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    SoulCyster #1 KatCarney's Avatar
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    Thumbs up Pcos - Required Reading!!

    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.


    PCOS VARIANTS


    In the previous section of this pamphlet, I discussed the diagnosis of PCOS and pointed out that it is a clinical diagnosis based upon two criteria - abnormalities of ovulation and evidence of increased androgen production.

    If I were doing a research study on PCOS, I would have to stick to the strict definition of PCOS which requires that the woman have menstrual cycles longer than 35 days in conjunction with either clinical and/or laboratory evidence of increased androgen production. Women who have this constellation of signs and symptoms would be defined as having "Classic Poly-Cystic Ovary Syndrome". According to some recent data, only about one-third of all women with PCOS have the full-blown classic syndrome. The other two-thirds have only one or two features but still, when looked at appropriately, do fit the criteria.

    There are, however, a number of women who do not fit the classic textbook definition of PCOS but who have many features which makes the diagnosis of PCOS the most appropriate one for them. We would term these women as having "Non-Classic PCOS".

    For instance, instead of having very infrequent cycles, some women will have totally irregular bleeding with periods coming every two weeks, sometimes alternating with much longer cycles.

    Other women with non-classic PCOS will have fairly normal cycles and increased androgen production will have a typical "poly-cystic" appearance of the ovary on ultrasound. A number of studies have shown that the presence of a poly-cystic appearing ovary is frequently associated with many of the other features of classical PCOS even though the women may not fit the true definition.

    Another study has shown that there may be at least two different disorders associated with PCOS that, again, we would term "non-classic PCOS". The first of these (which I am not sure really falls under the category of PCOS) are women who are obese and hyperinsulinemic but not hyperandrogenic. Since we know that obesity produces insulin resistance by a different mechanism than classic PCOS, these women probably represent a totally different syndrome, although there may be considerable overlap.

    The second type of non-classic PCOS would be those women who appear to be hyperandrogenic but are not insulin resistant and/or hyperinsulinemic.

    Approximately two-thirds of all women with classic PCOS are overweight and, in this group of women, the majority are insulin resistant.

    Approximately one-third of women with classic PCOS are of normal body weight but only about one-third of these women are insulin resistant. However, for reasons that have yet to be explained, most of these women will still respond to insulin sensitizing therapy. This probably means that our criteria for insulin resistance and the ways we have of measuring it are not sensitive enough.

    It has also been shown in various studies that women with the clinical features of PCOS who also have the ultrasound manifestations of PCOS will show more severe abnormalities than women whose ultrasounds are "normal".

    A study published in 1988 in the British Journal "The Lancet" looked at the ovaries of "normal women". Of those women studied, 22% had "poly-cystic" ovaries on ultrasound and, of those women, 76% had irregular menstrual cycles and 6 of 8 women with regular menstrual cycles had significant hirsutism.

    Turning the numbers around, 26% of women with no menstrual periods (amenorrhea) and 87% of women with oligomenorrhea (infrequent menstrual periods) will have poly-cystic ovaries on ultrasound. In this particular study, 92% of women with hirsutism and regular menstrual cycles also had poly-cystic ovaries.

    Also, as has been mentioned elsewhere in this pamphlet, it is important to consider the ethnic background of the woman who is being evaluated. Your genetic make-up will determine how sensitive you are to the effects of increased androgen or whether you are in fact sensitive at all. It is well-known that hirsutism does not develop in Japanese women unless their testosterone is severely elevated. Similarly, women of northern European extraction (such as Scandinavia) will often show a much lesser response to testosterone; women of Mediterranean ancestry will often show a significant response to rather minimal elevations in their testosterone.

    Another common variant which I see involves women who may have regular menstrual cycles but who are insulin resistant in association with evidence of increased androgen production.

    While textbook definitions are important, it has always been my philosophy that the most important thing is to treat your patient properly. By widening the definition to include these other women, who I believe are in fact PCOS variants, it allows me the opportunity to offer them more effective therapies than would be possible if I were to insist upon a strict definition.


    Diagnosis

    This section and the treatment section are being included in the pamphlet so that you will know what I am doing and why I am doing it.

    It is also being included because I am an advisor to the Poly-Cystic Ovary Syndrome Association. You can access their web site at "www.pcosupport.org".

    As a result of this, I receive a number of requests over the internet from women who believe they have PCOS and are seeking additional information. Many of these women live in smaller cities or rural areas where they do not have access to a Reproductive Endocrinologist. Their local General OB/GYN and/or family physician may not be fully aware of the newest developments in the evaluation and treatment of a woman with PCOS. Therefore, the other reason for these sections is to help these women get the treatment they need even through their local physicians when they cannot see a Reproductive Endocrinologist directly.

    The diagnosis of these abnormalities is now fairly simple and straight forward. Any woman who has clinical evidence of increased androgen production is indeed producing too much androgen. However, these women could be producing increased androgen from the adrenal as well as the ovary. Not all women with increased androgen production have one of these partial enzyme deficiencies although a certain percentage do.

    For those women who are suspected of having PCOS, a number of evaluations are necessary. Routine blood chemistries, of course, are important.

    As an initial step, baseline hormone studies are drawn looking for evidence of increased androgen production. If the baseline studies indicate a problem, no further diagnostic tests are necessary and therapy can be instituted.

    Evaluation of thyroid function is also appropriate although I am not aware of any evidence that thyroid disease is any more or any less common in women with PCOS.

    Because excess androgen production is such a major part of this syndrome, a full evaluation of this problem is also indicated. Ideally, these tests should be performed in the very earliest part of the menstrual cycle - immediately after the period has ended. This is easy for the woman who has somewhat irregular periods but does not skip them for months at a time.

    However, as you can appreciate, if you are a woman who only gets a period every 3 to 6 months, you could wait a long time to complete your work-up. In such instances, I will either induce a period artificially with Provera or I will check the Estradiol, Progesterone, FSH and LH to verify that, hormonally, the woman has not ovulated. Some of the hormones will be higher after ovulation than they are before and, unless you know exactly where a woman is with respect to ovulation, an erroneous interpretation of the laboratory tests will be made. Keep in mind that women with PCOS may ovulate spontaneously on occasion, even though they do not ovulate regularly.

    I measure the following androgens:

    Total testosterone
    Bioavailable or free
    testosterone
    Androstenedione
    17 hydroxy Progesterone
    DHEAS
    Dihydrotestosterone
    Sex Hormone Binding Globulin (SHBG)
    Abnormalities of glucose and insulin production also play a major role in this syndrome; this too must be evaluated. A baseline screen can be drawn anytime the woman is in the office, regardless of when she last ate. Measurement of the glucose/insulin ratio is then an easy calculation. If this ratio is less than 4.5, there is strong presumptive evidence of insulin resistance.

    If the woman happens to be fasting at the time of her office visit (or has not eaten anything for at least 6 hours) then a fasting blood sugar and insulin level is also measured. If the fasting insulin level is over 20, insulin resistance is present.

    A woman who shows evidence of insulin resistance should be evaluated with a two hour glucose tolerance test with insulin levels measured with each sugar level.

    If you are going to have a glucose tolerance test, you should be "carbohydrate loaded" prior to the test to make it more accurate and valid. Carbohydrate loading means consuming at least 100 grams of carbohydrate everyday for three days prior to the test. This can be fairly easily accomplished by eating a couple of candy bars each day for those three days.

    The glucose tolerance test must be carried out first thing in the morning. Performing a glucose tolerance test in the afternoon may yield different results and lead to erroneous conclusions.

    You would come to the office fasting in the morning. Baseline blood studies would be drawn and you would then be given a bottle of concentrated sugar water to drink. This contains a standard amount of 75 grams of glucose.

    Blood sugars and insulin levels are then drawn at the one-half hour, one hour, and two hour time periods.

    Four different interpretations of a glucose tolerance test are possible. First, it could be completely normal.

    Second, at the other end of the spectrum, you could already be overtly diabetic and perhaps not even suspect it.

    There are two intermediate stages in which the glucose tolerance test is not normal but does not yet fulfill the criteria for diabetes. The first of these stages is called "Impaired Fasting Glucose." This diagnosis is made if the fasting blood sugar is over 110 but less than 126.

    Impaired Glucose Tolerance is diagnosed if the two hour blood sugar is over 140 but less than 200 and the fasting blood sugar is normal (less than 126).

    A diagnosis of diabetes is made if the fasting blood sugar is over 126 and/or the two hour blood sugar is over 200.

    Abnormalities of adrenal function are also commonly seen in women with Poly-Cystic Ovary Syndrome but, as I have already noted in this pamphlet, women with the so-called adult onset form of adrenal hyperplasia may present with a clinical picture that is identical to Poly-Cystic Ovary Syndrome. If there is any strong suspicion that these women have a predominantly adrenal problem, consideration should be given to evaluating the adrenal gland specifically.

