POLY-CYSTIC OVARY SYNDROME
ANDROGEN DISORDERS IN WOMEN AND MEN
THE METABOLIC SYNDROME
IT IS VERY IMPORTANT TO UNDERSTAND THAT PCOS IS NOT AN OVARIAN DISEASE, DESPITE ITS NAME
IT IS AN ENDOCRINE-METABOLIC DISEASE THAT AFFECTS THE OVARY
TOO MANY PHYSICIANS THINK OF POLY-CYSTIC OVARY SYNDROME AS SIMPLY A PROBLEM FOR WHICH YOU PUT THE WOMAN ON BIRTH CONTROL PILLS AND DO NOTHING ELSE. IT IS NOT.
POLY-CYSTIC OVARY SYNDROME IS A CHRONIC DISEASE REQUIRING LIFE-LONG THERAPY TO REDUCE THE RISK OF THE VARIOUS PROBLEMS (SUCH AS DIABETES, HIGH CHOLESTEROL, HEART DISEASE, NON-ALCOHOLIC FATTY LIVER DISEASE WHICH CAN LEAD TO CIRRHOSIS, UTERINE CANCER, AND OVARIAN CANCER) ASSOCIATED WITH THIS DISEASE.
IT IS NOT A DISEASE FOR WHICH YOU CAN TAKE BIRTH CONTROL PILLS AND DO NOTHING ELSE.
IF A WOMAN HAS HIRSUTISM (COARSE DARK HAIR GROWING ON HER BODY WHERE IT DOES NOT BELONG), BY DEFINITION, SHE HAS A HORMONE PROBLEM.
THERE IS NO SUCH THING AS “IDIOPATHIC HIRSUTISM”, DESPITE WHAT YOU MAY READ ON THE INTERNET
IDIOPATHIC IS THE TERM USED TO DESCRIBE ILLNESSES OR OTHER PROBLEMS FOR WHICH THERE IS NO OBVIOUS CAUSE.
MANY WOMEN PANIC WHEN THEY ARE TOLD THEY HAVE POLY-CYSTIC OVARY SYNDROME, THINKING IT MEANS THEY WILL NEVER BE ABLE TO HAVE CHILDREN.
THIS IS TOTALLY UNTRUE.
IN FACT, POLY-CYSTIC OVARY SYNDROME RELATED INFERTILITY IS USUALLY ONE OF THE EASIEST INFERTILITY PROBLEMS TO TREAT.
THE TERM “POLY-CYSTIC OVARY SYNDROME” IS THE WORST THAT COULD HAVE BEEN DEVISED. HOWEVER, IT HAS BEEN AROUND FOR OVER 80 YEARS AND WE ARE STUCK WITH IT.
THE CHANGES SEEN WITH POLY-CYSTIC OVARY SYNDROME ARE DUE TO UNDERLYING ENDOCRINE AND METABOLIC ABNORMALITIES, MAINLY INSULIN RESISTANCE.
THE CHANGES SEEN IN THE OVARY ARE THE RESULT OF THESE ISSUES. THE OVARY IS THE VICTIM, NOT THE CAUSE.
THERE IS NO CURE FOR PCOS. THERE IS NO TREATMENT SPECIFIC FOR PCOS. WHAT WE DO IS TREAT WHATEVER ABNORMALITIES THE PCOS IS CREATING SUCH AS INFERTILITY, HIRSUTISM, HIGH CHOLESTEROL, ETC.
IT IS AN INHERITED ENDOCRINE AND METABOLIC DISEASE WHICH CAN AFFECT MEN AS WELL.
THE “RED FLAG” IN MEN IS EARLY BALDING.
A significant percentage of my practice deals with evaluating and treating women with PolyCystic Ovary Syndrome. As this pamphlet will explain to you, PolyCystic Ovary Syndrome is a common but potentially very serious medical condition that affects not only women but men as well.
Too many people think of PolyCystic Ovary Syndrome as a disease that only affects women. Furthermore they think of it only as a disease that produces irregular periods, acne, facial hair, and not much else. Because of this, many physicians believe that the only treatment necessary for PolyCystic Ovary Syndrome is birth control pills. Since most women with PCOS have irregular periods, putting that woman on birth control pills makes the woman happy because she thinks the problem has been corrected – her periods are now regular. The physician is happy because the patient is not bothering him or her anymore.
