Advances in Treatment of PCOS

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Dr. Hugo Verhoeven: "I'm Hugo Verhoeven, and I'm a member of the Editorial Advisory Board at OBGYN.net. I now have the pleasure to talk to Professor John Nestler, who is Chairman and Professor at the Division of Endocrinology and Metabolism in Richmond, Virginia. Good afternoon. We are here to talk a little bit about advances in treatment of PCOS. Before we start talking about PCOS, our listeners need to know what PCOS means, exactly."

Professor John Nestler: "PCOS stands for polycystic ovary syndrome, and this is a common disorder. Features of the disorder are the inability of the woman to ovulate - that is, to release an egg from the ovary - and this is manifested by irregular menstrual periods. In fact, if a woman has eight or less menstrual periods a year, she has a very high likelihood of having polycystic ovary syndrome. The other part of PCOS is what we call 'hyperandrogenism,' which is an elevation of testosterone - the male sex steroid - levels in the blood. More commonly, this involves a clinical manifestation of excess testosterone-induced action such as excessive hair growth, for example, on the upper lip, chin, cheeks, or other areas of the body. The combination of abnormal menstrual periods and excess testosterone in the blood or testosterone action is what defines the women who have polycystic ovary syndrome.

Now, this is a very prevalent disorder. It's estimated to affect anywhere between 6% and 10% of women of child-bearing age, and in the United States that translates into between 3½ and 5 million young women. It's also a disorder that's frequently under-diagnosed. Many women who have polycystic ovary syndrome have not sought out the care of a physician, or if they're seeing a physician for other reasons, that physician has failed to ask many of the questions which the physician would need to in order to diagnose polycystic ovary syndrome. We used to think of polycystic ovary syndrome as an infertility disorder alone. Women would go to the doctor because they couldn't have babies.

The most important advance in the last decade, I think, is that we've come to realize that many, if not virtually all women with polycystic ovary syndrome suffer from an underlying metabolic disorder, and that specifically is something we call 'insulin resistance.' Now what that means is the following. Insulin is a hormone that usually controls the amount of sugar in the blood. When the body is resistant to insulin, the pancreas gland will make more insulin in order to keep the blood sugar level normal. There's good evidence now that the insulin resistance that these women have plays an important role in this disorder, and there are two reasons why the association of insulin resistance and PCOS is important. I should note that this insulin resistance has been shown to occur not only in overweight women with PCOS, but also in thin women who have PCOS. Now, the two reasons why this association is important are the following.

First, if polycystic ovary syndrome is related to insulin resistance and if these women have insulin resistance, you might think they would be at a higher risk for developing other disorders that have been linked to insulin resistance - specifically, diabetes, high blood pressure, abnormal cholesterol and triglycerides, and heart disease. In fact, that is exactly the case. Several studies have now shown that anywhere from 40% to 50% of overweight women with PCOS will develop either diabetes or something we call 'impaired glucose tolerance' by the age of thirty. Impaired glucose tolerance means that the body isn't handling sugar completely normally, and women who have impaired glucose tolerance are at a higher risk to develop diabetes. Several studies also indicate that women with polycystic ovary syndrome have abnormal lipids, especially low HDL cholesterol and high triglycerides, which predisposes them to heart disease. Several studies suggest that women with polycystic ovary syndrome are at a much higher risk for developing heart disease as they get older. So as you can see, if this is a disorder affecting between 3½ and 5 million women in the United States, and if it can be linked to diabetes and heart disease, this is a serious general health concern. It means that PCOS is not just a fertility problem, and it's not just a cosmetic annoyance - it's a serious disorder.

The second reason that the relationship between insulin resistance and PCOS is important is because there's good evidence emerging now that insulin resistance plays a critical role in the development of PCOS itself. The excess insulin that's being produced in these women stimulates the ovary to make testosterone, the male sex steroid, and through a variety of mechanisms, it may also interfere with ovulation, rendering women infertile. If that's true, then it stands to reason that a novel therapy for women with PCOS might be to administer drugs that improve the body's sensitivity to insulin, since that appears to be the fundamental abnormality. And indeed, there are now a number of studies showing that when women with polycystic ovary syndrome are treated with what we call 'insulin sensitizing drugs,' their insulin levels are decreased because their bodies' insulin sensitivity has been improved. The level of testosterone in the blood goes down and they begin to ovulate, and because they're beginning to ovulate, many of these women also become pregnant.

There are also several studies that show if you look at women with polycystic ovary syndrome who are trying to get pregnant, these women are frequently given drugs to induce ovulation, such as clomiphene or what we call the 'gonadotrophins' like FSH. But these methodologies aren't always successful, and now there are studies that strongly suggest that if you take these women and treat them with an insulin sensitizing drug first, they become much more responsive to clomiphene or to FSH in terms of inducing ovulation. So the insulin sensitizing drug holds a lot of promise for women with polycystic ovary syndrome in that it decreases testosterone levels and improve the ovaries' ability to release eggs for them to become pregnant. Finally, there's reason to think that these drugs might beneficially affect the long-term health of these women in terms of perhaps retarding or preventing the development of diabetes or heart disease. More studies need to be done to prove that latter point, but there's a lot of evidence that suggests this is probably the case.

