PCOS Articles - PCOS-Not Just An "Ovary" Disease

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01-19-2004, 01:26 PM
Poly-Cystic Ovary Syndrome - "PCOS"

Poly-Cystic Ovary Syndrome - PCOS - is the most common endocrine disease that affects women of reproductive age (puberty to menopause). It is also one of the most confusing. It affects approximately 10% of women in the reproductive age group. There have been some new developments that are giving us a much better understanding of this problem.

PCOS is an unfortunate term because the word "ovarian" appears in the name of this syndrome. For years, many people automatically assumed that it is purely an ovarian disease. We now recognize that it is in fact, a systemic endocrine and metabolic disorder. Multiple factors are at work. It should really be called the "Poly-Cystic Ovary/Excess Androgen Production /Adrenal Hyperplasia / Insulin Resistant / Hyperpipidemic / Often Overweight / Anovulatory /Hirsute / Sometimes Acne" Syndrome.

PCOS is a total body endocrine disease. It is unfortunate and confusing that the word "Ovary" appears in the name. The abnormalities in the ovary are really more the result of the problem - not the cause.

The problem is further complicated by the fact that there is really no universal definition of PCOS even though most endocrinologists would agree on a set of criteria necessary to make the diagnosis. If there is one absolute that is necessary to make the diagnosis of PCOS, it is the complete or almost complete lack of ovulation. Women who are ovulating regularly on their own, cannot, by definition, have PCOS. There are however Reproductive Endocrinologists who feel that women who have all the features of PCOS except for the fact that they ovulate may have a subset of the syndrome. However, these women are much less likely to be insulin resistant.

The other criteria that must be satisfied is that the women have either clinical or laboratory evidence of increased androgen (male hormone) production, either facial hair and/or acne. Laboratory confirmation is important because women from certain ethnic groups such as Oriental, Hispanic, or Native American may show very little clinical evidence of increased androgen production even in the face of significantly elevated blood levels.

The vast majority of women with PCOS have very irregular periods - usually on the order of every 2 to 3 months or even less frequently. One definition of PCOS requires that the woman have fewer than 6 periods a year. (As I have said, there is no one universal definition of the syndrome).

Another cardinal feature of PCOS is increased androgen (male hormone) production. Therefore, women with PCOS almost always have facial hirsutism (excessive hair) and frequently have acne as well.

Another common feature of PCOS is obesity. Many women with this syndrome are significantly overweight.

A major breakthrough in out understanding of this syndrome has come about with the recognition that many women with PCOS, particularly if they are overweight, are insulin resistant with elevated serum insulin levels - hyperinsulinemia. It is becoming increasingly apparent that the insulin resistance and the resulting hyperinsulinemia is an important part of PCOS. Women who are overweight, even if they show evidence of increased androgen production, do not usually have hyperinsulinemia if they have regular ovulatory menstrual cycles.

Women who have PCOS but are not overweight also frequently have insulin resistance, but not as frequently as PCOS affected women who are overweight. However, they are insulin resistant often enough that they too need to be evaluated.

The term "insulin resistance" means that your body is more resistant to the action of insulin than normal. Insulin is the hormone that keeps your blood sugar within "normal" limits. If you are insulin resistant, your pancreas has to make more insulin to keep your sugar normal. As long as your pancreas can meet the excess demand placed upon it, you are OK. If your pancreas cannot keep up with the increased demand, your blood sugar will rise and you will become diabetic.

Newer data indicates that the underlying problem is possibly an inherited genetic abnormality in which the affected individual is producing abnormal insulin - insulin that is close enough to normal that it still works to control blood sugar but not was well.

There is also evidence that there is an abnormality in the insulin receptor - the part of the cell that enables it to interact with insulin. A defect in the action of the receptor means that the insulin does not perform its actions properly, thereby blocking the movement of glucose (sugar) into the cell, which is the principal action of insulin.