    Clues that would indicate a possible adrenal problem would be a woman who has all of the clinical features of Poly-Cystic Ovary Syndrome but who also has a significantly elevated DHEAS level, an elevated 17 hydroxy Progesterone level, and who does not exhibit evidence of insulin resistance or any abnormality on a glucose tolerance test. A woman with the clinical features or PCOS but who ovulates regularly also needs to be tested for a possible adrenal problem.

    Keep in mind that abnormalities of glucose metabolism and insulin resistance are a cardinal feature of Poly-Cystic Ovary Syndrome but are usually not seen in the other syndromes.

    In women where there is a strong suspicion of an adrenal problem, a rapid ACTH stimulation test can be carried out. This test must be done right after a menstrual period has ended. The baseline 17 hydroxy Progesterone level is drawn and then 0.25 mg. of synthetic ACTH (Cortrosyn) is administered intravenously. A repeat 17 hydroxy Progesterone level is then drawn one hour later.

    If the baseline 17 hydroxy Progesterone is over 200 or the 1 hour 17 hydroxy Progesterone is over 500, then a diagnosis of adrenal hyperplasia is warranted. If the 17 hydroxy Progesterone levels do not meet these critical levels, the woman probably has Poly-Cystic Ovary Syndrome with disturbances of adrenal function that are now recognized to be a part of PCOS.

    Another problem that must also be thoroughly investigated is your cholesterol and other lipids. Women with Poly-Cystic Ovary Syndrome frequently have a significantly elevated cholesterol and this may be, in addition to their elevated insulin levels, another reason why there is an increased risk of cardiovascular disease and heart attacks later in life.

    There is now good evidence that in diabetics (who are known to have an increased risk of heart attacks), an elevated insulin level is a separate risk factor, independent of anything else. It is, therefore, reasonable to conclude that the hyperinsulinemia seen in women with PCOS may be a similar risk factor. Although the data has not yet been published, it is certainly a reasonable conclusion that ought to at least be considered in the overall management.

    Another important test is the measurement of Sex Hormone Binding Globulin (SHBG). Hormones circulate in the blood attached to specific proteins. In the case of Estradiol and Testosterone, the main protein is SHBG although albumin and other proteins also bind the hormones as well.

    It is now well established that decreased SHBG levels are a major predictor for the future development of Diabetes and alerts us as to who needs more careful monitoring.

    Therapy
    Making the diagnosis of an adrenal enzyme deficiency is usually rather simple and straight forward. Treating the problem is also simple in principle but often frustrating in actual practice. Suppressing the excess androgen production is easy in most instances. Correcting the clinical abnormality such as hirsutism, acne or infertility is often successful but also often frustrating.

    The problem is basically the inability of the adrenal gland to make the hormones your body requires - principally cortisol- in proper amounts. Cortisol is not only necessary for every day life, it is one of the body's main hormones in times of stress - both physical and emotional. Many people will notice that acne worsens in times of emotional stress. Women will notice that their facial hair growth is worse in times of stress. Menstrual irregularities may be worsened in times of stress and the over production of cortisol by the adrenal gland is one of the mechanisms for this.

    In times of stress, the adrenal produces increased amounts of cortisol. If the adrenal has to work overtime to produce the necessary amount of cortisol, it produces even greater amounts of androgen.

    It is impossible to fix the underlying adrenal abnormality although gene therapy is already a theoretical possibility. It may prove to be an actual therapeutic tool within the not too distant future.

    In the meantime, since the adrenal cannot be fixed and since the problem is to make sure that the body has a proper amount of cortisol, the solution is simply to give your body what it needs in terms of cortisol. By giving you cortisol or a hormone derived from cortisol, your body's daily needs are supplied and the overproduction of adrenal androgen is eliminated.

    Although it is possible to use cortisol or cortisone for this therapy, synthetic derivatives have proven to be much more useful in clinical practice. The two most common drugs that are currently employed are either Prednisone or Dexamethasone (Decadron).

    After the initial diagnostic evaluation, considerations as to the best choice of treatment must be made. Important considerations as to therapy are dependent in large part upon whether or not the woman is interested in becoming pregnant or whether she is simply seeking help for her endocrine abnormality. Treatments that would be very appropriate and helpful in women who are not trying to become pregnant would be totally inappropriate in the infertile woman.

    Generally speaking, it is far easier to treat the adrenal gland and correct its abnormalities than the ovary. Treatment of the adrenal gland consists of suppressing its hormone production using either prednisone or dexamethasone. Within a matter of weeks, it is possible to completely suppress adrenal androgen production and this can be easily monitored with appropriate blood tests.

    In some women, suppression of the adrenal androgen production "unblocks" the ovary and allows resumption of normal menstrual cycles and even conception.

    In other women, for reasons that are not well understood, the ovarian abnormality may persist even after the adrenal problem has been corrected. The ovary continues to be a source of increased androgen production. If the woman is not interested in conceiving, ovarian androgen production can be suppressed with the use of oral contraceptives. In these women, the combined use of birth control pills and prednisone or dexamethasone will result in a near complete suppression of all androgen production in the body.

    If the woman is interested in conceiving and prednisone or dexamethasone has not corrected the problem completely, additional drugs such as Clomiphene or Pergonal to correct the ovulatory abnormality may be necessary.

    Women with PCOS will need several therapies including treating any associated abnormality of insulin secretion, suppressing ovarian androgen production, and treating the effects of increased androgen production.

    For many women, their facial hirsutism is the principal reason that brings them to the office. In some women, the hirsutism is so excessive as to create a major cosmetic problem. This can result in significant social problems as these women do not consider themselves particularly attractive. Unfortunately for many women, even when androgen production is substantially suppressed, the hair keeps growing merrily along.

    There are several reasons for this. It appears that much less androgen is required to keep the hair follicle growing than it was to get it going in the first place. This, of course, is aided and abetted by the fact that androgen production can be suppressed but not completely eliminated. Secondly, once a hair follicle has converted from one producing vellus hair to one producing terminal hair, it takes a long time to reverse the process to any substantial degree. Therefore, suppression of the body's androgen production may prevent the growth of new hair. Getting rid of formed terminal hair is often a long process.

    Lastly, the hair follicle itself is an extremely efficient endocrine factory. The hair follicle can extract small amounts of androgen from the bloodstream and convert them to other more potent androgens at the level of the follicle itself and thereby maintain its own growth. One solution to this is the use of a drug called Spironolactone which blocks the effect of the androgen on the hair follicle itself. This drug has recently been shown up to be of value in treating women with androgen disorders but, again, can only be used in women who are not interested in conceiving.

    Another androgen blocker, Flutamide, is also very helpful in treating the cosmetic effects created by the increased androgen production. It too can only be used in women who are not trying to become pregnant.

    Proscar is also effective in treating these syndromes. Proscar is a drug that blocks the 5-alpha-reductase enzyme (see above), thereby reducing the amount of testosterone that is converted to di-hydro-testosterone. It is given to men with enlarged prostate glands because dihydrotestosterone is the hormone that stimulates the prostate, not testosterone itself. This drug is very beneficial in treating hirsutism, regardless of cause because dihydrotestosterone is the active hormone at the level of the hair follicle.

    The adrenal gland is probably the most important endocrine gland in your body. It produces a hormone - cortisol - which is absolutely essential for normal health and life. If your adrenal glands were removed and replacement cortisol therapy was not given, you would be literally dead in a matter of days. Therefore, the body has a very intricate mechanism to make sure that adequate amounts of cortisol are produced.

    It is easy and convenient to think of the control mechanisms for your endocrine system to be identical to the system whereby your thermostat controls the temperature of your house. The thermostat is a sensor and in cold weather when the temperature drops too low, the thermostat senses this and turns on the furnace. When the furnace has produced adequate amounts of heat, the temperature of the house rises to normal. The thermostat then senses this and shuts off the furnace.

    Consider your pituitary gland to be the thermostat. It senses the level of cortisol in the blood and when necessary, produces a hormone called ACTH. ACTH stimulates the adrenal gland to produce cortisol. When the level of cortisol is appropriate, the level of ACTH is normal. If there is inadequate cortisol, the level of ACTH goes up. If the cortisol level is too high, ACTH goes down. This type of control mechanism is called negative feedback. Most hormones in our body are controlled in a similar fashion.

    The adrenal gland makes many hormones - androgens among them. However, it is only the level of cortisol which is important in terms of determining the level of adrenal gland activity.

    You might consider cortisol as the "heat" produced by the furnace, whereas the androgen would be considered the smoke up the chimney. If, for example, your furnace were not working properly, it would have to work overtime to produce the amount of heat necessary to maintain your house at the desired temperature. Under these circumstances, you can understand that increased amounts of smoke would be going up the chimney.

