCOS. His translational approach combines the direct study of humans in a clinical research center setting with basic research techniques that evaluate inflammation at the molecular level in a laboratory setting. Dr. González spearheads the focus by combining his clinical expertise in the care of women with PCOS, and his knowledge of clinical study design, endocrine and metabolic dynamic testing, and human subject recruitment with his formal training to oversee a basic research laboratory and troubleshoot basic research techniques.
Findings stemming from Dr. González’s laboratory are presented regularly at national and international scientific meetings, and have led to over 135 publications that have established a well-recognized brand among investigators in the field of androgen excess. He has furthered the brand by chairing national postgraduate courses that educate piers by translating research findings from his laboratory into clinical management. Dr. González is currently studying the effects of reducing inflammation with medication to lower ovarian male hormone production and induce ovulation in women with PCOS, with the aid of forthcoming NIH funding for this venture.

Transcript:

Amy Medling: Hello and welcome to another edition of the PCOS Diva podcast. I am Amy Medling, I am your host. I am the founder of PCOS Diva and a certified health coach. I am so excited to be here with today’s guest. We are going to be speaking with a physician scientist. This doctor is really on the forefront of PCOS research. I hear from so many women who feel very alienated and they feel like the medical community is not doing enough to help them with their PCOS but I want to highlight doctors like Dr. Frank Gonzalez who is going to be speaking with us today to show you that there really are men and women out there that are working every day on our behalf. Thank you, Dr. Gonzalez for being with us today and welcome.

Dr. Gonzalez:                     It’s my pleasure and hopefully I can be of help.

Amy Medling:                    I want to just introduce you to the audience, tell everybody a little bit about you. Dr. Frank Gonzalez is an Associate Professor of Obstetrics and Gynecology in the Division of Reproductive Endocrinology and Infertility at Indiana University School of Medicine. He received his bachelor’s degree in biochemistry and molecular biology from Harvard University and an MD degree from Temple University School of Medicine. He trained in obstetrics and gynecology at the University of Rochester and Rochester General Hospital. You are, as I mentioned a physician scientist and you’ve received formal research training as a US National Institute of Health sponsored Reproductive Women’s Health Research scholar. Boy, that was a mouthful.

I actually just listened to you present of your latest research at the Association of Reproductive Medicine Conference, ASRM. It was held last week in Baltimore. You were speaking about PCOS AND inflammation and I thought it would be great to have you on to kind of talk about what you’ve been doing with your research. I think that a lot of us think of PCOS and insulin. We’re constantly hearing about that connection between PCOS and insulin resistance. I think for many of us, the thought of PCOS being kind of this pro inflammatory state is somewhat new. Maybe you could shed some light for us.

Dr. Gonzalez:                     No problem. I’ve been working quietly for the past decade or more to bring forward this field which emanates from work in other parts of science and medicine realizing maybe early on from the work of others who I have been fortunate enough to become friends and colleagues where we could sit across the table on a regular basis and just enjoy talking to each other about medicine and science. Inflammation is actually the underpinning of most major diseases. PCOS in itself is not a disease, it’s a conglomeration of signs and symptoms that we’ve yet to completely understand. Yet, it has certain aspects that come into play that funnel into some of these major diseases. Inflammation is the underpinning of cancer, diabetes, heart attack, stroke.

Conversations with those individuals who really started to study inflammation of those major diseases, it became apparent to me that maybe PCOS also would be one of those issues in medicine in which inflammation has a contribution. This was back in the very late 90s that we started this and we published the first paper, Inflammation in PCOS back in 1999. As a clinician seeing patients every day, it was like a light turned on and with the assistance of these, you could say really experienced clinicians and researcher, I got what I needed to get started. The passion has always been there but the need to learn more and gather the formal research training to follow that initial lead that turned the light on. This has been going on a long time. I just want you to know that it made sense to me once we saw our results in PCOS and with the general knowledge that inflammation really has a play in all medical problems. We went on and looked at molecular pathways pertaining to inflammation and the most important thing is realizing that the underpinning of insulin resistance is inflammation.

The most common cause of insulin resistance that we see nowadays is being overweight and there is known cellular and molecular mechanisms that have been studied at length. I used that information and what I knew about PCOS for many years taking care of patients to say how does it apply to PCOS because being overweight in PCOS creates a worsening of signs and symptoms but they are separate issues. Many had the idea that well, if you have PCOS that goes along with being overweight. Truth of the matter is, overweight people are present whether they have PCOS or not. It’s just if you’re overweight in PCOS, it makes PCOS worse. Women with PCOS may be more prone to weight gain but I don’t know that we have any clear mechanism on how that is a for sure. We just have statistics to say there are more overweight women with PCOS.