Other studies suggest the possibility that the insulin receptor is normal but somehow inactivated so that more insulin is needed to obtain the necessary actions. The mechanism of this inactivation is far too complicated for this pamphlet. I will explain it to you if you are interested.

Older people with so-called "Adult Onset Diabetes" are usually overweight and are also insulin resistant. However, the mechanism by which these people are insulin resistant is different from the abnormalities that cause the insulin resistance in women with PCOS.

Excess sugar, if it cannot be metabolized, is converted to fat by another action of insulin. As you can now appreciate, PCOS is a complicated syndrome with many interactions combining to produce the clinical picture.

It is also critically important to recognize that, as I have already mentioned, PCOS is not purely an ovarian problem. There is a significant adrenal component as well. Many women with PCOS have increased adrenal androgens as well as increased ovarian androgens. In fact, this is what has led to much of the confusion in the past. Many women with PCOS have an increased level of hormones in their blood that we know are almost exclusively produced by the adrenal gland. This results in abnormal lab tests that are also seen in women with a primary adrenal problem - a problem that produces a clinical picture identical to PCOS. In other words, by all the symptoms and lab tests, these women cannot be easily distinguished one from the other. This is what has resulted in so much confusion in the past and continues to make it sometimes difficult to separate one from the other.

It is important to understand what is going on at the level of the ovary to explain, in part, where the terminology has come from. The ovary has 2 principal functions - the production of an egg each month for ovulation and the production of all the hormones necessary for normal reproduction. Although everyone is aware that estrogen and progesterone are critically important hormones for normal reproduction, many do not realize the important role androgens play in the regulation of normal ovarian function.

A woman is born with all the eggs she is ever going to have - approximately 1 million at birth. From that point on until she goes through menopause at approximately age 50, many eggs each day begin to develop but never go anywhere. These eggs die and are absorbed by the body. If you care to do the calculations, it averages out to about 100 to 150 eggs per woman per day.

As the eggs develop, in a structure called the follicle, small amounts of fluid begin to accumulate. If the egg goes on to full maturity and ovulation, the follicle becomes quite large (about 1 inch in diameter) and contains about 1 teaspoon of fluid. By definition, because it contains fluid, the follicle is a cyst.

In addition, each month during the normal ovarian cycle, many follicles begin to develop but never go on to full maturity and ovulation. Nonetheless, many of these immature follicles also acquire some fluid within them.

In order to make estrogen, the cells of the follicle take androgen from the surrounding ovarian tissue and convert the androgen to estrogen. Furthermore, it is important to keep in mind that in order for the follicle to grow to full maturity and produce estrogen, the egg must be alive and healthy. If the egg dies, the follicle loses its ability to produce estrogen. However, the cells surrounding the follicle continue to produce androgen even though the egg has died.

Under normal circumstances, the amount of androgen produced from the dying follicles is not of major consequence since the estrogen produced from the healthy ovulating follicle is so great. However, you can now begin to appreciate that if a woman does not ovulate, there is no "dominant" follicle producing large amounts of estrogen but there are many half-developed follicles that are producing androgen. Also keep in mind that these half-developed follicles may have accumulated some fluid. Therefore, in a woman who does not ovulate, the ovary often has many small half-developed follicles producing increased amounts of androgen. You will recall that I also mentioned that any structure in the body that has fluid in it is called a cyst. Therefore, an ovary that does not ovulate properly has multiple small cysts in it. In other words, it is "poly-cystic".

For many years, people believe that the multicystic ovary that is characteristic of this syndrome was the cause of it. In fact, it is the result. Any hormone problem that interferes with normal ovulation results in a "polycystic" ovary. A polycystic ovary, regardless of cause, will produce increased amounts of androgen. People confused cause with effect.

Another area of confusion is that not all women with androgen disorders have polycystic ovaries. Many women can have a significant androgen problem and yet ovulate normally and can even conceive without difficulty.

Normally, there is a significant increase in androgen production at puberty. It is for this reason that pubic hair begins to appear at this time. If a teenage girl's androgen production is significantly increased compared to normal, this often initiates the entire process and many women can date the onset of their androgen disorder back to their teenage years.