The types of drugs that we have available at this time to improve insulin sensitivity basically fall into two categories. One is a drug called 'metformin,' which has been around for a long period of time - about 30 to 40 years. It's been available in Europe for about 40 years, rather, and in the United States for about the last five years. It is a drug that is commonly given to diabetic patients to improve insulin sensitivity. Most of the studies in polycystic ovary syndrome have been done using this drug, metformin, and it's proven to be quite efficacious in most of those studies. It's usually well tolerated, the primary side effects being GI distress, some nausea, or some diarrhea. You take the medication two to three times a day with meals, and usually those side effects will disappear for most women taking the drug.

The other class of drugs is what we call 'thiazolidinediones,' and basically the three drugs that fall into that class are troglitazone, rosiglitazone, and pioglitazone. These drugs have not been around that long. Troglitazone has been around for about two to three years, and pioglitazone and rosiglitazone have been around for less than one year. So there's not a lot of experience with these drugs, but we think we're beginning to know what their side effect profile is. They had been linked to liver problems, especially troglitazone, and that makes some of us a little worried about using it for long-term use in women with PCOS. That situation may change because so far rosiglitazone and pioglitazone do not seem to cause the same liver problems. Although as I said, the drugs have not been around that long, and some of us are still waiting to see what pans out after more patients have taken the drug.

At the moment, it seems to make no difference which insulin sensitizer you take - they all seem to be effective. No trials have been done looking to see whether one polycystic ovary syndrome one drug is preferable to another in terms of decreasing testosterone or improving ovulation. Also, we've not looked yet as to whether combining these drugs might be even more effective in this regard, and those are studies that I am sure will be forthcoming."

Dr. Hugo Verhoeven: "It was my understanding that the patients should go to their doctors as early as possible so diagnoses of PCOS can be given as soon as possible. Is that correct?"

Professor John Nestler: "Yes. I think it makes a lot of sense for women to have the diagnoses made as soon as possible because then we can intervene as early as possible, perhaps prevent some of the infertility, some of the cosmetic problems with excess hair growth, or the long term health risks. For women who are overweight, the safest intervention is weight loss, which can be accomplished by diet and exercise. Weight loss is not an option, obviously, for thin women who have polycystic ovary syndrome. So for thin women, or for overweight women with polycystic ovary syndrome who have failed to lose weight, that's when we would turn our attention to drug therapy, perhaps even using insulin sensitizing drugs as an initial approach."

Dr. Hugo Verhoeven: "So if the patient has only cosmetic problems, she's going to see her doctor, and he's going to treat her with metformin. Then she has infertility problems and she eventually gets pregnant, but what happens later on? Is this a treatment for the rest of her life, or what is the experience with long-term treatment with metformin?"

Professor John Nestler: "With metformin or any of the other agents, right now, the standard of practice would be to stop the drug once a woman becomes pregnant, because most of these polycystic ovary syndrome studies have been done where metformin has been given throughout pregnancy. So right now, the woman would take metformin, she'd begin ovulating, she'd get pregnant, and the drug would be stopped. What I think is important is for that woman to realize that after she's delivered her baby, she still has polycystic ovary syndrome. She still has a metabolic disorder that poses general health concerns. So my recommendation at this point would be that after she has delivered the baby, she should go back to the doctor and start back on the metformin.

Is it life-long therapy? I think that depends. If the woman is successful in losing weight, she may be able to stop metformin because weight loss itself is associated with an improvement in insulin sensitivity. If she hasn't lost weight, then there is a good chance that the metformin therapy would be continued for a prolonged period of time, or at least until menopause. We don't know what would happen at menopause - that's still an open issue as to when women with polycystic ovary syndrome need to be treated for their metabolic disorder after menopause. But I usually tell my patients that, at least for the immediate future, they would likely remain on metformin. The drug companies are developing a whole slew of new insulin sensitizing drugs which will be slowly entering the market in the next five to ten years. I suspect that all of these drugs would be tested in PCOS and that they will all prove to be effective. So I do tell my patients "right now, you're on metformin for the foreseeable next couple of years. It may be that in five years we'll have a drug that you can take less often or that's more effective, and you might be switched over to that." But it's very similar, I think, to high blood pressure. It's an underlying disorder which needs to be treated for a lifetime."

Dr. Hugo Verhoeven: "What about treatment with metformin during pregnancy?"