The truth of the matter is in speaking with researchers who are you could say in the twilight of their careers who began studying PCOS in our era, early ’60s ’70s, they will testify to say that the study subjects in their studies that they had are not the same study subjects that may present regularly to our clinics today. I think that the impact of the environment and an increase in obesity related to what happens in the uterus has increased that. If you go to other parts of the world where there are different environmental and genetic factors where there is less overweight, you will find what I think other researchers mentioned years ago still exist today. There is a lot to know in studying PCOS how to try root out the answers. I’ve come up with seeing that inflammation really feeds into many of the things … I just tried to put together the links of things that have been discussed and are the concerns including insulin resistance to both patients and physicians who take care of women with PCOS.

Amy Medling:                    When you’re talking about environmental factors, I know from my own personal experience and women that I coach, changing their diet and kind of weeding out the inflammatory-type foods and for me personally I know that’s gluten and dairy. Eating more anti-inflammatory foods, vegetables and healthy oils and clean animal protein has really made a tremendous difference in my symptoms for PCOS. Have you looked at any studies with diet changes and inflammation in PCOS or is that something that might be on the horizon?

Dr. Gonzalez:                     What I would say is that from personal experience in caring for patients, many of whom need to find an appropriate to lose weight, to improve their signs and symptoms, and to help them conceive, I’ve come to realize that enmeshed in this issue of inflammation and insulin resistance is the fact that women with PCOS have a very sensitive metabolism. They need to eat in a very healthy fashion. Really, if you go back over a hundred years ago, the foods that are available today as normal in your supermarket are not what people used to eat and so we have seen changes. PCOS is an ancient disorder, it’s been around for 2,000 years but the presentation of PCOS has changed.

With regards to what has been studied in diets and PCOS, it’s still in its infancy. I think we all understand that trying to achieve and maintain a normal weight, whatever way possible is better than not. Because we have a pandemic, pandemic means that it’s worldwide of overweight individuals in this world in industrialized countries, we wonder what did it and we’ve come to realize it’s really … You want to say environmental factors, it’s more like what’s going on with fetal exposure to metabolism that’s not completely healthy if you’re overweight and become pregnant. You could say that we’ve had an up shoot of overweight individuals who have conceived, and then in subsequent generations we’re seeing what happened during the offspring’s time in the uterus.

There are animal studies that have clearly shown it and that it’s reversible. We also have human studies to support it. I hope that I’m answering your question. I have not given you specifics as to what diets are preferable anti-inflammatory. I can give you my input because I lean on those experts in nutrition. A lot of what I do looks at dietary components and what is pro-inflammatory, what promotes inflammation but really it all falls in the realm of metabolism. Understanding that it’s important to eat in a healthy fashion and exercise in order to maintain a healthy weight for all humans but especially for women with PCOS. I have tried various things but I have also listened the obesity and bariatric society’s protocols for weight loss and weight maintenance. Right now what’s being promoted is the ketogenic diet and I’m not saying that’s the end all for women with PCOS.

We really don’t have really large definitive studies but I know that in general for humans who are insulin resistant and inflamed because inflammation is really what leads to insulin resistance, particularly in overweight individuals that limiting pro-inflammatory things like sugars in particular will flip the switch to instead burn what’s already present as energy in our adipose tissue compartment. That’s what I do clinically. I don’t know that I give you specifics, eat this or eat that but I can tell you that you can flip the switch metabolically and then saw automatically from an inflammatory point of view, if you need to maintain and lose weight by avoiding excesses of starches and processed foods, which are commonplace in the American or industrialized country diet. When you grow up with foods that seem normal but they exist years ago, we’ve had a natural progression in weight and American women are 16 pounds heavier than they were 16 years ago and that’s just been a progressive phenomenon based on what food is present in the supermarket without clarity.