Another term that is sometimes used to describe women with these problems is "Stein-Leventhal Syndrome". This term has historical interest only and has no place in modern medical practice. It was named after Drs. Stein and Leventhal who published, in 1935, the first article describing what we now know to be PCOS.

One of the features of the Stein-Leventhal Syndrome is obesity. We know that a substantial percentage of women with androgen disorders are overweight. Whether the obesity play a role in the causation of these symptoms or whether it is simply a part of the overall clinical picture is unknown. More recent evidence suggests that obesity is a part of the androgen excess syndromes and not simply the result of increased androgen production. However, overweight women produce increased androgens even if they have no underlying abnormality in the adrenal gland. (Gets confusing, doesn't it?!)

Based upon the available data at this time, it appears that in some women, androgen disorders start out as an abnormality in adrenal function. The adrenal gland produces increased amounts of androgen either at puberty or at some time later in life due to significant stress. The adrenal gland produces increased androgen if the woman has been born with one of the adrenal enzyme deficiencies. In some women the problem remains isolated to the adrenal gland. These women show clinical evidence of increased androgen production with hirsutism and/or acne but they often do not show any alteration in menstrual function and are often normally fertile.

In other women, the increased adrenal androgens affect the normal growth of the follicles in the ovary. They prevent the eggs from developing normally and halt the growth of the follicle. As I have pointed out, under these circumstances, the egg dies and the follicle is no longer able to produce adequate amounts of estrogen but does continue to produce significant amounts of androgen. Therefore, by the time the woman appears in the office for evaluation, she no longer has a simple adrenal problem nor does she have a purely ovarian disorder. Rather, she has a combined problem with increased androgen production from both the ovary and the adrenal and, if she is overweight, with a substantial contribution from her body fat.

The HAIR-AN Syndrome (discussed later in this pamphlet) was thought to be a separate entity. Newer information now suggests that it may in fact maybe a subset - a special and often more severe case of Polycystic Ovary Syndrome.

It has been known for a long time that a substantial percentage of women with these syndromes are overweight. It was never known with certainty whether the obesity is a cause and effect or simply a part of this syndrome. This newer evidence now suggests that the weight problem may in fact play a major role in creating the syndrome.

Further confusing the attempts to distinguish adrenal abnormalities from PCOS is the fact that both begin at puberty. In the case of PCOS, the problem may start out as a weight problem in a teenage girl. It has been known for a long time that people who are overweight are insulin resistant. By this it is meant that your body must produce greater amounts of insulin to maintain a normal blood sugar. So long as the pancreas is able to keep up with the body's demands and so long as there is an adequate supply of the cells within the pancreas that produce insulin, your blood sugar will remain normal and you will not be diabetic. If however, for whatever reason (and it is usually autoimmune) your pancreatic islet cells become depleted, then your pancreas is no longer able to make enough insulin to control the blood sugar, the blood sugar increases, and you become diabetic.

It is fairly easy to determine whether someone is insulin resistant. One of the most common ways to find out is simply to measure the fasting blood sugar and fasting insulin level in the morning. Most women will also need to undergo a Glucose Tolerance Test, measuring both blood sugar levels and insulin levels. If the insulin levels are higher than they ought to be, this indicates insulin resistance.

Many teenage girls who are significantly overweight are insulin resistant.

Many women with PCOS have an abnormal Glucose Tolerance Test that is in between "normal" and Diabetes. This stage is call "Impaired Glucose Tolerance". It is important to identify such women because appropriate therapy can dramatically alter the situation.

A substantial percentage of women, a number that is higher in some ethnic groups than others, have an underlying adrenal abnormality that also results in increased androgen production. This increased androgen production from the adrenal gland disrupts normal ovulation from the ovary. As a result, these women also develop polycystic ovaries.