It is critically important to understand that PCOS is a serious endocrine and metabolic disease. The fact that it produces irregular periods or acne or facial hair is the least important issue.
Women with PCOS are at increased risk to become diabetic – many already are or are on their way. What is very important is the fact that many women do not realize this.
Women with PCOS are at increased risk to become diabetic when they are pregnant. There is some evidence that women with untreated PCOS have a higher miscarriage rate than the general population.
Women with PCOS are at increased risk for serious abnormalities in their cholesterol leading to an increased risk for heart disease.
Women with PCOS, especially if they are overweight, are at increased risk to develop uterine cancer.
Women with PCOS are at increased risk for ovarian cancer although the numbers are of borderline statistical significance which makes their clinical significance somewhat questionable.
Treating PCOS involves evaluating all of these various issues and dealing with them as seems most appropriate. Simply putting a woman on birth control pills for irregular periods is not the way to do it.
In fact, there is now good evidence that, at least for some women with PCOS, birth control pills actually make things worse. A study done in 2010 looked at women with PCOS who also had “Impaired Glucose Tolerance” (IGT). IGT is diagnosed by a glucose tolerance test and is one step away from full-blown Diabetes. My own experience is that IGT is not rare in women with PCOS.
They then put these women on either metformin or birth control pills. They then looked at various “markers” that we know are risk factors for cardiovascular disease such as High-Sensitivity CRP and Insulin Resistance. At the end of 6 months, it was found that these markers improved in the women on metformin but worsened in women on birth control pills.
This is not to say that birth control pills do not have a role to play in the treatment of PCOS but you have to be careful and monitor those women very carefully to make sure you are not creating other problems.
Poly-Cystic Ovary Syndrome (PCOS) is the most common endocrine disease in women between the ages of 10 and 50. At least 10% of all women have the classic disease. Based on newer information and a better understanding of the underlying pathology, 25% or perhaps even more, have some features of PCOS, even if they do not fit the official definition. This is especially true since obesity is becoming such a significant problem in our country. Even a woman does not fit the “classic” definition of PCOS, many have various features of the disease which we now know puts her at risk for problems later in life such as Diabetes and heart disease.
PCOS is even being diagnosed in girls before puberty. Women after menopause, if you take a careful history, can also be diagnosed retrospectively as having had PCOS when they were still menstruating.
One of the problems with PCOS is the terminology. When people see the term PCOS, they automatically assume (understandably) that it is primarily an ovarian disease - it is not. The abnormalities in the ovary are the result of the problem - not its cause. However, the term has been around for over 70 years. We are stuck with it.
PCOS is a disease of insulin resistance. Insulin is the hormone produced by your pancreas and its main function is to help transfer sugar from the blood stream into the cells where it is used as a source of energy. When you are insulin resistant, the insulin your body is producing does not work properly. To compensate, your body must produce more insulin. The excess insulin stimulates the ovaries to produce androgen (male hormone).
The increased androgen production from the ovary does several things. First, it interferes with normal ovulation and one of the hallmarks of PCOS is irregular menstrual periods. However, some women can have regular periods and still fit the criteria for PCOS.
Another thing excess androgen does is stimulate the hair follicles to produce coarse, dark hair. It also stimulates the sebaceous glands to produce excess amounts of oil. Therefore, women with PCOS also show either hirsutism (coarse dark hair in places that women normally do not have it) or acne - occasionally both.
Perversely, excess androgen also worsens insulin resistance, which helps perpetuate the vicious cycle. On the other hand, estrogen is an “insulin sensitizer” (see below), which helps the problem. For instance, we know that post-menopausal women who are Diabetic achieve better control of their Diabetes if they take Hormone Replacement Therapy.
There are two ways you become insulin resistant. The first is an inherited abnormality in the way insulin interacts with the cell. PCOS definitely runs in families and it is not at all uncommon for me to see a mother and daughters all with PCOS.