It’s coming to bear now because we are trying to reverse that effect. I would say the medical community is now more attuned than they were 20 years ago. I don’t know if that answers your question clearly because I’m not going to tell you eat this is better for inflammation versus that. I think that I’ll stick to general concepts and what’s being done today to lose and maintain weight and why. From a metabolic point of view, which really means what is metabolism? The foods we eat and how our body processes them for energy. There’s carbohydrates, fats, and proteins. It just so happens that the complex carbohydrates in PCOS, especially if you’re overweight may be not the first thing to ingest on a regular basis if you need to lose and maintain weight. Using that approach, I have had wonderful success in improving fertility without even needing medicines. We also have wonderful medicines that can assist if need be. The individual woman with PCOS has separate needs depending on what’s going on with them at the time they present for whatever sign and symptoms whether it be an issue of fertility or other things that present.

Amy Medling:                    I think the takeaways here are that it is reversible for women it’s showing in animal studies and in human studies and you said that sugar and simple carbohydrates are very pro inflammatory and kind of feeding those flames of inflammation in PCOS and it’s important to avoid those.

Dr. Gonzalez:                     The issue of being overweight is definitely reversible so I’m just filling the blank. Obviously, it’s not easy to lose weight but there is an approach. I was referring to the modern phenomena of an increase in being overweight in the population of this world in industrialized countries. There has been a huge upsurge starting in the ’90s that has come to the realization of the medical community as the need to try to change that and studies have begun. I just presented to you, it’s called the epigenetic phenomenon of being prone to gaining weight because of a change in metabolism when you’re an embryo because your mother was overweight when she was pregnant. That phenomena permanently affects the next generation but it’s reversible if that next generation can get pregnant at a healthy weight.

There was a study done in humans in women who were overweight. They either went through bariatric surgery and I’m not recommending that that’s the first line, it’s simply a study in women who were candidates of bariatric surgery. Half went through the surgery, the other half didn’t. When both groups conceived and followed the children, the children who had lost weight and bariatric surgery was a tool because they were candidates, the next generation had a significantly lower number of children who became overweight around adolescence in comparison to those who conceived without having lost the weight.

It kind of carries through from the animal studies that have shown that this is an epigenetic phenomena. A phenomena in which the genes of a body that are normal are silenced that are needed for a healthy metabolism. The animal studies now show that if the affected offspring who became overweight as a result of what happened to them in utero were given a healthy diet and you could opportunity to have regular physical activity if they were female offspring and conceived at a lower weight because they were given the appropriate lifestyle change, the next generation that wasn’t observed. That’s what I meant about reversibility. Being overweight is reversible but it requires that we eat like we did many years ago, not the modern common diet in which many things are not healthy for us.

If you go to the supermarket, this is just a general adage I tell patients, you want to eat food that’s around the edges of the supermarket rather than in the aisles in the middle. Many of the things in the middle, that’s just a generalization, are in boxes and cans and unfortunately they’re preserved with sugars, which are not useful. I also recommend eating fresh. I think in the process of saying not simple carbohydrates, starches are complex. Sugars and starches are complex carbohydrates are what I’m saying lead to more inflammation in the long run. Insulin resistant individuals have to mount a greater insulin response from their pancreas. If they eat a starch, their pancreas has to secrete more insulin in order to store it because the normal amounts of insulin are insufficient in insulin resistant individuals. That extra insulin converts the start to individual fat molecules that are then stored in adipose tissue. With that in mind, most overweight individuals are insulin resistant whether they have PCOS or not.

What is interesting in PCOS is that we see insulin resistance in normal weight individuals but there are many women with PCOS who don’t have insulin resistance as well and it’s almost as if everybody is lumped into one category. What I would say is if you have PCOS, you want to work your best to try to maintain a healthy weight and avoid becoming insulin resistant from gaining weight. There are some ethnic groups who this is probably of genetic origin that they’re automatically insulin resistant. You see many south central Asians who their body composition in general has more body fat and that may contribute to it but that’s not 100% clear. Just the same, there are some normal weight individuals who are insulin resistant whether they have PCOS or not but especially if they have PCOS based on their ethnicity and I gave you one example.

Then again, insulin resistance is not necessarily present in all women with PCOS. From my experience even though we don’t have a clear prevalent study on insulin resistance strictly in normal weight women with PCOS, there are many who don’t. The prevalent studies that exist to date say that as many as half don’t or more and in general they’re lumped together of all weights. They run the spectrum of weight with a prevalence of insulin resistance of about 30-50% of all women with PCOS but we don’t have a clear study dividing them separately to say only in normal weight want’s the percentage. Yet in general, I would say that many are not.