Any event that results in increased androgen production can initiate the entire process that results in the clinical syndromes we are talking about here. As I have already indicated, a significant stress is one factor. Often such women will have a history of some menstrual irregularity and minimal hirsutism that suddenly and significantly worsened after a stressful situation.

To further confuse the issue, there is good evidence that abnormal ovarian hormone production may cause the adrenal gland to produce excess androgen. Suppressing ovarian hormone production will ultimately lead to a decrease in adrenal androgen production but it takes a long time. Nonetheless, the fact that this does occur is good proof that not only does abnormal adrenal hormone production affect the ovary but the opposite is true as well.

If the woman is ovulating normally, the cells of the follicle wall are producing estrogen. The estrogen in the follicle is made from androgen produced in the cells of the ovary that surround the follicle. It is also important to understand that unless there is a normal egg within the follicle, the cells of the follicle wall cannot produce estrogen. However, the surrounding cells continue to produce androgen. Therefore, if a woman has any sort of endocrine problem that interferes with normal ovulation, the ovary will not produce normal amounts of estrogen but will often produce increased amounts of androgen.

The increased androgen from the ovarian tissue is very easily converted in body fat to various forms of estrogen. We have known for a long time that women who are significantly overweight produce considerably more estrogen than women who are of normal body weight. This increased estrogen production in a woman who does not ovulate accounts for, in part, the increased risk of uterine cancer and pre-malignant changes in the endometrium (lining of the uterus) often seen in women with PCOS.

The recent recognition that women with PCOS are insulin resistant with evidence of hyperinsulinemia shed further light on what is going on with this syndrome. It has now been clearly shown that the increased insulin found in women with this syndrome stimulates ovarian androgen production. Increased androgen production in turn contributes to insulin resistance and the woman gets locked into a vicious cycle. Increased androgen production also leads to an increase in body weight which also contributes to insulin resistance.

It is also important to understand that many hormones do not act directly on their target tissues. Instead, they stimulate the production of intermediate hormones and hormone like substances that in fact control and modify the actions of the hormones. One thing we have learned in the last few years is that the body has incredibly complex interactive control mechanisms. Every hormone action is usually modified and controlled by several other hormones which may in turn be controlled by the original hormone. Sometimes more than one hormone will control other modifiers and it becomes a series of loops within loops within loops.

Growth hormone, produced by the pituitary gland, is a typical example of this. While growth hormone may have some direct action on tissues, many of growth hormone's actions are the result of another hormone like substance produced under the stimulus of growth hormone. This other hormone like substance is called Insulin Like Growth Factor - I (ILGF-I). ILGF-I is a substance found all over the body and, in keeping with this discussion, happens to be stimulated by insulin. People with elevated insulin levels will therefore have increased amounts of ILGF-I.

It also turns out that ILGF-I also stimulates ovarian androgen production. As you can now begin to see, the story is beginning to unfold. An overweight teenage girl who becomes insulin resistant will begin to produce increased amounts of ILGF-I which in turn stimulates increased amounts of ovarian androgen production. This increased ovarian androgen production interferes with the normal maturation of the controlling clock in the central nervous system that ultimately gives most women regular menstrual cycles. If this "clock" does not develop a normal cyclic rhythm, the women's menstrual cycle remain irregular. Androgens are known to interfere with this process.

The stage is then set for the PCOS picture. You end up with an overweight teenage girl who has irregular menstrual cycles and often the stigmata of increased androgen production with acne and/or hirsutism.

Putting all these factors together allows us to come up with a scenario that appears to help us understand (though perhaps not completely) exactly what is going on. PCOS appears to be a disorder that arises at puberty although signs of it can often be detected in girls before puberty. If a teenage girl going through puberty is overweight, she will frequently be insulin resistant just as a result of her obesity. Obese adults are insulin resistant and this frequently sets the stage for the development of diabetes.

However, it appears that just being overweight is not sufficient. Many women who are overweight do not have PCOS. Conversely, women can develop PCOS who are of normal weight. No one knows exactly what the initiating factor is. It may very well be that the abnormality that leads to increased androgen production is the ultimate cause and that being overweight simply compounds the problem.

