Pediatrics and PCOS

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Dr. Mark Perloe:  “Hi, this is Dr. Mark Perloe, and I’m here with Dr. Silva Arslanian from the Children’s Hospital in Pittsburgh where she’s is a Professor in Pediatrics.  I very much enjoyed your presentation earlier on PCOS and the pediatric population.  Is this something that we need to be concerned about in younger sisters of our patients or in patients themselves when they appear like they may have PCOS?”

Dr. Silva Arslanian:  “The answer is yes, actually, that’s why I kept on repeating in my lecture that if a mother is suspicious that her teenager is starting to follow her footsteps, she should not delay taking her to a physician because I think there a lot of adolescents who are not being diagnosed until they are in their mid-twenties after having had the condition for maybe a decade or so, and the younger sisters too.  The last patient I saw was because the twenty-one-year-old sister had just been diagnosed with PCOS after she had been complaining for seven years of the symptoms.  When that happened, the mother realized that the eleven-year-old daughter was following the footsteps of the twenty-one-year-old so she said maybe it’s time for her to be seen, and lo and behold, the girl had high testosterones and she did have the phenotype by chemical profile of PCOS.  So I think most physicians have to be educated that this entity exists in adolescents and that you don’t need to be thirty- or forty-years-old when you’re trying to find solutions for your infertility to be the first time that you get the diagnosis.  My advice is, and this is a total bias, the earlier you address a problem maybe the success rate in treatment is better, I don’t know.  If the abnormality has been there for twenty years maybe the derangement is so engrossed that no matter what you do, you may not be able to reverse it, whereby if the function of the abnormality has been there for a year or two and you start treatment earlier, you may be more successful.”

Dr. Mark Perloe:  “When we see the older sisters who respond to treatment with insulin sensitizing or lowering drugs, it will be hard to find women who may want to participate in the longer term studies that are necessary as part of the placebo group.  I want to change the subject and go back a minute because the normal physiology of adolescents includes a period of time where many adolescents become insulin resistant.  How would you separate out the patient who is going through a normal pubertal insulin resistance from one who is destined to develop PCOS?”

Dr. Silva Arslanian:  “We did a study and I showed some of the results; the insulin resistance associated with PCOS is much more severe than the natural insulin resistance of puberty.  Those girls who have hyperandrogenism have 50% lower insulin sensitivity compared with their peers of the same maturation stage, the same age, and the same degree of obesity.  So it’s not just the natural insulin resistance, which is transition from pre-puberty to puberty, there is around 25%-30% reduction in insulin sensitivity then you recover once you complete your puberty.  But the adolescents with PCOS, they never recover from the insulin resistance, it stays with them because it’s part of their syndrome.  Whether or not the insulins themselves are involved in the whole pathogenesis is now a favorite…”

Dr. Mark Perloe:  “It is difficult outside of a clinical research setting to really measure insulin resistance.  Are there clues from history or other clinical signs or tests that you would recommend to clinicians in evaluating the teen to make that differential or is that something that at present is only possible in a research setting under a clinical research trial?  Because other than the program in Pittsburgh, I’m not aware of many people who have a lot of experience evaluating teens with the condition.”

Dr. Silva Arslanian:  “You know you’re right, a lot of the studies we do are very sophisticated metabolic studies and things like that.  But if you ask me what is the one phenotype I see where I would say this kid has insulin resistance and that’s if I see acanthosis nigricans, I know that person has insulin resistance and hyperinsulinemia.  It’s a very simple test, just ask the physician to look at the neck of the individual or even ask the parents, does your child have ring around the collar kind of or darkening, if they say yes, then that is associated with insulin resistance.  Studies have shown that over and above obesity, if you have acanthosis, your insulin levels are twice as high as without the presence of acanthosis.  Now if you read textbooks, typically, they say acanthosis is associated with GI malignancies.  We never see that, and we see a lot of kids.  Actually, in the African American population it’s very, very common and that population is much more insulin resistant too so if I see acanthosis nigricans, I know that person is insulin resistant, and I know that person’s fasting insulin levels are going to be high.”

Dr. Mark Perloe:  “What would you tell a mom who has other people in the family with PCOS, and the history of presentation may be premature pubarche or a dramatic weight gain in a one year period?  A woman where who might experience a sixty pound or forty pound weight gain in one year, is that something that would signify that additional testing might be indicated?”