Insulin resistance is still something to be aware of but the underpinning is inflammation from all the studies that have been done in humans. The mechanisms for insulin resistance may not be unique to PCOS despite what maybe has been published in the past in you could say pieces. We don’t have the entire piece. I hope that helps. I think that inflammation is present in PCOS not just from myself but from many other studies even though you could say I started thinking about in the late ’90s and maybe published the first papers but not at the molecular level until I decided to get more training to understand the molecular pathway. Even if you don’t have insulin resistance, we still see inflammation in PCOS.

That was the data that I presented at the recent American Society for Reproductive Medicine Meeting. We treated women with an aspirin-like medicine to see if we could reverse the inflammation we had known was present in normal weight women with PCOS and in women who were overweight with PCOS but we focused on the normal weight individuals who were insulin resistant who we had seen were inflamed from previous studies to see if treating with an aspirin-like drug would reverse the inflammation and improve ovarian function. That is what our data showed and that’s what we presented. As a result of that data, we were able to you could say, most recently heard that we had some government funding to pursue this further.

Amy Medling:                    Great, great. I think the inflammation as your saying is impacting the insulin resistance. Is the inflammation impacting in the lean women that don’t have the insulin resistance, does it seem to be impacting the ovarian dysfunction as well.

Dr. Gonzalez:                     That’s what I was referring to. You could say we put together, we meaning those of us who talk about this all the time but you could say I talk to lots of individuals, I talk to my patients, I talk to scientists, I talk to clinical doctors, I read all types of journals from nature and science which are high basic to throw away journals, articles from 30 years ago that nobody could make sense of and putting it all together. It made sense that there may be some molecular mechanisms within the ovary which would allow inflammation to change ovarian function towards making more male hormone and stopping ovulation. At the meeting, I presented some of that data.

It was putting all the pieces together to say gee, is there a molecular basis by how inflammation can do this. We first started by characterizing or determining whether we could see inflammation in women with PCOS in our first studies. We put it on the map at the molecular level simply by saying, gee certain dietary components have been shown to up regulate or increase inflammation in individuals who were described to be inflamed, mostly in overweight individuals, not in the PCOS community.

Then I thought, gee those individuals have inflammation and insulin resistance and they’ve shown the molecular connection on how inflammation leads to insulin resistance in overweight individuals and we found evidence of inflammation in women with PCOS of all weight classes, even in normal weight. Well gee, is it the underpinning of insulin resistance? Oh my goodness, some individuals don’t even have insulin resistance and we see inflammation. Gee, what’s causing the ovary to malfunction? What information is there in the scientific world that might support that? I was able to find it to say gee, it’s worth going further based on this information that some of which has been sitting there for years to try to reverse what we found in our early studies to see if we could reverse the pathways we found might be involved and then what do we see clinically, the outcome. We actually see a decline in the output of male hormone from the ovary with the measurements that we know how to do in research. Do we see any improvements clinically that would be important for women like ovulation?

My study is the first but it’s early and that’s why we have the funding to say, is this really true on a large scale? The way you do that is in a controlled randomized study with enough patients to have enough scientific and statistical significance. Our pilot project sounds great but I’m the first one as a researcher to know that gee, in order to say this is definitive … Yet, it’s all been leading in that direction over the years. I told you that Aldo has come to the forefront most recently. In started in a room discussing the possibilities years ago and with the desire to know more, to get the training to explore it further at a higher level. How many years ago was that and where are we now? At least 18 years worth of the process before we actually have where we’re at know that you saw at the meeting.

Amy Medling:                    A lot of work has gone into this but it’s just so fascination. This next study, will you be looking at the same aspirin-like anti-inflammatory in this larger group study?

Dr. Gonzalez:                     There’s a story to that. Just so you know, the answer is yes because that seemed to be a useful tool. The verdict is out yet whether that will be the best medication to use for women on a regular basis and I’m not recommending that. This particular aspirin lytera has been studied extensively in a diabetes trial to see if it would improve blood sugars. We’ve known for a hundred years that aspirin-like drugs lower blood sugar but no one can give aspirin at the doses required, higher doses. No one would be able to do it because high doses of aspirin can lead to ulcers in the stomach and bleeding. Many years ago, about 30 years ago they came up with a medicine for individuals with rheumatoid arthritis that need a high-dose aspirin to improve joint inflammation and pain and that by combining two molecules of salicylic acid and a result of it combining the two molecules together because aspirin is not a combined molecule, it bypasses the stomach and therefore you don’t end up with the bleeding.