It appears there is also another necessary component to this syndrome - namely that the woman has inherited a defect in the way either the ovary or the adrenal (or both) produce their hormones. It has been recognized for many years that PCOS definitely runs in families. It is inherited as an autosomal dominant trait. Therefore, if a woman has PCOS, it should be looked for in her mother, sisters, and daughters.

Since it is autosomal dominant, male relatives will also carry the gene. These men are also often insulin resistant and at increased risk for diabetes. Some evidence indicates that the marker for the PCOS gene is men is early balding. If a male relative develops significant balding before the age 30, he should be evaluated.

If a teenage girl is overweight, is insulin resistant, and has inherited the trait that predisposes her to abnormal ovarian/adrenal function, the stage is then set for her to develop PCOS. The increased insulin resistance results in elevated serum insulin levels which then stimulates excess androgen production. This results in evidence of excess androgen production with facial hirsutism and/or acne.

The excess androgen may also worsen the obesity, adding fuel to the fire.

Increased androgen production interferes in normal ovulation. Women with this syndrome then stop ovulating (or probably never started in the first place). The increased androgen production blocks development of the follicles and so the ovary becomes "polycystic". The abnormal ovary then begins to produce increased amounts of androgen.

If the ovary is producing increased androgen and this androgen is being converted in the body fat to estrogen, the estrogen appears to stimulate excess adrenal androgen production, even if the woman was not born with an adrenal abnormality to begin with. Furthermore, the increased estrogen produced from the conversion of androgen blocks ovulation at the level of the pituitary, which in turn increases ovarian androgen production. And so the process goes, each abnormality feeding on others which in turn feeds back on itself.

Once the woman gets locked into this vicious cycle, it becomes self perpetuating.

Is there anything we can do about it? The answer is definitely yes. Depending upon the age of the woman, the symptoms it is producing, whether or not she is trying to become pregnant, whether or not the facial hirsutism is a significant cosmetic problem for her, etc., there are numerous therapeutic options available.

It is now well documented that the anti diabetic drug - Metformin (trade name Glucophage) - will reduce insulin resistance and lower serum insulin levels. There is now overwhelming evidence that if women with PCOS who are either diabetic or have impaired glucose tolerance are put on Metformin for a period of time, their "PCOS" may be reversed.

The other drugs, Actos and Avandia, also decrease insulin resistance and early data indicates this may break the PCOS cycle. Actos is probably the better drug, especially for people who are already diabetic. This is an exiting new development because if teenage girls are diagnosed early, we may be able to prevent the syndrome from developing. At the very least, we can minimize the adverse consequences of PCOS.

A new drug was released in June, 1999 - Avandia. Soon after, another drug - Actos - also became available. These are in the same class as Rezulin and so far, careful monitoring has revealed no evidence of liver problems. If they remain safe, it will definitely be a major breakthrough in the treatment of PCOS as well as diabetes.

Losing weight will often accomplish the same thing. Losing as little as 7% of body weight many allow the resumption of normal menstrual cycles. However, as most people are well aware, losing weight is an extremely difficult thing for many people to undertake. None-the-less, weight reduction is an important part of the syndrome's treatment if it can be accomplished.

The other problem is that the insulin resistance associated with PCOS is an inherited, genetic disorder whereas the insulin resistance associated with obesity is an acquired problem. Losing weight will not affect the inherited disorder.

Suppressing ovarian function with either oral contraceptives or other drugs is also a significant therapeutic option. The problem is that oral contraceptives may increase insulin resistance and therefore contribute to the problem. They can be used, but with caution and careful monitoring. The use of drugs to block the effect of androgen on the peripheral tissues is also another treatment that is commonly employed.

