POLYCYSTIC OVARY SYNDROME (PCOS)

PCOS was first described as an entity by Drs. Stein and Leventhal in 1935. They described a group of women with obesity, excess hair growth, and ovaries with multiple cysts. We have learned a great deal about PCOS since their original description. We now understand the cause of PCOS and know that it affects thin women as well as women who are overweight.

PCOS affects far more women than Stein and Leventhal ever imagined. It is the most common cause of female infertility and ovulatory dysfunction in the United States.

PCOS is characterized by ovulatory dysfunction. Periods do not necessarily have to be absent. Many women with PCOS continue to ovulate, but do so either irregularly or with compromised progesterone production. Many women with PCOS are not obese, and many women with PCOS do not have excess hair growth, but to some extent virtually all women with PCOS have some degree of insulin resistance. Insulin resistance implies that the peripheral tissues - skin, muscle, fat etc, do not respond to insulin normally. The pancreas responds to this by increasing insulin production which results in increased insulin levels.

The diagnosis of PCOS can be made by many different criteria. History is very important, and is usually characterized by some degree of menstrual irregularity or ovulatory dysfunction. Laboratory tests may also be needed to be sure that there is not some other problem. Finally, ultrasound has become the most important tool for diagnosing PCOS. An ultrasound picture of the ovaries can give one great insight into the status of the ovaries and how they function.

One of the primary goals of laboratory evaluation is to be sure there is not some other problem affecting the ovaries and their function. For example, elevated Prolactin levels can cause irregular periods. (Prolactin is a pituitary hormone that controls breast milk production. If mildly elevated, it can adversely affect ovulation.) Abnormal thyroid function can also alter ovarian function, be it hypo- (low) or hyper- (high) thyroidism. LH and FSH are the pituitary hormones that control ovarian function. Normally, FSH is higher than LH. In women with PCOS, this ratio can be reversed, with LH being higher than FSH.

The first four tests in the previous slide are male hormones. If there is excess hair growth or other evidence of increased male hormone production, these four hormones may be checked to be sure that the problem is arising in the ovary and not from some other condition.

The discovery of the role of insulin and insulin resistance in PCOS has changed the entire approach to PCOS. There are many techniques for measuring insulin levels and determining the extent of insulin resistance. In our experience, this testing is not necessary except in unusual circumstances. One can assume that there is some degree of insulin resistance in every woman with PCOS. The exact extent of the insulin resistance, and the insulin level, do not really matter. The degree of insulin resistance is related to the level of obesity and excess hair growth – obese women have more insulin resistance than do thin women. We rarely measure insulin levels anymore.

In 2003, an international workshop defined PCOS, focusing primarily on ultrasound criteria. This is the criteria upon which we base the diagnosis of PCOS – if the ultrasound demonstrates the presence of an excess number of small follicles in the ovaries, the diagnosis of PCOS is made.

These are pictures of a polycystic ovary as seen as the time of laparoscopy and by ultrasound. The laparoscopy picture shows the classic appearance of a PCOS ovary, a large ovary with a smooth capsule and “neo-vascularizations”, the multiple small blood vessels on the surface. The ultrasound picture shows the many small follicles. There are at least twenty present on just this one view. The cysts of PCOS are not large; they are small follicles as seen in this picture.

This picture demonstrates a normal ovary. In every ovary there are a few follicles that are developing, and one of these eventually will develop into a mature follicle that will ovulate. In PCOS, the follicles that start to develop can’t do so, and they “stack up” at an immature phase of development. It is a relative excess of male hormones that prevents the follicles from maturing. In essence, the excess of male hormones almost acts like a barrier preventing them from progressing. They continue to “stack up” until the ovaries look the one seen in the previous slide.

This results in there being many more small follicles. And the eggs contained in those follicles may not be healthy. The follicles have been arrested, and so has the development of the eggs. Once again, it is the relative excess of male hormones that results in these changes.

In individuals with a significant degree of insulin resistance, the elevated insulin levels directly affect the ovary and the ovary makes higher than normal levels of androgens (male hormones). It is the elevated androgens that result in the changes that characterize PCOS. In thin women, the relative excess of androgens occurs for other reasons that we will discuss later. The end result is the same – PCOS.

Elevated insulin levels affect other organ systems than just the ovary. Women with PCOS complain all the time that they don’t eat that much and still gain weight. Well, it’s the truth! Because of the elevated insulin levels, any carbohydrates taken are almost immediately converted to fat and stored in fat cells. And insulin makes it almost impossible to lose weight – insulin works very hard to prevent mobilization of fat from fat cells. Weight loss is virtually impossible – at least until the insulin levels are lowered.

