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OBGYN.net Conference CoverageFrom "Endocrine Basis in Reproductive Function"held in Tampa, Florida - January, 2000
Dr. Hugo Verhoeven: "Good afternoon. My name is Hugo Verhoeven from the Center for Reproductive Medicine, in Dusseldorf. I am a member of the Editorial Advisory Board of OBGYN.net, and I have the honor of talking today to Dr. Silva Arslanian from Pittsburgh. Dr. Arslanian is an endocrinologist, specializing in pediatric endocrinology, and we would like to talk about the subject of PCOS and treatment possibilities. Good afternoon."
Dr. Silva Arslanian: "Good afternoon."
Dr. Hugo Verhoeven: "I listened this morning with a lot of interest to your data on treatment of polycystic ovaries with medications. For our listeners, maybe the first question should be, what are polycystic ovaries, and what are the symptoms that you observe?"
Dr. Silva Arslanian: "Actually, it's polycystic ovarian syndrome, and it comprises or is characterized by hyperandrogenism, which implies elevated androgen levels and its manifestations can include acne, hirsutism, and irregular periods. The second criteria would be anovulation and infertility. As a pediatric endocrinologist, however, we don't deal with the infertility part of it, but we do deal with the anovulation or irregular periods and hyperandrogenism. Now, in the past, the presence of cysts in the ovaries was considered as diagnostic criteria, but that is not true any more because a lot of women or young girls have the syndrome without having polycystic ovaries. It is most likely that polycystic ovaries develop over time, with unabated stimulation of the ovaries."
Dr. Hugo Verhoeven: "What is the reason patients come to see you? What are their problems?"
Dr. Silva Arslanian: "Typically, patients come to us because they have irregular periods, acne, or hirsutism with obesity. The most referred reasons are obesity and irregular periods."
Dr. Hugo Verhoeven: "How old are those patients?"
Dr. Silva Arslanian: "I would say the average age we see them at is probably around fifteen or so, and if you take a careful history you can tell that the history often goes back two or three years, when they first started having periods. They get one period, and then for six or seven months they don't get another period, and then they progressively develop the hirsutism and the obesity, hand-in-hand."
Dr. Hugo Verhoeven: "What is the reason why a girl develops PCOS?"
Dr. Silva Arslanian: "If I knew I would win the Nobel Prize, but there are actually two opposing theories. One of them is gonadotrophin over-stimulation of the ovaries - that was the old theory, and it's giving way to the new theory, which is that high insulin levels are stimulating ovarian androgen production. This theory is becoming very popular because all the studies that have used different methods of lowering insulin levels have resulted in normalization of periods and in lowering elevated androgen levels in ovulation and infertility as detected by rate of pregnancy."
Dr. Hugo Verhoeven: "Now we're coming to the important points. What is new about your treatment of PCOS?"
Dr. Silva Arslanian: "Right now, the standard treatment for PCOS - the common, general approach - is to put the patient on contraceptive pills. The contraceptive pills are going to take care of the manifestation of the syndrome, they will lower the androgen levels, and cycles will become regular. However, they do not alter the underlying pathophysiology, and if one bears in mind that a lot of these patients are insulin-resistant, putting them on oral contraceptive pills could make them even more insulin-resistant and could push them into impaired glucose tolerance. So based on very recent information that insulin sensitizes and lowers circulating insulin levels, it could be helpful.
We performed a trial of Metformin hydrochloride in adolescent girls with PCOS. Now, being a pediatrician, safety is a major concern when using any therapeutic approach. Therefore, we have to be very selective and go with the medication that has a long track history of being safe. The reason why we chose Metformin is because there is a thirteen-year history in Europe of it being very safe if it's used appropriately in the right patient population, versus some other insulin sensitizers that are very potent, but have significant side effects. They haven't had such a long history of being used. Therefore, we tried Metformin hydrochloride and what we demonstrated - and this is very preliminary - is that although the study is not totally completed, we showed that total testosterone levels went down by almost 50%. Free testosterone levels went down, and 17-hydroxy progesterone response to ACTH stimulation was less. So all the hyperandrogenic parameters were getting better. This was with three months of Metformin treatment at 850 mg, twice a day. It was an open label study, which means the patients knew what they were taking, and we knew what the patients were taking. I suppose one could criticize that this was not a double-blind study, but this is a first step in seeing whether it's efficacious or not."