    It is important to understand that about two-thirds of adrenal hormone production occurs between midnight and 8 AM. Between 8 AM and the following midnight, the remaining one third takes place. By giving prednisone or dexamethasone at bedtime, it is possible to suppress the bulk of adrenal hormone production and this is the preferred way of giving this medication.

    It is very natural and common for people to talk to their friends and relatives about their medical problems and the therapies they are receiving. If you were to mention to a friend or relative that you are taking prednisone or dexamethasone, you will probably get a horrified look and then receive a ton of medical advice telling you how horrible and dangerous these drugs are and scaring you out of your mind.

    The problem is that most people are only familiar with prednisone or dexamethasone when they are given in large amounts to people with serious medical problems such as asthma, rheumatoid arthritis, lupus, etc. In large doses, it is true that prednisone and dexamethasone have serious and potentially dangerous side effects.

    The point is that very few people are aware of the type of problem that I have described in this pamphlet and very few people are aware of the use of prednisone or dexamethasone in the smaller doses that you would be taking to control this problem. It is like comparing a pebble to a boulder and assuming that they are both the same thing just because they are both made out of rock.

    This does not mean that there are not potential risks from taking prednisone or dexamethasone. Every drug or treatment in medicine has a down side. Medical decisions are not based upon whether something is safe or not - they are based upon whether the benefit outweighs the risk. For men and women with adrenal enzyme block, the risks of therapy are small and the benefits to be derived are great and, therefore, the therapy is recommended.

    As with any disease process, the most important factor is to first make the correct diagnosis and then to identify those problems that demand treatment. Women with PCOS have a number of problems including infrequent or complete lack of ovulation, increased androgen production, insulin resistance with altered glucose metabolism, and abnormalities of their various serum lipids including elevated cholesterol and elevated triglycerides.

    In addition, the cosmetic problems associated with PCOS also demand therapy for many women including the problems of obesity, hirsutism, and acne.

    My usual approach is to sit down with the woman and try to identify which problem bothers her the most and which problem should be the principal focus of our attention. Obviously, those problems which must be treated for reasons of health will not be ignored.

    For most women with PCOS, insulin resistance will be a major focus of the treatment. Treating that specifically may ultimately allow the other problems to be almost self correcting. As I have mentioned elsewhere in this pamphlet, there are now reports of women treated with the various drugs that reduce insulin resistance but have permitted spontaneous ovulations and pregnancies to occur without any other therapy.

    There are two main classes of drugs that are used to treat insulin resistance - Metformin (Glucophage) and the Thiazolidinediones, either Pioglitazone (Actos) or Rosglitazone (Avandia). Rezulin is no longer available.

    Glucophage works on the liver to reduce glucose production and it undoubtedly has other mechanisms of action as well but they have not yet been fully elucidated.

    The Thiazolidinediones work on muscle and other peripheral organs and directly produce a reduction in insulin resistance.

    It is my personal opinion that the Thiazolidinediones are the better choice of drugs. Rezulin was the first of these drugs but its use has been curtailed because of the occurrence, albeit rare, of serious, sometimes fatal, liver damage.

    The other drugs in this group - Actos and Avandia - so far have not shown any evidence of liver toxicity but they are being monitored very carefully because no one knows what the long-term effects may be.

    Reducing insulin resistance will ultimately lead to a reduction in serum insulin levels. This, in turn, will reduce ovarian androgen production and allow resumption of ovulation and regular menstrual cycles. Women with PCOS have conceived on one of these drugs with no other therapy necessary.

    The reduction in serum insulin levels should also help lower your serum cholesterol although specific cholesterol lowering drugs may also have to be employed.

    As I have also pointed out, we have known for many years that women with PCOS are at greater risk to develop gestational diabetes and, later, overt adult onset type diabetes. It is everyone's fervent hope that early intervention with these drugs that reduce insulin resistance may either prevent or significantly delay the development of diabetes later in life.

    Depending upon whether the woman is trying to become pregnant or not and depending upon whether or not other therapies have resulted in a lowering of serum androgens, direct ovarian and/or adrenal suppression may be necessary.

    Adrenal suppression using Prednisone is often of great benefit, particularly in women who are trying to become pregnant. Ovarian androgen suppression can only be used in women who are not interested in becoming pregnant. The drugs that would suppress ovarian androgen production would suppress all other ovarian function as well, including ovulation.

    Also, as I have pointed out elsewhere, once androgen levels are suppressed, the use of the various androgen blockers is also very helpful in helping to reduce the unsightly facial hair that so frequently accompanies this syndrome.

    The biggest problem for many women is loss of weight. We don't know exactly how the weight loss figures into this entire syndrome. Nonetheless, although everyone tries to lose weight, it may be important for you to recognize that significant weight loss simply may not be possible. This would spare you many months and years of frustrating attempts to lose weight.

    As I mentioned earlier in this pamphlet, conversion of testosterone to dihydrotestosterone is the final step which stimulates the production of course dark hair by the hair follicle. There are currently available drugs that specifically block the 5 alpha reductase enzyme. The chemical name for this drug is Finasteride. Proscar contains 5 mg. of the drug - Propecia tablets contain 1 mg. of the drug. Therefore, the use of these two drugs has a well established place in the treatment of hirsutism by reducing the production of dihydrotestosterone.

    Dihydrotestosterone does a lot more in the body than simply stimulate the growth of hair. It plays a critical role in the development of the external genitalia in a boy. Therefore, if a woman who is pregnant is exposed to one of these drugs and she is carrying a male fetus, the development of that boy could be seriously affected. This is the reason why the drug comes with a warning that women who are pregnant should not handle this medication.

    If you are under treatment for hirsutism and you are taking either Propecia or Proscar, it is absolutely mandatory that you avoid a pregnancy. If you were to become pregnant while taking one of these medications, because of the serious potential for harm to the fetus, termination of the pregnancy would be advised.

    For those of you who might be interested, an accident of nature has given us a great deal of insight into this entire situation. There is a group of people in the Caribbean where congenital absence of the 5 alpha reductase enzyme is very common. Boys born to women in this group have very under developed external genitalia. However, all is not lost. Even though the fetus requires dihydrotestosterone to fully mature the external genitalia, an adult can do almost the same thing with testosterone itself. Even though these boys do not have the ability to convert their own testosterone to dihydrotestosterone, they are certainly producing adequate amounts of testosterone.

    When they go through puberty, the increased production of testosterone is sufficient to overcome their inherited defect and they then begin to develop reasonably normal external genitalia. This entire process was called the "penis at 12 syndrome" and we now understand the underlying physiologic mechanism for it.


    Electrolysis
    I would like to offer a few thoughts on electrolysis since almost every woman with hirsutism tries it sooner or later.

    First of all, as I have already pointed out, if a woman has hirsutism, she has an underlying hormone problem. That is a given. Unless the hormone problem is treated, removing the hair by electrolysis alone without addressing the hormone problem will not work - new hair will simply continue to grow.

    The initial approach should be the identification and treatment of the underlying hormone problem. This will almost always slow the rate of regrowth of the hair that is present. However, hormonal therapy by itself usually does not completely eliminate the hair.

    Once the hormone problem has been treated to the degree that it can be, then electrolysis should be the next step to remove the hair permanently. The concomitant hormonal therapy would prevent the hair from regrowing. Using this 2-pronged approach, most women can be helped to achieve a satisfactory solution for their problem.


    Myths Concerning Hair Removal
    One of the common myths states that shaving worsens hirsutism. This is not true and it is a typical example of confusing coincidence with consequence.

    It is important to keep in mind that a woman is not going to begin shaving until she starts to develop a hair problem. Therefore, once a woman grows enough hair that she begins to consider it unsightly, she will begin to take steps to remove it. Shaving is one of the more common methods chosen. The more serious the underlying endocrine, the faster the hair will grow and the more the woman will need to shave. It is therefore easy to see how many people concluded that the shaving was making the hair grow. In reality, the increased need to shave was the result of the increased hair growth and not the other way around.

    The same arguments can be made for the use of depilatories, waxing or other types of hair removal. Again, if a woman has true hirsutism, treating the underlying endocrine disorder will have a much higher success rate than any method of hair removal.

    There is now a laser technique to remove the unsightly hair. I have spoken to a plastic surgeon who is quite knowledgeable about this technique. He has told me that the lasers currently available really do not do a very good job in removing hair. There are some newer lasers under development that may be far superior but, at this time, he does not consider it to be a viable option. You may get temporary relief of the hair that is there but it almost certainly will grow back and then you will have spent a great deal of money for nothing.

    I would also caution against trying to remove vellus hair. It will usually be an exercise in frustration. If a woman has darkly complected vellus hair, particularly on the upper lip, I would recommend bleaching. But again, I would strongly urge that it not be removed.


    Hair-An Snydrome
    A fairly common but often unrecognized part of androgen disorders in women is called the HAIR-AN Syndrome. It is important to understand this syndrome, particularly for those women who may have it.