Another way you become insulin resistant is by being overweight. The mechanism is different but the end result is more or less the same, at least in some people. It has been my experience that women who are insulin resistant just on the basis of their weight do not always exhibit the classic features of those women whose PCOS is genetic in origin.
Two-thirds of women with PCOS are overweight and one-third are of normal body weight. However, even women in the latter group are still insulin resistant although often not as severely as those who are overweight as well.
There are drugs available that we call “insulin sensitizers”. These are drugs that allow insulin to work better and by reducing the amount of insulin the pancreas has to produce; many of the features of PCOS will regress with this therapy. These drugs are especially important in women trying to become pregnant. Women with untreated PCOS have an increased risk of early miscarriage and also of becoming diabetic while pregnant. Treatment with insulin sensitizers prior to conception and during pregnancy (depending on the drug) reduces the risk of both problems.
Menopause is the most common endocrine disease in women. All women will eventually experience it.
Androgen problems constitute the most common endocrine disorder in women of reproductive age (puberty to menopause). In fact, other than menopause, Poly-Cystic Ovary Syndrome is the most common endocrine disorder in women of any age. It has now been described in pre-pubertal girls. Many women who are post-menopausal also have histories that indicate that they would have been diagnosed with Poly-Cystic Ovary Syndrome if they were still menstruating.
Poly-Cystic Ovary Syndrome and its many variants is the most common reason for excess androgen production. A great deal of confusion exists concerning these problems not only among the women who suffer them but also their treating physicians as well. The purpose of this pamphlet is to explain this confused area of endocrinology to provide you with a better understanding of the problem you have and the therapy employed.
“Androgen” is the overall term applied to any hormone that produces male characteristics. In this way, it is similar to the term “estrogen” which describes any hormone producing female traits.
Men and women both produce androgen - obviously men are producing more androgen but even normal women produce some androgen.
There are certain physical characteristics that we associate with maleness. These include a beard, large muscles, acne, a deep voice, baldness and enlargement of the Adam’s apple. Men have these characteristics not because they are genetically programmed to develop them but because the male endocrine system produces far more androgen than the female endocrine system.
In order to understand what is happening, it is necessary to define certain terms that you may come across in your readings.
As indicated, “androgen” is the term used for any hormone or substance that creates male-like symptoms or physical changes.
“Estrogen” refers to any hormone or substance that confers female symptoms or characteristics.
It is important to understand that everyone, both men and women, have hair over their entire bodies. The only exceptions are the palms of the hands and the soles of the feet.
There are two main types of hair - “vellus” and “terminal”.
Vellus hair is finely textured. It may be light or dark in color depending upon the characteristics of the individual. It is not the color of the hair that makes it “vellus” - it is the thickness and texture of the hair.
As a result, darkly complected women will have dark hair on their face, arms, legs, abdomen and back; whereas a blonde woman will have lightly colored hair.
Terminal hair is coarse and thick. Again, it is not the color of the hair per se, but the texture that is important. However, all other things being equal, terminal hair is almost always darker than the vellus hair on any given individual.
All women have vellus hair on their face. It is therefore critically important to understand that increased androgens in a woman do not cause hair to grow. The increased androgen converts vellus into terminal hair - the same process that normally occurs in a boy at puberty.
It is therefore critically important to understand that any hormone therapy will not eliminate the hair. The purpose of hormone therapy is first to slow the growth of new hair and then to ultimately reduce the hair altogether. Permanent removal requires physical elimination of the hair. In today’s world, this is best done using a LASER (available in our MedSpa). Electrolysis is rapidly becoming an obsolete procedure. The best treatment requires a combination of both a hormonal and a physical approach.
Hirsutism is defined as the growth of terminal hair (i.e. androgen stimulated hair) in women in places where it normally does not occur. Such places include the chin, neck, the skin over the upper breasts (not around the nipples), the skin over the breastbone between the breasts, and the lower abdomen.