Dr. Hugo Verhoeven: "You say that Metformin is quite an old medication that's been on the market for thirty or thirty-five years, and from what I've heard this is true not necessarily in the United States, but especially in Europe. Why is it so new, here? Why are you using this medicament only now? Why wasn't anybody in the rest of Europe using this medicament earlier? Is it because they didn't know the pathophysiology of the PCOS? What is so special about your treatment, now? You said Metformin is now the golden standard in the treatment of PCOS...."
Dr. Silva Arslanian: "I'm not saying Metformin is the gold standard, although maybe Dr. Nestler would say that because he did most of the studies. It's based on his studies and other studies which showed that weight loss is associated with lowered insulin levels. Diazoxide, Metformin, and troglitazone lower insulin levels. All of these therapeutic approaches are needed for the lowering of androgen, improvement of menstrual cyclicity, and the resumption of regular periods. The last publication by Dr. Nestler was on D-chiro-inositol, which is an alternative pathway of insulin action - again, treatment with D-chiro-inositol resulted in better pregnancy outcome than others. Therefore, there is this whole issue that maybe insulin is the driving force, and there is enough information in the literature that would show in vitro that the insulin does stimulate ovarian androgen production. So that is why the focus is now on lowering insulin levels, and since Metformin is an insulin sensitizer and because it's been safe, that's the reason we tried Metformin. There are more important insulin sensitizers, but their safety track record is not as impressive."
Dr. Hugo Verhoeven: "How long is the treatment before you see any effects? You say that one of the major problems is hyperandrogenemia. After what amount of time does the patient see any improvement? And my second question, is this a treatment for the rest of her life, or can we expect that after a certain amount of time, she can stop the medication and not have anymore cosmetic problems or infertility problems later on?"
Dr. Silva Arslanian: "Let me take the first question. How long after does one see a response? We did this study, then after three months we did pre- and post-. The post- was three months later, and we could already see some improvement in androgen levels. But clinically, when these patients were followed-up again within four to six months, there was normalization of their menstrual cycles. These are the patients who reported two to three years of irregular periods, and now they are menstruating every twenty-eight or thirty-two days regularly. So I would say that after four to six months, they should definitely see a response.
Now the second question, as to whether this is going to be a lifelong treatment... well, at this point, I don't know because this study is in its infancy, in a way. I think we need to have more subjects and longer periods studied to be able to see the outcome of these patients. Is it possible that at one point they may be able to stop it, but I think it would be unlikely because the natural history of PCOS is that once it starts, during puberty, then it's tracking through adulthood, and it persists in adulthood. So it might end up being a life-long treatment, but again, we don't know if changing the initial course of the inlays may impact a later outcome. It would be very interesting to see if we can twist it and change the progression in the first four or five years. Maybe we can hope that the future will bring advances to treat the disease, I don't know. It will be interesting to find out."
Dr. Hugo Verhoeven: "So you will not find an insulin resistance in all the patients coming to see you because of irregularity of their periods or hyperandrogenemia. Do you have any idea on how many patients you have where their symptoms are caused by hyperinsulinemia?"
Dr. Silva Arslanian: "Actually, it's probably in all of our patients."
Dr. Hugo Verhoeven: "Really?"
Dr. Silva Arslanian: "Almost 99% of the patients who come to us are obese. So obesity goes hand-in-hand in with insulin-resistance, but in this group, when we did this study, we took a group of the obese hyperandrogenic girls and compared them with obese non-hyperandrogenic girls. The hyperandrogenic girls or the girls with PCOS were even more insulin-resistant. They were 40% more insulin-resistant than the otherwise obese but not the PCOS girls. So they all are insulin-resistant, but it's the derogation of the insulin resistance. Some could be more insulin-resistant than others, but if you compare them to the non-diseased population, they're definitely very insulin-resistant. If you compare them to normal adolescents, they're much more insulin-resistant because they have the added burdens of obesity and PCOS together."
Dr. Hugo Verhoeven: "That means that in all young patients presenting the symptoms that we were talking about earlier, not thinking about the insulin resistance is a mistake. There should be screening of all those patients and to really think about insulin resistance and to screen them for that, is that correct?"