Insulin has adverse effects on lipo-proteins. The effect on lipids and the cardio-vascular system results in about a ten fold increase in the risk of heart disease. The risk of diabetes is increased to about the same extent – the pancreas just can’t make that much insulin forever, and eventually can’t make enough and diabetes results.

Fortunately, there are medications available that are very effective in lowering the insulin levels. Metformin (glucophage) is by far the most commonly prescribed for women with PCOS. It is cheaper, it is more effective, and Actos and Avandia are only used when using Glucophage is not an option.

Glucophage has several mechanisms of action. It does increase peripheral insulin sensitivity. In other words, it decreases the lack of responsivity of the tissues to insulin. More importantly, it dramatically reduces the production of sugar by the liver. If sugar levels are decreased, insulin levels will decrease. With decreased insulin, the production of male hormone from the ovaries decreases and the PCOS improves. Glucophage also works very well in thin women without significant insulin resistance. Almost as a side effect, it increases the activity of an enzyme call aromatase. Aromatase increases the conversion of male hormones to female hormones – less androgens and more estrogens result.

Glucophage comes in a couple of forms, and our experience is that some women tolerate one form better than the other. Thin women typically do better taking regular glucophage three times a day, whereas heavier women seem to do very well on the extended release form taking four tablets every evening with dinner. Everyone has to get used to glucophage and slowly taper up their dose, beginning with one pill a day and increasing as tolerated.

The major side effects of glucophage are diarrhea and abdominal cramping- these can be avoided if one eliminates carbohydrates from the diet. Thin women can slowly add carbohydrates back into their diet as tolerated. Heavier women should not – our goal with them is to lower insulin levels and it doesn’t do much good to decrease the production of glucose by the liver if one keeps eating carbohydrates which are converted to glucose. It takes about three months for glucophage to have maximal effect on the ovaries. Many women conceive with no other intervention than glucophage, and couples should go ahead and try to conceive during those three months.

To understand the three month delay in the maximal effect of glucophage, one must understand Anti-Mullerian Hormone), a hormone produced by the developing follicles.

MIS is increased in women with PCOS, which is not unexpected given the number of follicles that are present. MIS decreases aromatase activity, which results in an increase of androgens and a decrease in estrogens. This perpetuates the PCOS changes.

While glucophage treatment will lower androgens rather quickly (androstenedione in this slide), MIS really does not decrease significantly for almost three to four months.

This makes sense if one understands that it takes about three months to “turn over” the follicles in the ovary. In other words, it takes about three months to get rid of those follicles and eggs that have developed under the influence of high male hormone levels and have had their development arrested, and get a new cohort of follicles and eggs that can develop more appropriately under a more normal hormonal environment.

Glucophage decrease insulin, and/or increases aromatase activity. The decrease in male hormone levels decreases MIS, and the combined effect of these changes is a healthier environment for follicles and eggs to develop.

If heavier women take glucophage and follow what we call a low amylose diet (no simple carbs, no potatoes, no bananas, no corn, no bread, no pasta, no cereal) they will lose about ten pounds a month. This food plan was recently endorsed by a cover article in Newsweek (Dec 10, 2007). In fact, thin women on glucophage must take care not to lose additional weight while on glucophage.

For many years, helping thin women with PCOS conceive was very frustrating. Clomiphene was not successful for this group because of its anti-estrogen properties- it would result in the lining of the uterus getting too thin, or cervical mucus production being too poor or side effects that just were not tolerable. Gonadotropins would result in an excessive response. And regardless of what approach was used, oocyte quality was compromised for the reasons we have already discussed. We will discuss Letrozole in detail later, but it has essentially replaced clomiphene for ovulation induction.

For heavier women, PCOS occurs because of the excess production of male hormone, which results in the abnormal androgen/estrogen ratio. Thin women don’t really have excess androgen production. Instead, they typically have normal androgen levels. However, at one point in time their estrogen levels were low. (Estrogen comes from two places – the ovaries and the fat cell.) In young, thin athletic women with very low percent body fat, estrogen levels are low. The end result of this is that the androgen/estrogen ratio is altered just like that in the heavier women (the androgen level is normal but he estrogen level is low). The absolute levels are lower in the thin women, but the ratio is still altered.