Making a diagnosis of PCOS early is important. First, it many prevent the development of the full blown syndrome. Furthermore, women with PCOS are at increased risk of developing Diabetes, Coronary Artery Disease, lipid disorders including an elevated cholesterol, high blood pressure, abnormalities in the lining of the uterus and an increased risk of uterine cancer, and possibly breast cancer as well.

The problem is that many teenage girls with PCOS end up being treated for the symptoms only, such as the acne or hirsutism, but the underlying endocrine and metabolic abnormalities are ignored.

Women with PCOS and close family members need to have a glucose tolerance test looking for diabetes and they also need to be monitored for abnormal changes in the lining of the uterus that might be indicative of cancer or pre-cancerous problems.

Based upon this information and other information that definitely shows a significant hereditary tendency to develop PCOS, it is critically important to evaluate teenage girls at the time of puberty if there is reason to believe that they are genetically predisposed to develop these problems. This is definitely a disease in which early diagnosis and treatment may make a profound difference in later life.

Advances in medical research are allowing us to get down to the actual molecular basis of human disease. Virtually all human diseases that are either not infectious or traumatic involve defects in a gene. Keep in mind that the human body is a huge biochemical engine. Everything that happens in our body is the result of some chemical reaction. Almost all chemical reactions in the body are controlled by enzymes. Enzymes are chemical catalysts which allow the chemical reactions to take place in a controlled manner. Enzymes are nothing more than very complex proteins. The body makes these proteins using a pattern or template controlled by a gene.

If there is an abnormality in the gene, the protein that it controls will be abnormal. Therefore the reaction or the process or the hormone or whatever that protein is suppose to regulate will be defective. Many human diseases have already been traced to a defect in one or more genes and the number is growing by leaps and bounds every year.

It has recently been discovered (and this received a great deal of publicity in the popular press) that fat produces a hormone called leptin. Hormones work by attaching themselves to special proteins in the cell called receptors. If the body produces a hormone normally but there is a defect in its receptor, the body has no way of recognizing that hormone and therefore, as far as the body is concerned, that hormone either does not exist or it functions at an extremely low level.

There is a receptor for leptin in the brain and it is felt that this helps us regulate how much food we eat and how much we weigh. There is now good animal evidence that obesity is, at least in part, the result of a defective leptin receptor in the brain. Therefore, obese people are unable to properly regulate their food intake and their body fat composition. Giving leptin to obese individuals helps them lose weight, though not to the degree we would like to see.

For reasons that have not yet been discovered, there are also leptin receptors in the corpus luteum. Newer information suggests that leptin should be considered a reproductive hormone although it obviously has other functions.

In a normally menstruating woman, each month an egg develops in a structure called the follicle. The follicle produces estrogen prior to ovulation.

Following ovulation, the follicle undergoes a transformation and becomes the corpus luteum. The corpus luteum produces estrogen and progesterone. The corpus luteum has a normal built in life span of approximately 14 days and it is this that helps regulate the menstrual cycle.

With occasional exception (and there are always exceptions in medicine) women with regular menstrual cycles ovulate and women with irregular menstrual cycles do not, or at least they ovulate very irregularly and infrequently. We also know that the body does not do anything by accident or without a very good reason. It may take us a long time to discover that reason but there has to be one. The purpose of leptin receptors in the corpus luteum at this time is not known. It must also be understood that since each human being is ultimately formed from a single egg and a single sperm, the genetic makeup of all of our cells is identical. If a person has defective leptin receptors in the brain, they will also have defective leptin receptors in the ovaries. Therefore, a woman who is born with an abnormal gene for the leptin receptors will not only be obese but she will also have irregular menstrual periods as there is a corresponding defect in the ovary as well.

I point this all out because it gets very frustrating for women with these syndromes when they try to lose weight and they cannot do so. It appears from the data that is currently available that women with these syndromes are genetically programmed to be overweight. To the degree that you can lose weight, the whole situation will be improved. However, although I don't want to sound too discouraging, it may be physiologically impossible. However, if a woman is insulin resistant and appropriate therapy reduces or eliminates that resistance, weight loss may be possible.