    The term "HAIR-AN" is an acronym for three phrases. The HA stands for HyperAndrogenism.

    The IR stands for Insulin Resistance.

    The AN stands for Acanthosis Nigricans.

    HyperAndrogenism simply means that the woman has either clinical evidence, laboratory evidence, or both, of increased androgen production. Women with this syndrome usually exhibit significant hirsutism, significant menstrual irregularities, and they are usually significantly overweight.

    The insulin resistance refers to the fact that many women with this syndrome have a very insulin resistant form of diabetes. Whether this is related to their obesity or is an inherent part of the syndrome is uncertain. It is probably the latter, based on what has been learned over the past few years.

    Acanthosis Nigricans is a peculiar pigmentation of the skin characterized by a velvety brownish black areas most commonly seen around the neck, but it can also be seen under the arms and under the breast.

    Women who have Acanthosis Nigricans are very frequently upset about it because they think their neck is dirty and they spend a great deal of time trying to wash it away. They are usually quite relieved to learn that the discoloration is not dirt, but simply a reflection of their endocrine problem.

    I have had a number of women over the years who have come in with significant irregularity in their menstrual cycles accompanied by significant hirsutism and other evidence of excess androgen production. When I detect the presence of Acanthosis Nigricans, this is often the first clue that these women are diabetic or insulin resistant as well - something that was often not detected prior to their coming to see me.

    No one fully understands exactly how this problem develops and what the link is. Certainly it is known that people who are significantly overweight develop insulin resistant diabetes. This is different than the more common forms of diabetes in that controlling the blood sugar is often quite difficult.

    One theory holds that the obesity leads to insulin resistance. These women have elevated serum insulin levels as a result.

    The theory then states that the excess insulin stimulates increased ovarian androgen production. Of course, increased androgens will often cause a woman to gain weight which then puts you on to the merry-go-round.

    Unfortunately, even though the HAIR-AN Syndrome is easy to diagnose, it is often very difficult to treat. None-the-less, many people with a particular medical problem find it very comforting learning exactly what their problem is even though therapy will not always be readily available.

    Reversing the insulin resistance with the drugs now available often lessens the amount of the Acanthosis.

    Current research indicates that the HAIR-AN syndrome is probably an uncommon but severe subset of PCOS with exaggerated symptoms of those problems normally seen in PCOS.


    Patient Instructions - Prednisone/Dexamethasone
    The following section contains the instructions and comments concerning therapy and precautions for those people who have been started on suppressive therapy.

    You are being given Prednisone or Dexamethasone to suppress increased male hormone production from the adrenal gland. The vast majority of people who are given these drugs take them for severe arthritis, asthma, Lupus and other serious illnesses. The reason that you are being treated with these drugs is completely different. Even most physicians are not familiar with the therapy that I am giving you. All of the horror stories that your friends will tell you are related to the very high doses of Prednisone or Dexamethasone that are used for these serious problems.

    The dose you are being given is just sufficient to suppress the adrenal gland's excessive male hormone production.

    The Dexamethasone is taken each night at bedtime. The Prednisone is also taken at bedtime. Occasionally, a morning does of Prednisone is also required.

    If you are going to be up much past midnight, try to take the medication at midnight.

    If your job requires that you sleep at other times of the day than most people, please let me know as this will necessitate changing the schedule of your medication.

    You may take Prednisone or Dexamethasone with food or on an empty stomach. You may drink alcoholic beverages. You may take any other drug or medication - prescription or non-prescription. These drugs do not interfere with anything else. With one exception, no other medication affects Dexamethasone or Prednisone and you may, therefore, take any other medication prescribed for you.

    If you are taking Dilantin, Phenobarbital or any other drugs for epilepsy or a seizure disorder or any other reason for that matter, you must let me know.

    The only precautions are 1) that any physician or dentist who needs to treat you for any problem must know that you are taking these drugs and 2) you must not stop taking these drugs abruptly. If there is a need to stop these drugs, you must be weaned from them slowly. If your family physician or dentist has any questions, please have them contact me.

    I am, by these drugs, deliberately suppressing your adrenal glands. The adrenal glands produce cortisone which is of critical importance in an emergency or stress situation. Under such circumstances, your own adrenal glands would produce increased amounts of cortisone and I am deliberately interfering with that.

    In an emergency situation such as a serious illness or serious injury, or the need for surgery, additional supplemental cortisone would have to be given to you. This is the reason for notifying any other treating physician.

    It is not necessary to increase your dose of these drugs for every minor cold. However, if you develop an infection with a fever over 100, please double the dose of your medication and contact me as soon as possible.

    Side effects from these medications are uncommon but can include mild degrees of weight gain along with some bloating and fluid retention. The fluid retention and bloating will usually respond to salt restriction. If this is not sufficient, please contact me.

    Ovulation/PCOS

    THIS SECTION WAS ORIGINALLY WRITTEN FOR THE PAMPHLET ON "OVULATION AND INFERTILITY". I HAVE INCLUDED IT HERE AS WELL SO YOU MAY SEE HOW THIS PROBLEM RELATES TO INFERTILITY AND THE NEWER ADVANCES THAT ALLOWS ME TO TREAT INFERTILE WOMEN WITH PCOS MUCH MORE EFFECTIVELY.

    OBVIOUSLY, SOME OF THIS SECTION IS REPETITIOUS BUT IT WAS EASIER TO INCLUDE THE WHOLE SECTION RATHER THAN EDIT IT.


    Poly-Cystic Ovary Syndrome (PCOS) is the most common endocrine problem in women of reproductive age (puberty to menopause). At a minimum, 5% of all reproductive age women have it; some studies have put the figure as high as 10%.

    Not only is PCOS the most common endocrine problem in women of reproductive age, it is the most common endocrine problem in infertile women and, overall, is one of the most common reasons for infertility.

    There are two criteria that must be fulfilled in order to make a diagnosis of PCOS - the woman must not ovulate (or ovulate very infrequently) and she must have either clinical or laboratory evidence of increased androgen (male hormone) production. The two most common manifestations of increased androgen production are either hirsutism and/or acne.

    For women who are trying to conceive, there have been a number of therapies available for many years. The first specific therapy to treat ovulation problems was Clomiphene which was introduced in 1968. Although Clomiphene is an excellent drug for the treatment of the infertile woman with PCOS, and a very substantial number of women will ovulate, only about 40% will conceive.

    There are other therapies available, most notably Pergonal and related medications. Unfortunately, for many women, their insurance will not pay for Pergonal and if the Clomiphene doesn't work, they have, to a considerable degree, reached the end of their ability to have their problem successfully treated. However, newer therapies are offering significant hope to these formerly untreatable women.

    It has been known for many years that a considerable number of women with PCOS are overweight. People of both sexes who are overweight are often insulin resistant. This is one of the major causes of Diabetes. It has been known for many years that insulin resistance is a major part of PCOS.

    Insulin resistance means that the insulin that you are producing does not work as effectively as it ought to and hence, your body must produce increased amounts of insulin to keep your blood sugar normal. This leads to elevated levels of insulin in the bloodstream and these increased levels of insulin stimulate increased androgen production by the ovary. The increased androgen production in turn interferes with development of the egg and further blocks ovulation. As you can now begin to see, the process locks itself into a vicious cycle.

    It has also been known for many years that the dose of Clomiphene necessary to induce ovulation is directly related to the woman's weight. Women of normal body weight may require only one or two tablets of Clomiphene daily for five days each month to stimulate ovulation. Women who are significantly overweight may require four or five tablets a day and even then only about 20% of obese PCOS women will ever ovulate on Clomiphene therapy.

    The good news is that there are now drugs available which reduce insulin resistance. Reducing insulin resistance means the pancreas has to produce less insulin, thereby reducing serum insulin levels. This should, at least in theory, help reduce the excess androgen production from the ovary.

    There are two main classes of drugs which reduce insulin resistance. We call them "insulin sensitzers". The two principal types of drugs that are available are the Thiazolidinediones and the Biguanides. The first thiazolidinedione was Rezulin. This was taken off the market because of rare but sometimes severe liver damage. The 2 newer versions (Avandia and Actos) have so far shown no evidence of liver toxicity. Metformin (trade name Glucophage) is the most commonly prescribed biguanide.

    The thiazolidinediones and Glucophage have slightly different mechanisms of action. The former work mainly on peripheral tissues whereas Glucophage works in large part on the liver.

    Increasing reports have shown that women placed on thiazolidinediones alone will sometimes ovulate and become pregnant.

    Both Glucophage and the thiazolidinediones can be used as a sole treatment for diabetes, particularly in the earlier stages. However, they are usually used in combination with other drugs. On the other hand, they are frequently used alone to treat people who are insulin resistant but not yet diabetic.

    A recent study has shown that the combined use of Glucophage with Clomiphene will allow ovulation to occur in women with PCOS, particularly those who are overweight, where therapy with Clomiphene alone had been unsuccessful.