This is why we discuss “relative hyperandrogenism”, the alteration of the normal androgen/estrogen ratio. Two of the standard questions we ask are “What is the least you have weighed in your adult life?” and “were you an athlete?” We want to know if there was a time of low estrogen production that may have “set up” the pattern of PCOS. There is excellent evidence that once this ratio is altered, it sets up a pattern of functioning in the ovaries that will persist into adulthood, i.e., PCOS.

We used to think that thin, athletic women who stopped having regular periods had “hypothalamic amenorrhea”. We now know that if we do an ultrasound evaluation of the ovaries, many of these women will have changes of PCOS. The process in thin women should probably have a different name from the process that occurs as a result of insulin resistance in the heavier women, but for now we just call it “Thin woman PCOS”.

While most current definitions of PCOS discuss hyperandrogenism as a criterion of PCOS, we feel this should be “relative hyperandrogenism”. PCOS can often occur in women with normal androgen levels and no evidence of hirsutism (excess hair growth). Many thin women with PCOS exhibit only irregular periods or less than optimal ovulation.

Dr. Baillargeon was the first to demonstrate that glucophage was of value in treating thin women with PCOS. 90% of her patients ovulated after treatment with glucophage. Thin women must be cautioned about weight loss with glucophage, as this is not the goal in this group. As noted earlier, we know that glucophage works in this group because of the increase in the activity of aromatase, with the resulting increase in estrogens and decrease in androgens – in other words, correction of the androgen/estrogen ratio.

Glucophage does improve insulin sensitivity in this group as well, but this does not appear to be the primary mechanism of action.

This slide demonstrates the percentage of women that ovulated as a result of treatment with glucophage. It is apparent that the effect of glucophage does not really begin to occur for at least three months, and maximal effectiveness occurs after four to five months of treatment. This is just like in the heavier women – a new cohort of follicles must develop under the improved androgen/estrogen ratio that results from glucophage treatment.

Profound hormonal changes result from glucophage treatment. Testosterone and androstenedione, the principle androgens produced by the ovary are dramatically decreased, as is insulin.

For many years, clomiphene has been the first line treatment choice for women with PCOS. Because it lowers estrogen levels, it increases FSH (Follicle Stimulating Hormone) production which increases the stimulation to the ovaries to develop mature follicles. Unfortunately, clomiphene does not work very well in thin women with PCOS. The anti-estrogen effects are profound enough that although egg development and ovulation may occur, pregnancy will not. (This is just an observation, but women that experience side effects from clomiphene such as hot flashes will not conceive on clomiphene.)

This data looks at the percent of pregnancies that result from clomiphene treatment. It is pretty clear that if pregnancy does not result within the first four cycles of clomiphene use, it probably is not going to – something else has to be tried.

85% of all clomiphene pregnancies occur within the first three months of treatment with clomiphene. After four months, very few additional pregnancies result.

The goal of clomiphene treatment is to increase the production of FSH. We actually have FSH available in the formulations on the left. We can administer FSH directly and thereby increase the stimulation to the ovaries. If monitored appropriately, the risk of multiple pregnancies with this approach is low. And if the underlying problem is addressed first, i.e., glucophage treatment is initiated, the response even of PCOS ovaries to FSH administration is controllable.

Even if we consider IVF, the androgen/estrogen ratio must be corrected first. IVF is clearly more successful if we get good eggs. There is also evidence that part of the difficulty conceiving that women with PCOS experience is related to the negative impact of “relative hyperandrogenism” on development of the lining of the uterus and implantation.

This is just one piece of data that demonstrates the improvement in IVF rates as a result of treatment with glucophage. The results are dramatic – a 70% clinical pregnancy in those that were treated vs. a 30% rate in those that were not.

Letrozole is a medication that is approved only for the treatment of post menopausal women with breast cancer. Using Letrozole to induce ovulation is an “off-label” use, but Letrozole has proven to be very effective and safe for ovulation induction. It does have some anti-estrogen effects, but these are much shorter in duration and less profound than those induced by clomiphene.

Letrozole has a short half life, and is cleared from the body by the time conception occurs. Letrozole and FSH are synergistic – using Letrozole first allows us to use FSH in relatively low doses and achieve an excellent response by the ovaries.

We have found this combination to be so effective that we now use it almost exclusively. Three cycles with this combination is more successful than four months of clomiphene, and then three or four cycles of FSH. It also takes much less time and costs much less. On day 10 an ultrasound is performed to evaluate for follicular development and if mature follicles are present, hCG is administered to trigger ovulation within the next 36 hours.

We have seen that while there are significant differences in the cause of the PCOS in thin women and heavier women, the end result is essentially the same. The underlying principle in both is to correct the androgen/estrogen ratio.