A term you may frequently encounter is “idiopathic hirsutism”. “Idiopathic” means unknown or unexplained. As will be discussed later in this pamphlet, much confusion has arisen because women who were evaluated for androgen disorders were often found to have “normal” serum levels for the various hormones. It was therefore - incorrectly - concluded that because the hormone levels in the blood were normal, there was no underlying hormone problem. We now know that this is incorrect and there is no place for the term “idiopathic hirsutism”. A reason for the hirsutism exists and can usually be found in almost every woman.
The reason these women were told that their hormone levels were normal is that the normal range listed by most labs is wrong. There are other reasons as well which will be discussed later in this pamphlet.
The term “hirsutism” itself simply refers to the presence of terminal hair (i.e. androgen stimulated hair) on a woman in locations where it simply does not belong. However, the presence of terminal hair in all locations does not necessarily convey the same significance. The general rule is that hair in the mid-line of the body is more important than hair farther away. For instance, hair on the breasts around the nipples is fairly common and by itself has no endocrine significance. However, hair between the breasts over the sternum (breast bone) is very significant.
Again, hair on the chin and neck is important; hair in front of the ears (like side-burns) is less significant — especially if that is the only location.
Many women, particularly women with darker complexions, are very distressed because they begin to grow a mustache. Again, the presence of hair on the upper lip is normal - it is supposed to be there. However, if the woman is dark, her hair will be dark and although it is often unsightly, by itself, a mustache usually has no endocrine significance if the woman does not have hirsutism elsewhere on her body. Under such circumstances, the best therapy is simply to remove it by LASER. It is simple, inexpensive, and effective with little chance of problems.
Some women, especially if darkly complected, have significantly more prominent and darker body hair. However, so long as the hair is vellus (which is usually is), it is normal though it may be unsightly. Such “excess” hair (it really isn’t) is termed hypertrichosis. The hair is supposed to be there and it is darker for hereditary, not hormonal, reasons. Again, unsightly hair can be removed by LASER even it there is no hormonal cause.
All women produce some androgen in the same way that all men produce some estrogen. To a great degree, the differences between men and women are more a quantitative rather than a qualitative difference. Therefore, women will develop “male” characteristics if their androgen production is increased for whatever reason. Since increased androgen production in women is a very common problem, the treatment of such disorders constitutes a very large part of my practice.
It is also becoming apparent that some men may produce too much male hormone and this may play a significant role in infertility. It may also be of importance in men with severe acne. Early balding (before age 30) is often a sign of an androgen disorder in men, especially if that man has any female relatives with Poly-Cystic Ovary Syndrome.
There are many hormones that are classified under the overall heading of androgen. There are two principal biologically active androgens — Testosterone and Di-Hydrotestosterone or DHT. Testosterone is produced directly by the ovary, the testicle and the adrenals.
DHT is produced by the conversion of testosterone by an enzyme called 5-alpha-reductase. In addition, the ovaries and adrenals produce another hormone - androstenedione - that can be easily converted to testosterone. Lastly, the adrenals produce an additional hormone, DHEA. DHEA has a very short biological “life” but the body converts it into a much longer lasting hormone, DHEA-S. DHEA is, unfortunately, sold over-the-counter in drug stores. The manufacturers are able to get away with this because they have slipped it past the FDA by calling it a nutritional supplement, even though it is a very powerful hormone with potentially serious side effects.
The same is true for androstenedione. It too is sold over the counter as a “nutritional supplement” but is in fact a very powerful hormone with potentially dangerous side effects. It should not be available without a prescription and proper monitoring.
These other hormones, especially DHEA, are easily converted to testosterone. Much of the conversion of these other hormones to testosterone takes place in the body fat. It is for this reason that obese women commonly show evidence of increased androgen production. Overweight women have elevated serum androgen levels even they do not have significant acne or hirsutism.
While the names of these hormones are not words you would tend to use at a cocktail party, you may see them on a bill from a lab or in a letter or report or on the Internet and I wanted you to at least know what they are. Furthermore, DHEA is now sold over the counter in drug stores and health food stores. Many people are taking it, and there is the potential for significant problems as your body will convert DHEA into more potent androgens very easily. This will result in increased androgen levels in your blood, resulting in hirsutism, acne, elevated total cholesterol, increased LDL cholesterol (the bad one) and decreased HDL cholesterol (the good one). DHEA should never have been allowed to be sold without prescription and I would caution you not to take it without careful supervision.
