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Polycystic ovary syndrome (PCOS) is the most common cause of infertility among women in the United States, affecting 6 to 10 percent of women of child-bearing age.

The hallmark of PCOS is a lack of ovulation. Eggs mature in the ovaries, but they aren't released, resulting in fewer than eight periods a year. Other symptoms are acne, excess hair growth, and abnormally high levels of testosterone in the woman's body.

But there's another side to PCOS: It often co-exists with insulin resistance, a condition in which the body's cells do not use insulin efficiently and a major cause of Type 2 diabetes. Women who have PCOS are two to four times more likely to develop Type 2 diabetes than women who don't have PCOS.

The relationship between insulin resistance and PCOS has been keeping Theodore Ciaraldi, PhD, busy in the laboratory at the VA San Diego Healthcare System and University of California, San Diego. Under a grant from the American Diabetes Association, Ciaraldi and his team of researchers are studying the interplay between insulin resistance and PCOS and trying to sort out why the conditions often - but not always - occur simultaneously. Is it a genetic defect? Does one cause the other or is their common occurrence together a coincidence? Why do some women with insulin resistance have PCOS while others don't?


The team will culture the cells in petri dishes for about two months to grow cells that have not been exposed to the body's environment. Then the team will expose the cells to various combinations of sugar, insulin, and androgens (male hormones) that might occur naturally in the women's bodies and see how the cells behave. One aim would be to mimic, in the petri dish, the environment seen in either the normal, diabetic, or PCOS state.

Tying It Together
Here's where it all comes together, says Ciaraldi. First the team will expose the cultured cells from all three groups of women, grown under normal conditions, to insulin and sugar and see whether the cells are insulin resistant. At that point, any cells that are insulin resistant were probably genetically programmed to be, because they have never been exposed to sugar, insulin, or androgens in the environment of the women's bodies. "If cultured cells are insulin resistant, then we know the insulin resistance is intrinsic to the cell. It might be genetic, and not because of an effect of their environment [the body]," he says.

In earlier studies with muscle cells from subjects with Type 2 diabetes, Ciaraldi and Robert Henry, MD, estimated that about 50 percent of the insulin resistance seen in skeletal muscle tissue in Type 2 may be acquired from the body's environment (high blood sugar and insulin) and that 50 percent could be an intrinsic property of the muscle. One question under investigation in the current study is whether the same properties exist in PCOS. Another question is: What are the effects of high androgens? And another: Might women with PCOS be more sensitive to high insulin or androgen levels than their counterparts who don't have PCOS?

For instance, if cultured cells from the women with PCOS are not insulin resistant at first, but become insulin resistant after being exposed to high levels of androgens or insulin in the petri dishes, that might indicate that excess androgens or insulin in a woman's body - which both occur in PCOS - might be causes of insulin resistance.

"Basically, for each insulin resistant group [the first two groups] we are comparing what happens in the test tube to what happens in the body to tease out where the problem is occurring," says Ciaraldi.

From there the team can narrow down exactly what is happening in the cells from the first two groups compared to the cells from the third group, and better define which comes first - PCOS or insulin resistance - and whether one condition causes or worsens the other.

The possibility exists that insulin resistance in women with PCOS has a different cause than insulin resistance in women without PCOS. In women with PCOS, it may be a result of their bodies' environment. In women with Type 2 and no PCOS, insulin resistance may be determined by genetics.

All the better for developing treatment specific to each kind of insulin resistance, says Ciaraldi. "By finding out exactly what's going wrong in cells, that tells you what you need to target," he says.

He points to a special protein, called an AKT protein, as an example. "There is a 75 percent reduction of this protein in the skeletal muscle tissue of women with PCOS when we look at muscle right after it is taken from the women. But after culturing the cells for two months outside the body, there is no reduction in this protein. So that indicates that this specific muscle cell defect in women with PCOS is probably acquired in the body, and not caused by genetics," he says.

But is that reduction in protein tied to the PCOS or the insulin resistance? And if there was some way to stop the reduction of that protein, would it stop the insulin resistance, the PCOS, or both?

Ciaraldi notes that even current treatments for PCOS are not well-understood. Some doctors prescribe the diabetes drugs metformin (Glucophage), pioglitazone (Actos), or rosiglitazone (Avandia) to treat PCOS. (This is considered "off-label" usage, as these drugs are not approved by the Food and Drug Administration specifically for treating PCOS.) All are Type 2 drugs, and all have been used successfully to treat some women with PCOS, but they work differently. The "glitazones" sensitize cells to insulin; metformin slows the production of sugar in the liver.

Ciaraldi adds that researchers don't know why two different kinds of drugs would have the same effect on PCOS. Is it because they keep blood sugars in check, or because, by keeping blood sugars in check, they keep the amount of insulin in the blood in check as well?

"We know that the drugs do work, but that's all," he says. "It would be helpful to know exactly why."

Terri Kordella is associate editor of Diabetes Forecast.