Pape: Hi. I’m Joy Pape with Diabetes in Control and we’re here in Boston at AACE 2018. And I have to say, I’m so excited to be talking to Dr. Cobin. She’s going to be talking about PCOS, a subject so near and dear to my heart. I’m going to go no further than just getting to asking you some questions.
Pape: Why is PCOS a concern for diabetes general medicine community?
Cobin: Well Joy, the main reason it’s such great concern to the general medical community, not just to obstetricians and gynecologists, is that PCOS, first of all, is the most common endocrine disorder of women of the reproductive age. And secondly, besides its frequency, it’s a serious illness and it’s associated with very serious consequences that are not simply reproductive or cosmetic. PCOS is very highly associated with type 2 diabetes, impaired fasting glucose, impaired glucose tolerance, metabolic syndrome which has many consequences, and finally, even cardiovascular risk. So, over the years as we’ve been looking at PCOS in this large population of women, we’re seeing even from a rather young age increased risk, increased components of the metabolic syndrome, increased risk of impaired fasting glucose that then can progress to full blown diabetes. So, how many people are we talking about? The last time I talked to you about this, there was a census in 2000, since then the 2010 census has actually found more women of reproductive age. I can’t remember the total number. But the total number of people with PCOS, if it’s 7% or 8% of that population is somewhere over 8 million women. And if those 8 million women have somewhere around a 30% or 40% chance of having impaired fasting glucose, metabolic syndrome, type 2 diabetes, we’re talking about three or four million women. So, this is a really common problem and it’s a very serious problem. And that’s why everybody needs to know it, not just endocrinologists but people who see children, because we see it now in the pediatric age group, people who see women in any age groups, dermatologists because there are some dermatologic manifestations of PCOS that should alert them to look for this disorder, diabetes educators, obviously, and anyone who is practicing medicine in the family setting that might be able to identify people and say, “Oh, well, maybe you have this,” and maybe we should then go further with some testing.
Pape: You said something earlier and I just wanted to clarify this. So, do you see this defect, PCOS, and women who have excess weight and obesity, or what about people who are lean?
Cobin: Okay. So, one of the things — when we talk about metabolic syndrome, we’re also talking about a condition called insulin resistance. And insulin resistance is kind of part and parcel of PCOS and can lead to impaired fasting glucose, impaired glucose intolerance, and diabetes. So, when we talk about whether or not we’re looking at this population of people, we’re looking at people all along the spectrum of that disorder and trying to tease out who has what and when they have it and try to get to them early on in their lives, so that we can identify it and treat it.
Pape: Right. Because a lot of people think PCOS means obesity.
Cobin: It’s not just in obese people. So, yes, to answer your question. Some early studies that were done, oh, goodness, years and years ago indicated that there was insulin resistance even in lean PCOS women. That’s almost as bad or as bad as the insulin resistance that you see in obese women who don’t have PCOS. So, then when you add obesity on top of that then you amplify that insulin resistance and that risk. So, we don’t think PCOS necessarily causes obesity but obesity on top of PCOS is not a good combination. And obesity is so common now. Of course even if it’s not caused by PCOS, it’s very common in the population, so now we have a huge number of people who have PCOS and obesity on top of it. I think the figure in the United States now is at 90% of women who are studied with POCS have obesity. If you look in Europe or other places where obesity isn’t so prevalent it maybe is around 50%, so it’s an additive.
Pape: And so, when does this risk begin?
Cobin: Early in life. Very early in life. So, there are some studies that have been done on people who we think we are genetically at risk because they’re members of the family. And they’ve been studied with interesting techniques to demonstrate insulin resistance over the course of their lives. And it looks as if that insulin resistance in people — in the family setting, at least, starts probably in late puberty. So, even before girls are fully developed in menstruating or could be identified as having PCOS by some of the other reproductive features, they may already have insulin resistance.
Pape: Sometimes there are mothers that will ask me about like their two-year old or three-year old, “You know, she’s overweight. She doesn’t eat that different, or may be hungrier than my other children.” What have we have found in toddlers and — or have we found anything?
Cobin: Yeah, I don’t think we found too much in that age group. Again, if you look at young children and actually if you look at newborns, there are some disorders, I’ll put it that way, that are really only detectable by very elaborate biochemical means that would not be done in the general population or would not even — I don’t think at this point, be done even in a youngster, but that may indicate that, yes, this may be genetically programmed. And that early on we’re seeing some things that might be clues. But not something that somebody is going to do in the doctor’s office or say, “Oh, I’m going to send you for this fancy test.” And again, stay tuned, because these tests, procedures and these studies of populations change over time. And so, in five years I might come to you and say, “Well, maybe we’ve got a test for that to see if that person is programmed.” And with that, I should just say that PCOS often occurs in familial settings. And there have been studies that show an increased risk of diabetes, an increased risk of hypertension, an increased risk of metabolic syndrome, and probably an increased risk of cardiovascular events in family members of women with PCOS. And not just women.