The source of androgen production in both men and women is principally the adrenal gland and the gonad (either the ovary or the testicle). Men produce approximately 10 times as much testosterone per day as women and the serum concentration of testosterone in men is 10-20 times that of women. This accounts for the fact that men have all the manifestations of androgen — namely hair on the face, increased dark body hair, deepening of the voice, larger muscles and, in later years, thinning of the hair or baldness.
It is important to understand that women will develop symptoms of excess androgen if they produce too much androgen. It is also important to understand that the total daily production of testosterone is the critical factor. The amount of androgen produced each day may be increased but because of how the body functions, the actual concentration of the male hormones in the blood may not rise. Failure to understand this fact is what causes much of the confusion surrounding androgen disorders.
After a hormone is produced, either directly or indirectly, it travels through the bloodstream to the various parts of the body. The hormone then leaves the bloodstream where it acts on its target organ such as the hair follicle. The hormone then is metabolized, usually by the liver, after which it is excreted in the urine.
When a woman produces too much androgen, it is easy to suspect that she has a hormone problem. The symptoms of increased androgen production in women include menstrual irregularity often proceeding to a complete cessation of menstrual periods, hirsutism, acne, obesity and often infertility. While actual baldness in women, particularly younger women, is uncommon, thinning of the hair in younger women may also be an indicator of this particular type of hormone problem.
The amount of hormone produced by the body on a given day is called the “production rate”. The amount of hormone removed from the bloodstream, metabolized and then excreted is called the “clearance rate”. Therefore, you can readily appreciate that the concentration of a hormone in the bloodstream is simply the difference between the production rate putting the hormone into the blood and the clearance rate which is removing the hormone from the blood. This is an important concept to understand.
One of the most important things to understand about androgen disorders is that if a woman shows clinical evidence of increased androgen production, she is indeed making too much androgen. In other words, the production rate of androgen is increased. However, it is also true that through mechanisms that we do not fully understand, androgens have the ability in influence and control their clearance rate. When the production rate of androgen is increased, the clearance rate is also frequently increased. In other words, the faster the body is making it, the faster the body is getting rid of it. Therefore, in a situation such as this, the levels of the hormones in the bloodstream will remain normal or perhaps only slightly elevated.
Failure to understand this has caused people to state that if a woman has hirsutism but normal serum androgen levels, she has “idiopathic” hirsutism, incorrectly believing that the normal hormone levels rule out a hormone problem. WRONG! This is why there is no such entity as idiopathic hirsutism. A woman with hirsutism has or had a hormone problem — it is just that simple.
Increased androgen production in both men and women is often due to increased androgen production from the adrenal as a result of an underlying enzyme deficiency or from the ovary in women who do not ovulate. In many women, both the ovary and the adrenal play a significant role along with body fat in women who are overweight.
Another source of increased androgen production is the increased conversion of testosterone to DHT by the 5-alpha-reductase enzyme. This conversion occurs in the hair follicle itself. DHT is the principal androgen acting on the hair follicle. It is now recognized that some women have evidence of increased androgen effect because of increased 5-alpha-reductase activity even though there may not be an increase in their total daily androgen production. They are still making too much androgen but it is a localized increase at the level of the follicle rather than a generalized increase in total body androgen production.
Rarely, a tumor of the ovary or the adrenal may produce too much androgen. These tumors are almost always benign, they are usually quite small and they are very uncommon. However, they produce large amounts of male hormone. When these tumors occur in women, they do much more than cause irregular menses, acne, hirsutism and infertility. These tumors will actually virilize a woman — in other words, she will develop male characteristics such as a deeper voice, male pattern baldness, increased muscle mass, a male body contour, etc. The presence of these tumors can be suspected by either the symptoms the woman comes in with or the level of male hormones in her blood.
Women with evidence of increased androgen production exhibit symptoms that are classified into 2 main categories — those that we term “defeminizing” and those that we term “virilizing”. Defeminizing symptoms are much, much more common and are usually the result of an overproduction of androgen by the ovaries and/or adrenals due to an alteration in the basic normal functioning of these glands. Defeminizing symptoms include menstrual abnormalities, acne, hirsutism and infertility.