Dr. Silva Arslanian: "I'd say absolutely. It's very important not only to screen for the possibility of insulin resistance, but also to screen to see if these adolescent children have impaired glucose tolerance or Type II diabetes. When we were doing our research, we got kind of worried because there was a wide variation in insulin levels. We thought that maybe some of these kids already had failing pancreases, and so we took the study a step further to look at it, and lo and behold, a significant proportion of these obese adolescents have abnormal glucose tolerance with a two-hour glucose level. It was above 140 during oral glucose tolerance testing, making them impaired glucose-tolerant, and based on the adult literature, some of this impaired glucose tolerance will end up being Type II diabetes. Some may revert to normal glucose tolerance depending on life-style changes, but a significant proportion will progress to Type II diabetes, and there are actually some girls who have Type II diabetes but nobody knew about it because nobody did any oral glucose tolerance testing. So I think if one wants to be a good doctor caring for the patient in totality, besides checking androgen levels, testosterone, and LHF-SH levels, one has to do a two-hour glucose tolerance test. One also has to check lipid levels because a significant proportion of these girls have low HDL's and high triglyceride, which are risk factors for cardiovascular disease in the future. If they're starting at thirteen or fourteen years of age, they may have the pathologic changes by the age of thirty or thirty-five."
Dr. Hugo Verhoeven: "Is it necessarily important to have the diagnose and the treatment, or to start the treatment as soon as possible?"
Dr. Silva Arslanian: "I would think so."
Dr. Hugo Verhoeven: "Do you think if you're starting too late, that the probability of infertility later on will be greater? Meaning, the sooner you start, the higher the probability that you will have no infertility problems later on?"
Dr. Silva Arslanian: "In general, if you fix something at the beginning, your chances are better than if you fixed it later on. You can bend a twig, but you cannot bend the trunk of a tree. So coming from that philosophy, I would think if you addressed the problem at the beginning, maybe you could reverse a lot of these abnormalities sooner and better than if you wait fifteen or twenty years, when there are associated pathologic changes that might be irreversible at that time."
Dr. Hugo Verhoeven: "Going back to the infertility of the patients, if you are treating a patient soon enough with Metformin, let's say, do you have any idea how high the infertility rate will be, anyway, because you still don't know exactly what you're treating? As you said at the beginning, nobody knows the exact pathophysiology, so it's important for our listeners to know - how many patients can you help and save their fertility by your treatments with Metformin?"
Dr. Silva Arslanian: "Based on Dr. Nestler's data, the data is very interesting in that the fertility rate was 90% in the women who received Metformin versus only 1% in the women who did not receive Metformin, and that was even true for the Clomid failures. So it seems that it's very promising for Metformin, as far as fertility improvement. In adolescence where fertility is not an issue, we don't know yet. In adult women, it's already so promising that there's no reason why it shouldn't be as promising in adolescents, once they continue on the treatment and become of an age that they are willing and ready to have children."
Dr. Hugo Verhoeven: "What are the side effects of the Metformin?"
Dr. Silva Arslanian: "It's mostly gastrointestinal discomfort. They may get a metallic taste in their mouths, they may have some abdominal discomfort, and some people have diarrhea. Interestingly, those gastrointestinal discomforts are much less common in adolescents than in adults. For some unknown reason, adults do not seem to tolerate it as well as adolescents."
Dr. Hugo Verhoeven: "Are those symptoms transient, where if you take the medication long enough, they'll disappear?"
Dr. Silva Arslanian: "Actually, the medication has to be built up. You start with one pill of 850 mg for a week, and if there are no GI symptoms, you escalate to 850 mg BID or 1 gm BID, but you definitely have to start with a low dose and build up. If after the first week the patient is having some GI discomfort, you prolong the period of staying on the lower dose because a lot of the discomfort disappears and the body gets adjusted to it. That's why it has to be a dose-escalation approach. Another problem is lactic acidosis, and before prescribing this, one has to make sure that kidney function is normal. These people cannot have renal failure, which in adolescents is never an issue. The other thing is alcoholism. These are the two total contraindications for using Metformin, and alcoholism in our population of adolescents is not an issue but, again, we warn them. Another thing for people to be aware of is that the long-term use of Metformin can result in B-12 deficiency due to malabsorption. Therefore, you can't stop the medication of B-12, and we make sure to let our patients know that in case they start vomiting or for any reason they might get dehydrated, they should immediately call us so we can institute proper hydration to prevent lactic acidosis. Luckily, we have not had any problems with this."
Dr. Hugo Verhoeven: "You seem to be quite happy with that medication. Any improvements in the near future?"
Dr. Silva Arslanian: "I'm enthusiastic that it might work, even in adolescents, but I would like to see the completion of our study and the addition of other studies or by other investigators to make sure that the results are reproducible."
Dr. Hugo Verhoeven: "Thank you very much for this interview."
Dr. Silva Arslanian: "Thank you. I hope it's helpful."