    Furthermore, not only was the Clomiphene therapy successful in inducing ovulation, it did so at much lower doses (one or two tablets daily), even in women who had not responded to higher doses.

    This is of great importance - first, because it allows women to ovulate with easier and simpler therapies, and secondly, it opens up doors to women whose insurance companies will not pay for Pergonal and who might otherwise therefore be shut out of any effective infertility therapy.


    ACANTHOSIS NIGRICANS and INSULIN RESISTANCE


    THIS SECTION WAS ORIGINALLY WRITTEN AS A SEPARATE PAMPHLET BUT BECAUSE THE SUBJECT IS SO CLOSELY CONNECTED WITH ANDROGEN DISORDERS THAT I HAVE INCLUDED IN THIS PAMPHLET

    SOME PARTS ARE REPETITIOUS - FOR THAT I APOLOGIZE

    Cardiovascular disease is the leading cause of death in the United States - not only for men but for postmenopausal women as well. After menopause, more women will die from cardiovascular disease than from all forms of cancer, accidents, and Diabetes combined.

    As more and more information becomes available, we are now able to identify problems that we know to be major risk factors for cardiovascular disease. Many of these problems are fairly easy to treat. In so doing, it is hoped that your risk factors for subsequent cardiovascular disease can be greatly reduced, allowing you to live a longer healthier life.

    Most everyone knows that Diabetes is one of the leading risk factors for heart disease and other forms of vascular disease. 80% of diabetics will die from problems related to coronary artery disease. If we can identify individuals who are not yet diabetic but are at increased risk to become so and if we can break the chain of events that might ultimately lead to Diabetes, we should be able to substantially improve that person's longevity and quality of life. We might even be able to prevent the development of Diabetes although this is still theoretical and not yet proven. However, current knowledge suggests this is so.

    Not only is Diabetes a major risk factor for cardiovascular disease, it is currently the leading cause of blindness in the United States. Diabetes is also the leading cause of non-traumatic amputations and end-stage kidney disease as well.

    As common as Diabetes is, there are still many individuals who are already diabetic and do not yet know it. It is, therefore, of critical importance to identify not only those who are diabetic but not aware of it but those who are at significantly greater risk to become diabetic.

    Most people already know some of the risk factors. The more common ones are significant obesity and a history of having been diabetic while pregnant (gestational Diabetes).

    We also know that people of African-American or Hispanic ancestry are also at increased risk to develop Diabetes when compared to the Caucasian population. African-Americans and Hispanics who have Diabetes have an increased risk of complications compared to Caucasians.

    Another risk factor for Diabetes is if a woman has delivered a baby that weighed more than nine pounds, even if she was not found to be diabetic while pregnant. Keep in mind that universal screening for Diabetes in pregnancy has only been carried out for the past 15 to 20 years or so.

    We now know that Poly-Cystic Ovary Syndrome is a major risk factor for Diabetes. There are several features that are frequently associated with Poly-Cystic Ovary Syndrome that are also identifiable risk factors for Diabetes and cardiovascular disease. It is now routine that treating the underlying abnormalities associated with Poly-Cystic Ovary Syndrome will allow these women to ovulate and conceive with no other therapy being necessary. The main problem we treat is insulin resistance.

    One of the most common markers for Diabetes or people who are at risk to become diabetic- a condition for which I routinely screen all patients - is acanthosis nigricans. This is simply a brownish/black velvety pigmentation of the skin, most commonly seen at the base of the back of your neck. Some women have pointed out to me that they really thought their neck was dirty and tried, in vain, to wash it away.

    Other less common areas for acanthosis nigricans include the lower end of the sternum (breast bone) between the breasts, under the arm, and in the fold of your elbow where blood is customarily drawn.

    Acanthosis is a marker (a red flag) for insulin resistance. By this, it is meant that the insulin your body produces does not work as efficiently as it should. Your body has to make more insulin in order to keep your blood sugar normal.

    So long as your pancreas is able to produce the additional amounts of insulin that you require, your blood sugar will be normal and you will not be diabetic.

    However, it is important to understand that people do not go from normal to diabetic in one step (the only exception being the acute onset of so-called juvenile Diabetes). It probably takes months or years for the entire progression to occur.

    The first step is insulin resistance.

    If you are insulin resistant, you have higher than normal insulin levels in your blood. You are hyperinsulinemic.

    We now recognize that hyperinsulinemia is, by itself, independent of other factors, a risk factor for cardiovascular disease. Diabetics who are significantly hyperinsulinemic are at greater risk for cardiovascular disease than diabetics who are not.

    As the disease process progresses and your body is unable to keep up with the demands, you go through an intermediate stage between normal Diabetes that we call either impaired fasting glucose or impaired glucose tolerance.

    To begin the evaluation, a baseline screen can be drawn anytime the woman is in the office, regardless of when she last ate. Measurement of the glucose/insulin ratio is then an easy calculation. A ratio of less than 4.5 is strong presumptive evidence of insulin resistance.

    If the woman happens to be fasting at the time of her office visit (or has not eaten anything for at least 6 hours) then a fasting blood sugar and insulin level is also measured. If the fasting insulin level is over 20, insulin resistance is present.

    If your fasting blood sugar to insulin ratio is less than 4.5, then insulin resistance is definitely present.

    Anyone who shows evidence of insulin resistance should be evaluated with a two hour glucose tolerance test with insulin levels measured with each sugar level.

    If you are going to have a glucose tolerance test, you should be "carbohydrate loaded" prior to the test to make it more accurate and valid. Carbohydrate loading means consuming at least 100 grams of carbohydrate everyday for three days prior to the test. This can be fairly easily accomplished by eating a couple of candy bars each day for those three days.

    The glucose tolerance test should be carried out first thing in the morning. Performing a glucose tolerance test in the afternoon may yield different results and lead to erroneous conclusions.

    You would come to the office fasting in the morning. Baseline blood studies would be drawn and you would then be given a bottle of concentrated sugar water to drink. This contains a standard amount of 75 grams of glucose.

    Blood sugars and insulin levels are then drawn at the one hour and two hour time periods.

    Four different interpretations of a glucose tolerance test are possible. First, it could be completely normal.

    Second, at the other end of the spectrum, you could already be overtly diabetic and perhaps not even suspect it.

    There are two intermediate stages in which the glucose tolerance test is not normal but does not yet fulfill the criteria for Diabetes. The first of these stages is called "Impaired Fasting Glucose." This diagnosis is made if the fasting blood sugar is over 110 but less than 126.

    Impaired Glucose Tolerance is diagnosed if the two hour blood sugar is over 140 but less than 200 and the fasting blood sugar is less than 126.

    A diagnosis of Diabetes is made if the fasting blood sugar is over 126 and/or the two hour blood sugar is over 200. However, recent data suggests that a level of 126 may be too high for African-Americans - that by the time the level reaches 126, problems are already present. Another philosophy holds that the threshold for the fasting blood sugar should be 140, not 126. This is preliminary and more studies are needed.

    One other criteria must also be met to make a diagnosis of Diabetes. Glucose, when present in excess amounts, attaches to various proteins in your body. Once the glucose attaches itself to the protein, it never comes off - it is there permanently. This glucose-protein combination damages the protein. This is how Diabetes leads to the various micro-vascular complications associated with it. These include eye damage, kidney damage, and small blood vessel damage.

    Your red blood cells contain Hemoglobin - the protein that carries oxygen. Glucose attaches to the Hemoglobin molecule to form a compound called "Hemoglobin A1C" or Glycosylated Hemoglobin. Red blood cells have a life span of about 120 days. At the end of that time, the body destroys the red blood cells and makes new ones. Therefore, the amount of Hemoglobin A1C in the red blood cell is an indicator of your average blood sugar over the past 120 days. It does not change with the daily variations in your blood sugar.

    Measuring the Hemoglobin A1C level is the best way to assess how well a person's Diabetes is being controlled. Studies have clearly shown that all the micro-vascular complications associated with Diabetes can be eliminated or significantly reduced by keeping the Hemoglobin A1C level less than 7%. Interestingly, large vessel disease, including coronary artery disease, does not seem to be helped. A normal person's level is between 4.5 and 6.5%.

    Because of this, the American Diabetes Association believes that if the Hemoglobin A1C is less than 7%, a diagnosis of Diabetes is not warranted regardless of the blood sugar level. This is because if the Hemoglobin A1C level is less than 7%, complications we associate with Diabetes do not occur and therefore, a person should not be labeled as having a "disease" if no damage is occurring.

    This does not mean however that elevated blood sugars should be ignored. If your fasting blood sugar is greater than 126 and/or your 2-hour (or random) blood sugar is greater than 200 but your Hemoglobin A1C is less than 7%, you would be classified as having "Impaired Glucose Tolerance". Careful monitoring would be necessary along with other therapies to try to alter the natural course of the disease.