Virilization means that the woman is taking on definite male characteristics. This implies a much higher level of androgen production and virilization usually means the presence of an androgen-producing tumor although it can be seen in cases of severe PCOS (see the section on PCOS later in this pamphlet. These tumors are almost always, however, benign. Virilizing symptoms include complete cessation of menstrual periods, deepening of the voice, baldness and enlargement of the muscles. Enlargement of the Adam’s apple and enlargement of the clitoris are also seen.
The underlying abnormality that creates these problems is somewhat complex but I believe that it is critically important for you to understand what is going on for several reasons. First of all, as will become apparent, these problems are inherited. Understanding them may help other members of your family to obtain help and successful treatment for their problem and it may alert you to the fact that indeed your whole family has had a problem for several generations that no one diagnosed. It also has some implications in terms of the children that you may have someday. Lastly, the therapy may require lifelong hormonal treatment to control the problem. It is, therefore, of critical importance that you understand exactly what is going on, why the tests are necessary to diagnose the problem and what the implications are for the future.
THE PATHOPHYSIOLOGY OF ANDROGEN DISORDERS
Although it doesn’t have to be, the evaluation and treatment of a woman with an androgen problem is perceived by many to be a very complex issue. It certainly can be confusing. One of the principal reasons for this is similar to the parable of the three blind men who had hold of an elephant. One blind man was holding the elephant’s tail; another was holding its trunk; the third was holding its leg. Each described the elephant based upon the part that he was holding - none of them could step back and see the animal in its entirety.
Similar problems have resulted when trying to evaluate androgen problems in women. There are three principal sources of excess androgen production in women - the ovary, the adrenal, and her body fat. Depending upon a researcher’s particular interest, one of these areas might be studied intensively to the exclusion of the others. Furthermore, until relatively recently, it was not fully appreciated how complex an interaction there actually is between these three segments. Although there has been a great deal of research done over many many years, a few pieces of the puzzle have finally fallen into place - pieces which go a long way in explaining the nature of this problem.
The term “physiology” refers to the normal functioning of a particular body organ or system. The term “pathophysiology” refers to the abnormal functioning of a particular body system which ultimately leads to disease. By explaining to you the pathophysiology of androgen disorders, I hope that you will understand better the tests that are involved, how to interpret those tests, and how the treatments are designed to correct the abnormalities.
All women produce some androgen. The term androgen itself refers to any hormone that either directly by itself or indirectly by conversion to other hormones produces changes that are classically associated with maleness. The degree to which these changes occur depends on many complex interacting factors but the most important is the actual amount of excess androgen that is being produced. The more androgen your body is making, the more severe the changes will be. However, genetic factors also play a significant role. Oriental women may show no excess facial hair whereas women of southern European extraction may have a considerable amount of hair for relative small increases in testosterone.
The principal biologically active androgen is testosterone. This is the name with which most people are familiar.
In certain body systems, particularly in the hair follicle, testosterone is converted to another hormone - dihydrotestosterone. In the hair follicle, it is dihydrotestosterone that is the active hormone.
Various other hormones are in and of themselves not biologically active. However, the body has the ability to transform these hormones into testosterone - either directly or indirectly. They, therefore, contribute to the overall body’s level of androgen.
The principal androgen of the ovary is androstenedione.
The principal androgen of the adrenal is Dehydroepiandrosterone (DHEA). The adrenal gland produces different amounts of its various hormones at different times of the day. Therefore, the concentration of DHEA in your blood stream depends upon the time of day it was drawn. However, the body adds a sulfate molecule to DHEA, creating a substance called Dehydroepiandrosterone Sulfate or DHEAS, sometimes abbreviated DS. The concentration of DHEAS in your blood stream is fairly constant throughout the day. This is the hormone that is usually measured since it does not show any time dependent variation and the levels can be checked at anytime the woman happens to be in the office.