Cobin: So, men — so, fathers and brothers have been studied, sisters and daughters have been studied, and many of them show these defects. So, now some of the genetic studies and some of the family studies are focused at looking at these people and seeing, well, yes, “When can you pick this up and what would you do about it?” But to answer your question about a two-year old, the routine evaluation — pardon me — in a pediatrician’s office would be looking for thyroid disorders or other metabolic disorders, and hypothalamic obesity, some genetic disorders that can manifest themselves in children which are quite rare. But, yes, someday we might be able to say, “Yes, here’s a marker for PCOS.” Dr. Andrea Dunaif, who presented at our conference this week, actually showed some studies where they were measuring certain chemicals, certain abnormalities and chemicals that come from tissue that’s abnormal in PCOS people in wet diapers. So, they were bringing out diapers and sending the diapers to the lab, and wringing it out and measuring some urine metabolites of some steroid hormones, and showing that they might be abnormal even in babies. But right now, that’s not a doctor’s office procedure.
Pape: And that reminds me years ago — and you had taught me that really PCOS is insulin resistance in women.
Pape: Or metabolic syndrome in women.
Cobin: PCOS is a manifestation, yes.
Pape: Right. Because who’s to say when they went to do studies on family members, well, a lot of the fathers had died young, so there weren’t a lot that they could find out. And I know we’ve come a far way from that.
Pape: But it is just very interesting. And —
Cobin: Yes, exactly. So, men obviously aren’t going to have the same manifestations. They — to go backwards, how does PCOS manifest itself in women? So, the diagnosis is made by seeing irregular menstrual periods, signs of what we call hyperandrogenism. Androgens are chemicals that in women cause facial hair growth, acne, loss of scalp hair, irregular periods, and when they’re present in great excess– usually not in PCOS, but in great excess they can cause deepening of the voice or thicker, stronger muscles, and some other physical changes in women’s genitalia. That being said, those are markers and those are definitely issues that need to be addressed; irregular periods, infertility, cosmetic problems. But yes, if you say, well, those things that are physical markers also indicate that this woman may have metabolic disorders. And it turns out that in large studies, and this is again an ongoing process, in large studies most of them relate the degree of hyperandrogenism. And in this case, the measurement of testosterone in a woman. And testosterone is a normal hormone in women. It’s just much, much higher in men. But the higher the testosterone in women, the more likely they are to have metabolic syndrome. So, again, it depends on how you define PCOS and what population you’re looking at. It also depends to some degree on where you’re studying these women because it makes the difference in their ethnicity, how old they are, their family history, and so on. But a good clue is the higher the testosterone, the more likely they are to have metabolic syndrome and its consequences.
Pape: So, how common are dysglycemic disorders in PCOS?
Cobin: Again, depends on age, location, ethnicity, et cetera. But a good rough figure would be 30% or 40% probably and probably goes up with age. If you look at impaired fasting glucose, impaired glucose tolerance, you see that even in adolescence. And again, if they’re obese that increases the risk. And then in studies that have looked over time, the progression of people who have abnormal glucose tolerances to full blown diabetes is somewhere around 3% to 5%, to even 15% in some studies, per year. So, if you’re following these people year to year to year, they’re going to progress as they get older as well.
Pape: And so, what are the long-term consequences of these problems?
Cobin: Serious ones. Serious ones. So, the first thing I should say is we’re focusing on diabetes. And we know from some of the pediatric endocrine clinics, for instance the children at Yale that have been studied, the younger they developed diabetes particularly if it’s not well controlled, the more likely they are to have microvascular complications of diabetes, so neuropathy, nephropathy, kidney failure, and eye disease, retinopathy. So, the longer somebody has diabetes, type 1 or type 2, the more likely they are to have small blood vessel disease. That really hasn’t been studied specifically in PCOS women. But you can imagine that if they start young and they’re not identified and they’re not treated, that by the time they’re picked up they may already have these microvascular complications. So, if you look at older literature where there wasn’t much in a way of diabetes screening, people with type 2 diabetes and that’s typically what PCOS ladies get, we had an incidence of retinopathy, eye disease, of somewhere around 50% when they were diagnosed with diabetes. They already had eye disease. Now, over time that has changed as the diabetes community has encouraged screening for diabetes even in the general population. So, if we know in these PCOS ladies that they’re looking at diabetes even at younger and younger ages, one could anticipate if we don’t pick it up that they may have more microvascular disease. There are not any good studies on that. But when you turn to macrovascular disease, that is to say diseases of the large blood vessels, coronary disease that causes heart attacks and carotid disease that causes strokes, we know that women with PCOS also have in addition to metabolic syndrome and hypertension, they have disorders of lipid metabolism. So, the classic metabolic syndrome lipid pattern is a decreased HDL, good cholesterol, and elevated triglycerides. But PCOS women have also been shown to have slightly higher LDL levels as well. And smaller LDL particles and larger numbers of small LDL particles which are more likely to produce a disease in the arteries. So, if we know that they have hypertension, they have impaired fasting glucose, they have insulin resistance, and they have lipid disorders, what are the risks? The risks are heart attack, stroke. And it’s been shown that over time now there are about five or six pretty good studies looking at women with PCOS. They tend to get heart disease earlier. It tends to be more progressive, and it tends to produce when they do have a heart attack, more death. So, in various studies the risk of having a heart attack is somewhere around three times as great as in the general population. And the risk of death from a heart attack in women with PCOS is probably twice that of the general population. And again, more and more studies are accruing overtime to look at this and this is sort of a work in progress. We’ll know more as time goes on.