This is the algorithm used to treat heavier women with PCOS. This is just a general outline, but does detail the steps along the way.

This is the same information for thin women with PCOS.

Drs. Stein and Leventhal developed a surgical procedure called a wedge resection for PCOS. In this procedure one would make a major incision in the abdomen, incise the ovary and literally scoop out the inside of the ovary and then sew it back together. This worked great – it is the inside part of the ovary that makes the androgens and removing this lowered the androgen levels. The problem was that it required major surgery, adhesion (scar tissue) formation was common, and the effects only lasted for six months or so. Since then many laparoscopic procedures have been developed to treat PCOS – we do not feel there is any role for procedures that cauterize or laser the surface of the ovary – these can cause terrible scarring and do not address the fact that the problem is not with the multiple follicles, but with the excess androgens from the inner part of the ovary.

Ovarian Diathermy is a procedure developed in Scandinavia. Using a specially designed needle that is insulated at all but the very tip, cautery is delivered to the inner part of the ovary, effectively accomplishing the same things as a wedge resection. Because the needle is insulated, there is no damage to the surface of the ovary where the eggs are. This can be done at the time of laparoscopy and is a minor surgical procedure.

In this schematic drawing, the small blue circles represent the follicles and the large red circles represent the areas cauterized at the time of the diathermy. One can think of the ovary as having two compartments – an outer one where the eggs are and an inner one where the androgens are produced. There are very few if any eggs in the inner part of the ovary.

This is a picture at the time of surgery. The tip of the needle can be seen before it is placed into the ovary.

The needle is now in the ovary and the cautery is being performed.

This is an ovary immediately after a diathermy. One can see that there is no damage to the surface of the ovary or to the part containing the eggs.

This is a picture of an ovary that has undergone laser drilling. Note the extensive damage to the surface of the ovary. In this procedure the laser has been used to drain all the little follicles. It is not the follicles that are the problem – it is the abnormal hormone ratio that causes the development of all the little follicles.

There are a number of studies demonstrating that diathermy improves IVF outcomes in women with PCOS. Diathermy is not the first line treatment – we really only do diathermy when all else has failed. If we still can’t achieve good ovulation even after glucophage therapy and attempts at ovulation induction with Letrozole and FSH, then the next step is diathermy.

Because the inner part of the ovary is cauterized, diathermy lasts much longer than did the effects of wedge resection. We have had the opportunity, as have others, to repeat laparoscopies after a prior diathermy and have seen no significant adhesion formation.

Most studies of diathermy have looked at the results in heavier women with PCOS. In 2004 we published the first study looking at diathermy results in exclusively thin women with PCOS. There were some misgivings about doing diathermy in thin women with normal androgen levels, but the “relative hyperandrogenism” theory convinced us this would be worthwhile.

During the study period we did 108 diathermies, and 74 of these were on women with a body mass index of 25 or less. We had follow-up data available on 59 women. 83% of these women conceived following the diathermy.

Not everyone conceived without intervention. If a perfect result is achieved, normal ovulation will result and patients may conceive without any other help. Sometimes this is not the case, and ovulation induction may be warranted. Some of these women needed IVF because of other problems such as male factor issues or tubal disease. Diathermy is indeed a very valuable tool for improving ovarian responsivity in thin women with PCOS.

Diathermy is of value in treating women with PCOS, both heavier and thin, prior to IVF.

Women with PCOS have a significantly increased risk of miscarriage. This risk has been quoted to be as high as 30%. A review of all the literature available, which is not voluminous, suggested that with glucophage treatment this risk can be dramatically reduced. We encourage women with PCOS to continue glucophage during the first 12 weeks or so of pregnancy.

If a woman with PCOS does not desire pregnancy, oral contraceptives are an excellent option. Proscar is a medication normally used for men to shrink the prostate. It is also very effective in women in reducing any excess hair growth. It takes about six months to achieve significant reduction of hair growth, but the combination or oral contraceptives and proscar will get rid of the excess hair.

In conclusion, glucophage is effective in both thin and heavy women with PCOS. The mechanism of action may differ, but it still works very well in both groups. Letrozole is a preferred medication to clomiphene, and is very effective particularly when coupled with FSH. Ovarian diathermy is an excellent treatment option for women whose ovaries do not respond to more conservative treatment. Correction of insulin levels, and correction of the androgen/estrogen ratio is crucial for success.

Thank you, and please do not hesitate to contact us with any questions you may have concerning PCOS.