Dr. Silva Arslanian:  “You have to measure the androgen levels.  I don’t suggest measuring insulin levels because I don’t think they help you in the management.  I like free testosterone because sometimes the total testosterone, especially in adolescents depending on your maturation state, could be 30 and it’s not very elevated, but if your free testosterone is 9 because your SHBG is so low, then that 9 free testosterone is very high.  So I go with measuring the free testosterone, as I said, I don’t measure insulin because it’s not going to help me in my management.  The next question is how do you manage it?  We try to implement lifestyle changes, dietary, activity, etc. if the child is overweight but unless the family is very supportive, it’s very difficult for the adolescent to implement that.  The next question is therapeutically what do you use?  You can use oral contraceptive pills, which is the most accepted therapeutic modality but more and more adolescents seem to reject that idea, they don’t like the idea of oral contraceptive pills.  One of the adolescents gave me the excuse that she doesn’t want her peers to think that she’s sexually active so she doesn’t want to be on oral contraceptive pills.  The other one didn’t like the weight gain associated with oral contraceptive pills, and in that situation, I’m pushed in the corner in a way.  If they fit any one of the clinical trial criteria for metformin, I say great then we can enroll you in the metformin trial.  There was one occasion that I had to use metformin in a girl who refused oral contraceptives and who had elevated testosterones.  I told her this is not an approved treatment in pediatrics, and these are the side effects.  I explained it clearly to her and her mother and she chose to use it, and after three months, she’s very happy with it because she’s lost some weight and her menses are regulated.”

Dr. Mark Perloe:  “In your experience, do you believe the insulin resistant patient be it a teen or adolescent or any of the people in this group when placed on birth control pills, do you believe that they are at increased risk from gaining weight on the pill?”

Dr. Silva Arslanian:  “I haven’t put too many kids on the pill to be able to answer that.  As I said, my interest started in this area because of that one case.  When she was severely hyperinsulinemic, she had the testosterone of 380, and when she developed insulin deficiency, her testosterone was down to 10 so that started the whole research interest of it.  So from a clinical point, I don’t typically see a lot of those patients to put them on the pill but we did a clinical study with the pill on these kids to see if the pill is making the insulin resistance worse or not, and it really did not change it much.  I think because they’re so insulin resistant to begin with, the pill is not really making a major contribution to it.”

Dr. Mark Perloe:  “We’ll get some data from the diabetes prevention trial that is looking at the use of diet and exercise and another arm is looking at the use of metformin to reduce the incidence of type 2 diabetes.  Do you think that the information from that study will be applicable to the younger individual in terms of allowing us to conclude that earlier treatment will prevent the more severe complications of PCOS insulin resistance?”

Dr. Silva Arslanian:  “I really don’t know.  I don’t know if the DPT-2 is going to give an answer that metformin might result in less complications but the UKPDS study did show that metformin treated type 2 diabetic adults and had better outcomes in the long run.  So considering its safety and efficacy, I think it makes sense for it to be a therapeutic choice in adolescents.  Lately we have been seeing increasing type 2 in adolescents which before was not necessarily heard of much, and there is a preponderance of females to males in type 2 diabetes is adolescents, a ratio of 2 to 1 and 3 to 1 and my bias is that a lot of these girls are PCOS type girls who don’t necessarily have the diagnosis but they’re presenting with type 2 diabetes, and these people are responding to metformin.  There was a trial nationwide with several centers and the results are going to be presented at the ADA meeting, it was a short study, a four month trial with placebo versus metformin but metformin was more effective in lowering plasma, glucose, and Hb1C levels.”

Dr. Mark Perloe:  “We saw work earlier about the progression of IGT to type 2 diabetes or development of IVT (IGT) in a normal glycemic population.  Do you have the sense that there is a similar progression in this population or are you collecting data that will allow us to answer some of the questions about progression in the younger population?”

Dr. Silva Arslanian:  “We don’t have longitudinal prospective studies but we did a cross sectional study in adolescents with PCOS that everybody underwent an oral glucose tolerance test.  I would say probably around 15%-18% turned out to have abnormalities in their 2-hour glucose level anywhere from IGT more than 140 to frank type 2 diabetes and actually two adolescents within nine and twelve months had converted from being normal glucose tolerant to impaired glucose tolerant.  These are kids whose mean age during the time of the study was around twelve and thirteen, and when we assessed their insulin sensitivity and secretion in the group with normal glucose tolerance versus impaired glucose tolerance, the impaired glucose tolerance had almost wiped out their first phase insulin secretion so their first phase insulin secretion was gone.  I think that’s very, very important that even in this very young age group who didn’t have hyperandrogenism for more than two or three years or even less and already had significant abnormalities in their glucose tolerance and had defects in their beta cell function.  In addition, we found that their blood pressure regulation may be abnormal too, which could be the earliest mark of vascular disease risk factor too.  So I think there are enough alarming signs to me, which make me think that we should be very careful with this population.  The earlier you intervene, and the earlier you treat the co-morbidities whether it’s hypertension, hyperlipidemia, and all that, the better the outcome should be.”