Pape: So, what could we do about this?
Cobin: Look for it, find it, and treat it, and educate women. So, first you have to look for it. And if we’re speaking to people who are seeing patients in their offices, pediatricians who are seeing young women, maybe not your toddlers, but your preadolescent young women if they have signs that they might have PCOS, early hair growth, early puberty can be a sign of impending PCOS. So, if a woman has early puberty, in addition for looking for other causes, you might think of PCOS as a reason. Women who have a funny discoloration of the skin. At the dermatologist’s office, there’s a condition that’s called acanthosis nigricans which is kind of a thickening velvety skin along the back of the neck. And the dermatologist may pick this up or the family doctor may pick this up, or even the child herself, and often this starts to occur in, again, preadolescent or adolescent girls. And sometimes they’ll go to their moms or the moms will say something like, “Gee, you didn’t clean your neck very well. What’s going on there?” And if the family doctor says, “Oh, no, no, no. That’s really a sign of an underlying condition called insulin resistance,” it’s a marker. And now, when you see a marker, you go on and evaluate further. So, pediatricians, dermatologists, family practice doctors, general internists, when you see irregular periods, signs of hyperandrogenism, some of these skin markers, this is the time to look for the other parts of PCOS. Dermatologists treating acne, right. Now, not all women with acne have PCOS but a lot of women with acne do have PCOS. So, if you look for and you find it, you then send this woman on for further evaluation and management. On the patient’s side —
Pape: So, you said, “Send on.” Send on to who?
Cobin: Often to the endocrinologist.
Cobin: Because the clinical endocrinologist is really the expert in polycystic ovary syndrome, certainly for women. And now, we’re learning even for men that they may be at risk as well. So, in addition to finding the woman in the office, the other part of this is just for people themselves to be aware of the situation and to report their symptoms, “So, I saw something funny,” or, “I’m breaking out,” or, “I’ve loss some hair,” or, “I’m growing hair,” or, “My periods are irregular.” Now, we give adolescent girls a couple of years from when their periods start for them to become regular, that sort of normal development. But if it’s more than two or three years since your period started and you’re not getting regular, then that’s already a sign. Irregular periods are a very good marker for PCOS which is the most common reason for this. It’s not the only reason but it’s a good place to look. So, if young girls and their mothers and their families know to look for these things and know to be aware of them, then they’re going to bring that to the physician’s attention. And then there’s the family, “Oh, yes. Well, let’s check Uncle Joe because mom has PCOS and she had some facial hair, and she had irregular periods, and she had an awful lot of trouble getting pregnant. She wasn’t ovulating regularly. How about her brother? And he’s a little overweight. Let’s just check to find out whether he has diabetes or prediabetes and counsel.” So, the last part of the puzzle of course is what do you do to treat. And there are specific treatments for the irregular periods, and there are specific fertility treatments, and there are things that you can for hair growth and acne. But more importantly if you’re going to look at, what we call the cardiometabolic consequences, the first thing you do is counsel them to eat properly, maintain an ideal body weight, and exercise regularly. And that alone has been shown in many studies, including the diabetes prevention trial that everybody talks about so much, that’s wonderful prevention. And you can delay the onset of full-blown diabetes or even in some cases reverse it with just diet and exercise. If that’s not doing the trick or there are lipid abnormalities, then obviously you are going to treat with oral agents or insulin, whatever you require to control diabetes, control the blood sugar, keep it in the normal range. We have targets for glycohemoglobin to make sure that people are well-controlled, keep the lipids under control, and certainly control high blood pressure. And all of those things then will reduce the risk of microvascular complications of diabetes, heart attack, and stroke. And that’s what we’re worried about.
Pape: All I can say is thank you very much. And to everybody reading or watching this, stay tuned because you’ll hear a lot more here at Diabetes in Control about PCOS. Thank you so much, Dr. Cobin!
Cobin: You’re very welcome, Joy!