    Another risk factor is a decreased level of sex hormone binding globulin in your blood stream. Sex hormone binding globulin (SHBG) is a protein which carries Estradiol and Testosterone in the blood. For reasons that are not fully certain, decreased levels of SHBG are associated with hyperinsulinemia and insulin resistance. Some studies have shown that a decreased level of SHBG is one of the strongest "red flags" for the future development of Diabetes that we know of.

    It is important to understand that the mechanism for insulin resistance in older overweight people is different than the mechanism for the insulin resistance seen in Poly-Cystic Ovary Syndrome. Nonetheless, once the process has been set in motion, the end result may be the same.

    Checking for acanthosis is very simple - simply lift up the hair on the back of your head and look at the base of your neck. If I find someone has acanthosis, the next step would be to evaluate them completely to determine whether or not they are in fact insulin resistant and then to determine whether they still have normal blood sugars, whether they have impaired fasting glucose, impaired glucose tolerance, or may actually be an overt diabetic.

    Identifying such people is critically important because we now have drugs that will reduce insulin resistance. These drugs are of great benefit in treating women with Poly-Cystic Ovary Syndrome and actually reverse the entire process in many women.

    These drugs also are of great importance in the treatment of individuals who are diabetic. Sometimes they can serve as sole therapy; other times they are combined with other oral agents or with insulin.

    Current evidence also indicates that they are of benefit in treating Syndrome X and other problems associated with insulin resistance. Treating that specifically may ultimately allow the other problems to be almost self correcting. As I have mentioned elsewhere, there are now reports of women with PCOS treated with the various drugs that reduce insulin resistance that have resulted in spontaneous ovulations and pregnancies without any other therapy.

    There are two main classes of drugs that are used to treat insulin resistance - Metformin (Glucophage) and the Thiazolidinediones, either Rosiglitazone (Avandia), or Pioglitazone (Actos).

    Glucophage works on the liver to reduce glucose production and it undoubtedly has other mechanisms of action as well but they have not yet been fully elucidated.

    The Thiazolidinediones work on muscle and other peripheral organs and directly produce a decrease in insulin resistance.

    It is my personal opinion that the Thiazolidinediones are the better choice of drugs. Rezulin was the first of these drugs but it was pulled from the market because of the rare occurrence of serious, sometimes fatal, liver damage.

    The second drug in this group - Avandia - so far has not shown any evidence of liver toxicity but it is being monitored very carefully because no one knows what the long-term effects may be. Actos was released in July, 1999. There is no evidence as yet of any liver problems associated with either of these drugs.

    Reducing insulin resistance will ultimately lead to a reduction in serum insulin levels. This, in turn, will reduce ovarian androgen production and allow resumption of ovulation and regular menstrual cycles. Women with PCOS have conceived on one of these drugs with no other therapy necessary.

    The reduction in serum insulin levels should also help lower your serum cholesterol although specific cholesterol lowering drugs may also have to be employed.

    Certainly, anyone who already has impaired glucose tolerance or is known to be diabetic and is hyperinsulinemic needs to have these problems corrected. What is not yet known is whether or not treating someone who is simply insulin resistant but does not yet show any evidence of impaired glucose tolerance will break the chain and prevent that person from becoming overtly diabetic.

    In theory, it should. If you reduce insulin resistance, your pancreas does not have to work as hard, your blood sugar will remain normal, and you will not become diabetic. However, since these drugs are relatively new, long-term studies will be necessary before a definitive answer is known.

    We do know that using these drugs in women with Poly-Cystic Ovary Syndrome will reverse the process, allow resumption of normal menstrual cycles and even a pregnancy without any other therapy. If it works in this instance, it should, theoretically, work in other cases as well.

    We are also becoming aware of the fact that people who are insulin resistant frequently have other endocrine and metabolic abnormalities. For instance, an elevated serum cholesterol is also very frequently found in such individuals and again, when present, needs to be treated. People who have a combination of hyperinsulinemia, insulin resistance, hypertension, and abnormal cholesterol readings are said to have "Syndrome X". The abnormal cholesterol levels may not just be a high total cholesterol but also a very low HDL-cholesterol (the good cholesterol). Other criteria are also part of this syndrome and are referred to in another pamphlet.

    There is one other treatment that is also of great importance and that is aspirin. Everyone over the age of 50 - both men and women - who have no specific contraindication, should be on an aspirin everyday. For the prevention of cardiovascular disease and heart attacks, a baby aspirin (81 mg.) is all that is necessary.

    However, there is compelling data that taking one full adult aspirin everyday may be better. The reason - good evidence that people who take at least four aspirin tablets a week have a reduced risk of developing colon cancer. People who take large amounts of Motrin or related drugs also have a reduced incidence of colon cancer. There is also evidence that these drugs reduce the risk of Alzheimer's disease.

    I hope this pamphlet has been informative and explains why I am doing many of the things I do. Even though we have made great strides in reducing deaths from cardiovascular disease in the last 10 or 15 years, we still have a long way to go. The only way we are going to achieve substantially greater reduction is to identify those individuals who are at greater risk and begin to treat them before they have their first heart attack. We know that lowering serum cholesterol with the various drugs currently available (Zocor, Lipitor, etc) is also highly effective in reducing the risk of heart attacks. Based upon what we now know concerning Diabetes , insulin resistance, and varying degrees of abnormalities in glucose metabolism, there is no reason to believe that treating these problems should not be effective in reducing the risk of heart disease as well.

    There is no doubt that drugs such as Glucophage, Actos, and Avandia are of considerable benefit in the treatment of people with diabetes - either as monotherapy or in combination with other drugs. These drugs are approved for this and are highly effective.

    Based upon everything we now know, treating people who are not yet diabetic but are showing one of the significant risk factors such as insulin resistance and/or impaired glucose tolerance should, in theory, prevent or delay the development of frank diabetes.

    Since most individuals with this problem are overweight, weight reduction is extremely important. Unfortunately, this is easier said than done and many people find that losing weight is extremely difficult.

    Sooner or later, most people with adult onset diabetes go on medication. The question is whether or not it is justifiable to use these drugs in people who are not yet diabetic but who are definitely on their way.

    The use of these drugs with Poly-Cystic Ovary Syndrome is already now well established and they are highly effective. I believe the same will ultimately be shown for those individuals who are simply at risk to become diabetic.

    I believe that if you are one of these people, such drug therapy should help. You would have to understand that giving you these drugs for this purpose would be considered experimental and you would have to signify to me that you are willing to undertake this therapy. We would then discuss these specific problems and potential risks associated with the drugs in the office.

    ADDITIONAL NOTES

    More recent information also has given us additional reasons why we need to be vigorous in evaluating people with metabolic disorders associated with PCOS including hyperinsulinemia and abnormal sugar problems.

    It has been known for a long time that diabetics are at increased risk to develop pancreatic cancer. However, there was no data concerning the association of abnormal glucose metabolism with possible development of pancreatic cancer.

    A large prospective study looked at people followed for many years. These studies showed that a high blood sugar was definitely associated with an increased risk of pancreatic cancer, even in people who did not necessarily meet the criteria for diabetes.

    Although the risk appears to be somewhat greater for men than for women, it is not insignificant in either group.

    MYTH - THERE IS A TEST FOR POLY-CYSTIC OVARY SYNDROME


    More and more, I am seeing women come into the office with classic Poly-Cystic Ovary Syndrome (PCOS) who have been told that they did not have it because their blood tests were all normal. If you believe you have PCOS, it is critically important that you understand that the blood tests that I do are not to make the diagnosis (or break it), they are simply to give me baseline information to help me assess your response to future therapy.

    It is critically important to understand that PCOS is a clinical diagnosis - it is based upon a woman's history and physical exam. Although there is no universally accepted definition of PCOS, most Endocrinologists would agree that two criteria must be satisfied. First, the woman must have some abnormality of ovulation and, secondly, she must have either clinical or laboratory evidence of increased androgen (male hormone) production.

    The two principal physical signs of excess androgen production are either acne or hirsutism (the presence of coarse dark hair on a woman's body in locations that it should not normally be found). The vast majority of women with excess androgen production will in fact have either acne or hirsutism. There are occasional women who do not have any physical signs of excess androgen but whose blood test will clearly show it.

    One of the problems that creates the confusion is the fact that, on paper, many women with obvious androgen problems have "normal" serum androgen levels. There are two reasons for this. First, although the total testosterone may be normal, the free (the biologically active portion) testosterone level is frequently elevated.

    More importantly, it is important to understand that the normal range for the serum testosterone that most labs use when they report their values is seriously in error. This has been known for many many years. The labs show no inclination to change it.

    Most labs report that the upper limit for a serum testosterone level in women is in the range of 60 to 75 (the numbers vary slightly from lab to lab). In fact, it has been clearly shown that when the test is done properly, a normal woman never has a testosterone level in excess of 30. Therefore, if a physician draws a testosterone level on a woman and the result comes back 50 or 60, that woman will be told that she is "normal" when in fact she is not.