Dr. Mark Perloe:  “So we get a 2-hour glucose screen, the criteria for screening for type 2 diabetes, unfortunately, is a fasting blood sugar.  Many physicians will do this once and send patients out but it’s quite obvious with an understanding of the disease that the 2-hour post-carbohydrate load test is necessary.  The patient gets one of these and it looks good or it’s IGT, and we know that the disease progresses.  How often in a clinical setting might it be appropriate to reinvestigate or retest?”

Dr. Silva Arslanian:  “Not necessarily all IGT’s progress to type 2 diabetes, of course, it’s a very high risk factor but some studies have looked at it and they’re shown that 30% regress back to NGT, but from this study, it’s difficult to tell if that was the natural history or there was some intervention with lifestyle modification.  As you said, you don’t necessarily need to lose weight to improve your glycemic profile; just modification of your dietary habits without weight loss can improve the IGT.  We really wanted to put in a grant to look exactly at what the natural history of hyperandrogenism in adolescents is, and what period did those with and without IGT become abnormal NGT to IGT, and if they’re IGT, when they developed type 2.  The problem is once those children and their families find out there is a problem, it’s unethical to let them go without intervention so that’s the dilemma we’re faced with.  As important as it is knowing the natural history because sometimes the puberty insulin resistance may decompensate them but once that’s completed, they can pull out of it.  But the only way to look at it is to let them be without any treatment - that to me is a problem.  They come to you asking for treatment, you have to do something to help them, so I don’t know what the answer is.”

Dr. Mark Perloe:  “I think it certainly creates a problem for all of us who are interested in the field.  We want answers and we want a better understanding of what we do in terms of a population but when it’s an individual patient sitting across from you, their concerns are dealing with the problems that they face.  Thank you so much, I appreciate your comments and look forward to hearing more about your work in the future.”

Dr. Silva Arslanian:  “I hope it’s helpful because I really truly believe that there is so much ignorance or unawareness in the medical community that a lot of those patients, whether they’re adult women or adolescents, are being missed.”

Dr. Mark Perloe:  “If a young girl goes to her doctor or a parent goes to her doctor with concerns and the response that they get is – well, take these birth control pills, you don’t need any additional testing, and they have the weight gain, hirsutism, and family history that’s suggestive - what do you suggest that they do?”

Dr. Silva Arslanian:  “It’s easy giving a pill and lowering the androgen levels but the rest of the problems are still there.  If the child has hypertension, that’s still there, and if the child has glucose intolerance, the pill could aggravate it, and if you don’t know it...  I think education is very important too, a lot of the times what happens is the teenager is given the pill with no explanation about what this entity is whatsoever.  No explanation that it’s associated with infertility down the line, and then ten years later when the pediatrician is no longer taking care of this child, all of a sudden a whole can of worms is opened up because the person for the first time realizes that this diagnosis that she was given ten years ago has all these co-morbidities with it.”

Dr. Mark Perloe:  “Dr. Marshall presented one interesting study where the ability of the birth control pill to suppress gonadotropin stimulation, which has got to be responsible for some of the androgens, is less effective in these patients with PCOS.  Can you comment on that finding, and does this say that maybe the pill is not as effective in the PCOS women because we’re not sufficiently suppressing LH?”

Dr. Silva Arslanian:  “Maybe, the studies he showed were very nice.  We haven’t done any studies looking at the hypothalamic pituitary hormonal secretions in adolescents but when you put them on the pill, they start having regular menstrual bleeding.  They think they’re cured, when they’re really not cured so I don’t know what to say.  I don’t think we have straightforward answers.  My feeling is that there is so much we don’t know, and that’s a lot more than what we know, and how we treat our patients is still very primitive.”

Dr. Mark Perloe:  “That’s one of the things that I think is so exciting about a conference like this.  We can get together as professionals and ask those type of questions, and it’s a bit humbling and I think it’s good that the patients see that there is disagreement and a lot of questions that make it hard for us to always know the best treatment.  Again, thank you so much.”