Professor John Nestler: "That's a controversial issue. Now why might you want to use a drug like metformin during pregnancy? There are at least two reasons. One is that women with polycystic ovary syndrome are probably at a higher risk for developing diabetes during pregnancy. So if you are able to give them a drug like metformin, you might be able to prevent the development of what we call 'gestational diabetes,' or diabetes during pregnancy. That might be one reason. The second reason might be early pregnancy loss. Women with polycystic ovary syndrome have a high rate of early pregnancy loss. We don't understand why that's so, and there are many theories. One possibility is that insulin resistance might be playing a role. If that's the case, then treatment with metformin might be effective in preventing early pregnancy loss, but that's all very speculative at this time. Scientists are beginning to turn their attention to that issue and to begin doing the studies needed to explore that. Until then, I would not be able to recommend that women take metformin throughout pregnancy. Although there have been no reports or no reason to think right now that metformin would cause a problem during pregnancy, we don't know. We need to do the studies to be sure that there are no adverse effects on the fetus."

Dr. Hugo Verhoeven: "Let's go back now to the adolescents. At what moment should parents think about seeing their doctor because their daughter has some problems? What are the first symptoms? When is it time to start a complete check-up of the patient, and what would that check-up be?"

Professor John Nestler: "In many cases, the first thing we realize is that polycystic ovary syndrome appears to be a genetic disorder, so frequently mothers who have polycystic ovary syndrome will have daughters who also have it. I think any woman who is a mother and has polycystic ovary syndrome has to be very aware that her daughter has a very high chance of having it as well. Therefore, you need to keep a closer eye on that daughter. I would say that any young girl who is showing signs of excess testosterone action, in terms of having, let's say, excessive hair growth, should certainly see her pediatrician or endocrinologist to be evaluated. Any woman after the age of about sixteen or seventeen that is not having regular menstrual periods should probably go and at least be evaluated for the possibility of polycystic ovary syndrome. Certainly any woman beyond the age of twenty who is having infrequent menstrual periods or irregular menstrual periods, in terms of having eight or less menstrual periods a year, should go see either her gynecologist or her endocrinologist for an evaluation because those women are at a fairly high risk for having polycystic ovary syndrome.

First of all, women themselves need to be aware of the syndrome. A lot of women don't give much regard to their abnormal menstrual periods. It's not unusual that an eighteen-year-old girl who's having four periods a year will go to her mother and say, 'I'm only having four periods a year,' and the mother will say, 'don't worry about it, you're Aunt Sally only had four menstrual periods a year - it seems to run in the family,' and that's as far as it goes. It's not normal, and women should have themselves evaluated. The second thing to understand is that physicians themselves are, I believe, undereducated about the prevalence of polycystic ovary syndrome, and there are many doctors who never take a menstrual history from their female patients. So sometimes a woman will have to bring it to the attention of her physician and be rather direct in asking, 'Do I have polycystic ovary syndrome? Have I been evaluated for that?' Again, it's important not just because there are now treatments for the disorder, but because of the high risk these women are at for developing diabetes or heart disease in the future."

Dr. Hugo Verhoeven: "So it seems to be that metformin is now the gold standard in the treatment of PCOS."

Professor John Nestler: "Among the insulin sensitizing drugs that are currently available, I think metformin has been the one that's been most studied, so that most of the studies in the field have been done with metformin. And because it's been around for thirty or forty years, we have a very good handle on its side effects and safety profile, and it's important that you feel very comfortable with it. So I think for the moment, in the year 2000, metformin would be my drug of choice."

Dr. Hugo Verhoeven: "So what do you expect for improvements of new medication?"

Professor John Nestler: "Although metformin is an excellent drug, there are certain drawbacks. For example, it needs to be taken twice or three times a day. As I said, it's main side effect is some dyspepsia, nausea, and maybe some diarrhea, which affects a relatively small portion of women, maybe 10% to 20%. But still, some of those women will not be able to tolerate the drug. So I think you're going to find insulin sensitizing agents being developed which need to be taken only once a day, perhaps, which will have less frequent side effects, and maybe women can better tolerate them. I think those agents are probably going to come on the market in the next five to ten years."

Dr. Hugo Verhoeven: "And now my final question. PCOS is a typical female disease, but is there some analogue in the male?"

Professor John Nestler: "That's an excellent question. If it's a genetic disorder, and one would think that there should be men who are affected as well. This hasn't been studied critically, but there are some early studies that suggest that the male equivalent of polycystic ovary syndrome is the forty-year-old man who suddenly dies of a heart attack. In other words, it appears that the brothers of women with polycystic ovary syndrome tend to have abnormal cholesterol, triglycerides, and premature heart disease. So you can see that although the men obviously can't have irregular menstrual periods, they still have evidence of the same underlying metabolic disorder in terms of insulin resistance and heart disease."

Dr. Hugo Verhoeven: "But no problems in their reproductive lives?"

Professor John Nestler: "I'm not aware of any reports of impaired reproductive ability in men who are brothers of women with polycystic ovary syndrome."

Dr. Hugo Verhoeven: "Thank you very much. It was a pleasure."

Professor John Nestler: "You are welcome."