    This was proven quite conclusively several years ago by a well respected Endocrinologist in Texas. He drew serum testosterone levels on his patients with obvious androgen problems and sent the result to 11 different commercial labs. He got back 11 completely different results and none of the results were anywhere near the true result that he obtained when he ran the test in his own lab.

    It is important that you understand this so that you realize that you may in fact have PCOS even though you have been led to believe that you do not.


    PLEASE MAKE SURE THAT ANY CLOSE RELATIVES READ THIS SECTION
    THEY MAY ALSO FIND THE ENTIRE PAMPHLET OF BENEFIT



    If you are reading this, it is because a close relative of yours is under my care and has Poly-Cystic Ovary Syndrome (PCOS). This has significant implications for your future health and it is important for you to understand what this all means.

    PCOS is the most common hormone problem in women of reproductive age (puberty to menopause). However, the implications and consequences of PCOS extend beyond menopause.

    We now recognize that the cause of PCOS is an abnormality in the insulin receptor. This means that the insulin your body produces is not able to work as effectively as it should to keep your blood sugar normal. To overcome this defect, your pancreas has to produce more and more insulin.

    The excess insulin affects the way the ovaries function and causes them to produce increased amounts of male hormone. This interferes with normal ovulation and many women with PCOS have very irregular menstrual cycles.

    The increased male hormone production also leads to facial hair growth and/or acne.

    It is also becoming increasingly apparent that the excess insulin production with the resulting elevated levels of insulin in your bloodstream has significant implications for your overall health and well-being. We now know that these excess insulin levels are a significant risk factor for cardiovascular disease including heart attacks and stroke - even in those people who are not yet diabetic. This whole problem falls under the heading of "Syndrome X". I can talk to you more about it if your wish.


    There is rapidly accumulating evidence that these high insulin levels also play a significant role in causing high cholesterol levels and hypertension as well.

    We know that women with PCOS are more likely to develop diabetes when pregnant and are also more likely to develop diabetes in later life. Insulin resistance is probably the abnormality that sets the stage for this.

    PCOS is an inherited disease and 50% or more of the close relatives of women identified as having PCOS will also have the disease although not all will manifest every symptom.

    Men can also inherit the genetic abnormality that in women would lead to PCOS.

    Although not everyone who is insulin resistant will ultimately develop diabetes, many do. Furthermore, you do not go from being normal to diabetic in one step. There are intermediate stages where you would not be classified as being officially diabetic but your body is not handling sugar properly and your blood sugars are higher than they ought to be.

    As a result of all of this, we strongly urge you to be evaluated for possible insulin resistance. It is a simple blood test - one that our office can easily provide for you. All that is necessary is that you come into the office first thing in the morning - fasting. Nothing to eat or drink from the time you go to bed at night until your blood is drawn in the morning.

    We would also encourage any men who are close relatives of our patient to undergo the same testing. This would especially include men who are significantly overweight with elevated cholesterol and hypertension as well.

    If you have any questions, we would be very happy to discuss this entire matter with you.


    MAKING SENSE OF YOUR LAB TESTS


    Hardly a week goes by when I do not see a patient in the office who has been told that there was nothing wrong with them because their lab tests were all normal. By the time you finish this section, I hope that you will have a far better understanding as to what is really happening.

    There are several reasons for the confusion. If you have seen copies of your lab tests, your result will be listed along with the normal range for that test. One of the main problems relates to the fact that the normal range that most labs list for serum androgen levels in women are wrong. I first became aware of this fact many years ago when I was seeing women with obvious androgen problems and the lab was reporting normal serum androgen levels. When I contacted the lab, they sent me a fairly complete analysis of how they derived their normal range. Usually, a lab will calculate its normal range by drawing blood from a number of individuals who are "normal" - they are free of the problem being investigated.

    It became immediately apparent to me when I looked at the lab's data that they were including women with androgen problems in their normal range study. I pointed this out to them - they could care less. They did absolutely nothing to correct the error.

    Another reason for the errors relates not only to the fact that the normal range as listed by most labs is wrong, the labs themselves are not terribly reliable. This was clearly shown in a study reported by Dr. Emil Steinberger, a well respected Endocrinologist who has spent his entire career looking at androgen problems in women. Dr. Steinberger drew blood from women and not only ran the tests in his own lab but sent them out to 11 commercial labs. None of the commercial labs came even close to the true value that he obtained in his lab where he was able to maintain strict control. Furthermore, virtually all of the commercial labs reported levels that were far above what they should have been.

    If you look at the normal range listed by the various commercial labs for a serum testosterone in women, you will usually see a number somewhere around 70 to 75. In fact, a normal woman without an androgen problem has a testosterone level in the range of 25 to 30 - never higher.

    There is another reason why the test results are incorrect and that is many physicians simply order a total serum testosterone level. If you are going to accurately assess a woman with an androgen problem, this is not the proper way to do it. To understand this, you have to understand how hormones are carried in your blood stream.

    Virtually all hormones such as testosterone are attached to special serum proteins. Each hormone has its own carrier protein although some hormones will share the same protein.

    This is the case for estradiol and testosterone. They both share the same carrier protein which is called "sex hormone binding globulin" - usually abbreviated "SHBG".

    Virtually all of the hormone in the blood is attached to the carrier protein. Only a minute fraction is "free" or unbound. However, it is the free fraction that is biologically active. If you are going to accurately assess a woman's androgen status, it is critically important that you measure the free fraction, or at least find some way of estimating the free fraction.

    The binding globulins are made in the liver. Estrogen increases the serum concentration of the various binding globulins including SHBG. Testosterone lowers the concentration of SHBG. I have seen many women who had normal serum testosterone levels but whose SHBG was quite low. This leads to an increased amount of the free or unbound testosterone since there are fewer binding sites available.

    It is possible to order a free testosterone level from the lab. Another test which I frequently order is a "bioavailable" testosterone. This tells me how much of your serum testosterone is actually available to exert its actions. All of these tests are far more meaningful and informative than simply measuring the total testosterone and nothing else.

    There is another simple way to estimate the free testosterone level and that is by calculating what is called the "free androgen index" or "FAI". This is a simple calculation using the SHBG as a correction factor on the total testosterone.

    This sometimes gets a little confusing because it involves two different units of measurement. Until around twenty years ago or so, all values were expressed in the metric system. The total serum testosterone level is almost always expressed this way. Most labs will report the serum testosterone level in "ng/dl".

    "ng" stands for nanograms. A nanogram is 10-9th grams - one billionth of a gram.

    "dl" stands for deciliter - 1/10 of a liter or 100 cc's.

    To try to make things uniform throughout the world, many countries have adopted the SI standard of measurement. The concentration of SHBG is usually expressed in SI units. I will not confuse you completely by trying to explain it. Nonetheless, you have to convert testosterone to the SI units in order to use the SHBG as a conversion factor.

    The formula is quite simple - T X 3.47/SHBG. This means you simply take the total testosterone and multiply it by 3.47. Divide that result by the concentration of SHBG and you get a number. This number is called the free androgen index.

    Because you get a pure number, it is very easy to assess a woman regardless of what other hormones she may be on, regardless of her age, regardless of whether or not she is postmenopausal, etc.

    A normal woman should have an FAI less than 5. Anything over 5 is elevated.

    I hope that this explanation will help to clear up any confusion you may have had. I hope it will help you understand and interpret the various lab results that you may receive.

    The same explanation applies to other serum androgens that we frequently measure such as the androstenedione. Androstenedione is an important androgen in the body. 50% of the androstenedione circulating in your blood stream comes from the ovary - the other 50% comes from the adrenal gland. Again, androstenedione is bound to serum proteins though not the same ones that bind testosterone.

    For most labs, the upper limit of normal for the serum androstenedione is somewhere between 250 and 270. I hope you can now appreciate that any androstenedione level that is very close to the upper limit of "normal" is almost certainly elevated. The same applies to the serum DHEAS level.


    SYNDROME X


    The term "Syndrome X" has been around for a number of years and was originally defined as the combination of hypertension and high cholesterol (or other fats) in combination with insulin resistance.

    As we have come to realize how large a role insulin resistance and its associated abnormalities plays in the development of cardiovascular disease (not only heart attack but stroke and possibly peripheral vascular disease as well), the definition and criteria for Syndrome X have been expanded to reflect this better understanding.

    Because a number of other factors are also involved, although we will retain the name Syndrome X simply because it is familiar, the entire Syndrome has been renamed as the "Dysmetabolic Syndrome X", reflecting the fact that many abnormalities are now recognized to play a role in this entire process and, therefore, require inclusion in the definition and criteria.

