Ovulation/PCOS

Introduction
    Genes, Chromosomes and Heredity
Post-cystic Ovary Syndrome (PCOS)
    PCOS Variants
    Diagnosis
    Therapy
    Electrolysis
    Myths Concerning Hair Removal
    Hair-An Syndrome
    Patient Instructions - Prednisone/Dexamethasone
Evaluation of Women with Androgen Disorders
Ovulation/PCOS
    Acanthosis Nigricans and Insulin Resistance

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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.