This multi-center study that was done was possible because they used that medicine, an old medicine used in rheumatoid arthritis that’s been available and extensively evaluated for tolerability and safety. Unfortunately, it didn’t seem to have tremendous results in improving diabetes. But I saw that it reversed the molecular pathway I was interested in and found that was relevant in PCOS. I’m not using it to reverse diabetes, I’m using it as a very potent medicine reduce inflammation in a very, very you could say significant way. I’m just saying it’s a potent inhibitor of the molecular pathways that promote inflammation to see what it does. Most of the patients with PCOS don’t have diabetes even though many are prone. My studies are really to try to understand the features, the hallmark problems that are confronted, particularly the ovarian malfunction that leads to infertility and leads to the excessive hair and acne, etc.

Amy Medling:                    Gosh, it’s been a long time in the works and I’m so glad that you’ve got the funding and you can continue down this path. We’ll be excited to see what the future has in store. It definitely makes me wonder thought about like natural anti-inflammatory agents like curcumin and ginger and whether those would be of value for women with PCOS.

Dr. Gonzalez:                     What I would say is obviously there are early pilot studies looking at some of those things in PCOS suggesting that that’s the case. What I advise patients to do is what is generally effective for what’s being observed in specific problem, how does it relate to PCOS and what things can be considered even if we don’t have large studies that do no harm but may be helpful. I would be the first to say that we don’t have large studies to prove these but whatever has been done, doesn’t do any harm. When you look at the world of nutrition and what’s been done without studies for thousands of years that seem to lead to longevity, it may make sense.

I’m not necessarily pushing medicines before a healthy diet and exercise. The truth is, that is the heart of keeping humans healthy especially women with PCOS who have a very sensitive metabolism that you could say is pushed awry by inflammation at the molecular level and as I’ve shown in my studies driven by dietary components. My answer to you, what do I think of those? I don’t think they do any harm. We have early studies that say, hey they may help. We don’t have definitive studies but we have thousands of years where these things have been used and people live longer. I just know that it is important to gather scientific data now that we know enough to make sure how could we be very discerning rather than general because we actually have scientific information for what we suspect may be useful.

Amy Medling:                    It’s just great to know that we’re understanding more about the inner workings of PCOS. We’re coming to a close but I want to ask you as a clinician and as a PCOS researcher and scientist, give us a word of hope for women with PCOS. Leave us with a word of hope.

Dr. Gonzalez:                     No doubt, I can tell you from personal experience this, there are humans you could say researchers who have a passion for PCOS. I gave you my story. You met me today but I’ve been doing this for a number of years, it takes a while. There are those people who are dedicated to try to understand what is going on. There are doctors who indeed have great passion for understanding why their patients have what they have and that we don’t know enough from what’s in the textbooks. Not just out of curiosity but simply out of compassion for our patients knowing what are we offering them and how can we do more? There are individuals out there and there’s a group of us who are actively on the trail to try to understand. We’re working hard at it but it doesn’t happen overnight.

The second thing I would say is I would tell this to any person, eating healthy and exercise is key to staying healthy and it applies to women with PCOS as well, especially to them. Many of the things that are described that they may be at risk for may be avoidable by eating healthy and exercise. It is true that sometimes finding the right physician to advise them in their care may not always be the first physician they meet. In our world that has become so sophisticated and we know so much more, I’m the first to admit that I couldn’t do neurosurgery and that I may not know everything that’s going on in neurosurgery, I try to find the person that may help them.

The first doctor I may meet may not be the one that knows everything. You could say that there are those individuals who do know and any advice given along the way may be from general knowledge but there are physicians who do know and it’s just being led to the right person in this sophisticated world where one physician may not know everything. I’m the first one to admit that. The word of hope is that really eating right, exercising, keeping a healthy lifestyle, you may avoid all of the things that are always described in textbooks that someone is at risk for. Most women with PCOS if they can follow that will eventually complete their family and avoid the worst of signs and symptoms that are described. That’s my word of hope. From my experience, most individuals with PCOS really do okay in general and what drives it is what would drive the need for every human to take care of their bodies, diet and exercise.

Amy Medling:                    Amen. You are so on point. Dr. Gonzalez, I just want to thank you and behalf of women with PCOS thank you for all the time and years of dedication and research and work that you’ve done for us. Thank you.

Dr. Gonzalez:                     Once again, it’s my pleasure and it’s my personal passion. It’s what helps me get up in the morning to deal with the all the stressors just to get to this point.

Amy Medling:                    We are very thankful and have a lot of gratitude. I just want to thank everyone for listening and I will look forward to being with you again next time.