    The American College of Endocrinology, of which I am a Fellow, has recently published diagnostic criteria for Syndrome X. These expanded criteria will obviously mean that more people will fit the definition. However, this will alert us to the need to treat these individuals aggressively so as to lower their risk for various problems later in life.

    Two sets of criteria have been put forth - "major" criteria and "minor" criteria.

    The first major criteria is insulin resistance which has already been discussed. However, instead of limiting the criteria for insulin resistance to abnormal insulin levels relative to the blood sugar, acanthosis nigricans, by itself, is now acceptable as an indicator of insulin resistance. This means that people who have acanthosis nigricans have to be looked at very carefully regardless of their actual blood sugars or serum insulin levels.

    Another major criteria is central obesity. This refers to individuals who carry most of their weight in the central portion of their body (chest and abdomen) while their arms and legs remain relatively thin in proportion.

    A man is said to have central obesity if his waist exceeds 40 inches. A woman is said to have central obesity if her waist exceeds 35 inches.

    Another major criteria for Syndrome X is termed "Dyslipidemia". We are not looking just at high cholesterol - we are looking at abnormalities in cholesterol and other fats.

    Recognizing that high levels of HDL cholesterol (the good cholesterol) is cardio- protective, a person is said to be dyslipidemic if, for women, their HDL cholesterol is less than 45. A man is said to be dyslipidemic if his HDL cholesterol is less than 35.

    People whose fasting triglyceride level is greater than 150 are also said to be dyslipidemic.

    Hypertension is still a major criteria for Syndrome X as it was under the old definition.

    As you might expect, abnormalities in glucose metabolism such as impaired fasting glucose or actual Type 2 diabetes are included in the criteria.

    Elevations in your serum uric acid is also a major criteria.

    There are a number of minor criteria, problems that we now recognize as being important, particularly if they relate to an increased risk of cardiovascular disease.

    Women with Poly-Cystic Ovary Syndrome (or their male relatives who are carrying the gene) is considered to be a minor criteria.

    For most people, insulin resistance is an acquired problem resulting from obesity. However, the insulin resistance that accompanies Poly-Cystic Ovary Syndrome is a genetic problem - one which is inherited. We know that Poly-Cystic Ovary Syndrome runs in families. How, therefore, does a man know if he is carrying the gene that predisposes to insulin resistance since obviously men cannot have Poly-Cystic Ovary Syndrome? However, they do have many of the associated endocrine and metabolic abnormalities associated with this syndrome.

    The most common and most widely recognized marker in men - one that should alert a man that he is in fact carrying the gene - is early balding. A man who becomes significantly bald before the age of 30 needs to be looked at very carefully to determine whether he in fact would qualify as having Syndrome X.

    People with established coronary artery disease also are included in the minor criteria category. Hopefully, by being more aggressive, we can prevent people from progressing to that stage.

    Hypercoaguability is also a minor criteria. By this, it is meant that some individuals have an increased propensity of their blood to clot. There are a number of different diseases which make a person "hypercoaguable" - some of these diseases are acquired and some of them are genetic. The most common genetic disorder is the Factor V Leiden mutation.

    It is important to keep in mind that your body has an extremely complex set of mechanisms to not only cause the blood to clot in case of an injury, such as a cut on your hand, but also to get rid of a clot that has formed so that additional damage may not occur. There are numerous factors involved in both the clotting mechanism and in the defense mechanism against a blood clot. An abnormality at any one of these steps can result in someone having an increased likelihood of developing a blood clot.

    People who are carrying the Factor V Leiden mutation (or one of the less common genetic abnormalities) will usually have a history of blood clots, often for no apparent reason. Other "red flags" would be a woman who develops a blood clot while taking oral contraceptives or a woman who develops a blood clot while taking postmenopausal estrogen therapy. Women who develop blood clots during or following a pregnancy should also be tested for this. Often, there is a family history of abnormal blood clots as well.

    There are a number of genetic disorders which can lead to an increased likelihood of forming blood clots but the Factor V Leiden mutation is the most common.

    There are a number of acquired problems and diseases which also make one hypercoaguable. Pregnancy is one such condition and you don't have to be carrying the Factor V Leiden mutation to be at risk. For the majority of women, the risk is not during the pregnancy but immediately following delivery.

    People undergoing surgery, particularly prolonged surgery, are at increased risk to develop blood clots. Being overweight compounds this risk.

    Cancer and other types of blood disorders also will increase your likelihood to form blood clots.

    A fairly common cause of hypercoaguability, one that probably plays a role in infertility, is the antiphospholipid syndrome. The antiphospholipid syndrome is an autoimmune disease and, like all autoimmune diseases, antibodies are produced. Some of the antibodies produced in the antiphospholipid syndrome increase the propensity of your blood to clot. There is compelling evidence that women who have the antiphospholipid syndrome are more likely to lose pregnancies although this is still somewhat controversial.

    Testing for the various diseases or conditions that make you hypercoaguable is fairly straightforward. A number of tests can be performed which assess the most common reasons such as the Factor V Leiden mutation and the antiphospholipid syndrome.

    You might ask why is this so important. The reason is simple. The whole rationale behind the movement to make people more aware of Syndrome X is the fact that it is a major risk factor for cardiovascular disease including heart disease, stroke, and peripheral vascular disease as well. Individuals who are identified as having a risk factor for being "hypercoaguable" should be doing something proactive to treat this problem. Some people actually end up on lifelong anticoagulant therapy such as Coumadin.

    Even if you are not hypercoaguable and even if you don't have Syndrome X, cardiovascular disease is still the leading cause of death in the United States. There is now a strong belief that all men over 40 and all women over 50 should be on at least a baby aspirin everyday unless you have a specific medical problem or are taking specific drugs that would contraindicate this therapy.

    I will tell you that I personally take a full strength adult aspirin everyday and have been doing so for the past twenty years. We now know that colon cancer develops at the tips of colon polyps. Aspirin and drugs who have a similar mechanism of action (such as Motrin) interfere with the development of colon polyps and, therefore, reduce the likelihood of your developing colon cancer. There have been studies that have shown that people who take at least four adult aspirin weekly have a reduced incidence of colon cancer. Women worry considerably about breast cancer. Many people do not realize that colon cancer kills as many women each year as breast cancer. Keep in mind that after menopause, cardiovascular disease kills 1 of every 2 women - breast cancer kills only 1 of every 25.

    Another minor criteria is "Vascular Endothelial Dysfunction". The endothelium is the layer of tissue that lines your arteries and veins. The term vascular endothelial dysfunction simply refers to disease processes that damage the endothelium and thereby predispose to vascular disease, blood clots, heart attacks and strokes.

    Your adrenal glands produce a hormone called aldosterone which helps control salt and water balance. There is increasing evidence that this hormone plays a major role in damaging the endothelium and there is increasing evidence (not yet definitively proven) that the aldosterone antagonist Spironolactone may have a significant protective role in people with cardiovascular disease.

    One of the actions of aldosterone is to help you retain sodium and excrete potassium. There is now very strong evidence that potassium deficiency is a major risk factor for cardiovascular disease. People who take diuretics that get rid of potassium are at increased risk. If you take a diuretic that contains Spironolactone, which helps you retain potassium, your risk factors go down. Along with this, there is now strong evidence that people who consume large amounts of potassium rich foods also reduce their risk of cardiovascular disease.

    Lastly, micro-albuminuria is a minor criteria. Albumin is the major protein in your blood stream. All of us excrete tiny amounts of albumin in our urine each day. People with severe kidney disease will excrete large amounts of albumin (more than 3 grams a day). However, there are many individuals who excrete small amounts of albumin - more than normal but less than those with significant kidney disease.

    The excretion of small amounts of albumin in the urine is called micro-albuminuria. It is a simple test to do in the office. The evidence is now rapidly accumulating that micro-albuminuria, in and of itself, is a significant risk factor for cardiovascular disease.

    By the use of these expanded criteria, we can now target those individuals who are at increased risk for cardiovascular disease, diabetes, and all their associated problems. Although it is obvious that many of the problems associated with Syndrome X are genetic in origin, there is one common thread that does run through this entire Syndrome and that is obesity. Everyone acknowledges that obesity is the number one health problem in the United States today. Keeping your weight normal or reducing your weight if you are obese is probably the single most important thing you can do to either prevent or treat Syndrome X and all of its attendant complications.

    There is no doubt in my mind that losing weight is probably the most difficult thing anyone ever tries to do. Nonetheless, to the degree that you can accomplish it, you will have taken a giant step forward in increasing your longevity. Not only will you live a longer life, you will live a healthier life as well.


    ?2003 Michael D. Birnbaum, MD, PC - All rights reserved
    All materials on this site are property of Michael D. Birnbaum, MD, PC


    source:
    http://www.infertilityphysician.com/...pcos.html#pcos
    http://www.infertilityphysician.com/...ovulation.html
    All materials on this site are property of Michael D. Birnbaum, MD, PC

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