There is another hormone that you may see mentioned frequently. Its name is “17 alpha hydroxyprogesterone”. Although it is not an androgen, it is an important intermediary step in the production of androgens and an elevated level is a marker for a somewhat common adrenal problem. More about that later.
There are a couple of other hormones that will be mentioned here simply because you may come across them in your reading. These two “hormones” are 11-desoxycortisol and 17- hydroxypregnenelone. Again, these hormones are intermediaries. They do have clinical significance but the number of patients in whom they would be important is very very small, particularly in an adult population.
It is important to understand that a normal functioning ovary and adrenal produces androgen. When these organs are functioning abnormally, they produce excess amounts of androgen and this leads to the various clinical syndromes.
One of the principal functions, if not the principal function, of the ovary is to produce an egg each month. The ovary does this in a structure called the follicle which has several layers of cells – each with a different function.
The outermost layer of the follicular cells produces androstenedione, which the inner layer then converts to estradiol - the principal estrogen produced by the ovary in a premenopausal woman. Anything that disrupts the normal ovulation process leads to increased androstenedione production by the ovary. It may also lead to increased testosterone production as well.
One of the principal functions - again, perhaps the principal function - of the adrenal gland is to produce cortisol. DHEA is an intermediary step in the production of cortisol. Again, anything that disrupts this normal sequence of events will lead to an increased production of DHEA. Many years ago, a few articles were published that showed that abnormal ovarian function would also lead to increased DHEA production. However, the data was scant and not well substantiated. Newer, better done studies now clearly show that the type of abnormal functioning that you almost always see in women with Poly-Cystic Ovary Syndrome (PCOS) leads to increased adrenal production of DHEA and when you control the ovarian abnormality, the DHEA levels will drop.
Insulin resistance leading to increased insulin production is known to stimulate ovarian androgen production. There is now some evidence that insulin also stimulates adrenal androgen production. Insulin is emerging as the main culprit in PCOS and related syndromes.
Adrenal abnormalities produce a number of clinical syndromes that are often indistinguishable from PCOS. Although at one time it was felt that these syndromes were common, we are now beginning to realize that purely adrenal abnormalities are less common. Much of the confusion developed because of our incomplete understanding as to how much altered ovarian function affected the way the adrenal gland produces its hormones.
GENES, CHROMOSOMES AND HEREDITY
Each of us is who we are because of heredity. Heredity is nothing more than the passage from one generation to the next of those physical features (and otherwise) possessed by our parents. Their parents passed along certain features to them and so on back through the generations.
Every piece of information that determines who we are is carried in our genetic code. Each unit of the genetic code is called a gene and genes are found on chromosomes.
Genes are specific areas on a chromosome that tell the body to make a specific protein. Many of these proteins are enzymes. Enzymes are specialized proteins that allow the body to convert one substance to another.
Chromosomes are strands of DNA found within the nucleus of the cell and are made up of thousands and thousands of individual chemicals called nucleic acids.
There are four different nucleic acids and each group of three nucleic acids on the DNA codes a specific amino acid. Remember that proteins are nothing more than chains of amino acids strung together like beads. You can now appreciate that the chromosomes are nothing more than master blueprints for proteins. Proteins are our body’s building blocks and every different protein in our body carries out a different function. Nothing happens in the body that is not under the regulation of at least one and often more than one protein.
A human being contains 46 chromosomes. However, they are not 46 different chromosomes; they are arranged in 23 pairs of chromosomes. Each sperm and each egg contains 23 chromosomes and when sperm and egg unite to initiate the process of fetal growth, the resulting baby that is formed has a total of 46 chromosomes.
These chromosomes are grouped into 22 pairs of what we call the body chromosomes or autosomes. The remaining pair is called the sex chromosomes. If you are a male, you have an X and a Y sex chromosome; if you are a female you have two X chromosomes.
When a cell divides, the chromosomes duplicate themselves so that each two cells that are formed contain the identical chromosomes as did the parent cell that formed them. However, the process of duplication does not always proceed correctly and mistakes may be made. These mistakes involve incorrect duplication of the nucleic acids which means that the genetic code for any one sequence is disrupted and that means that the protein formed will be defective in some way.
These defects in the duplication process are called mutations.
In an attempt to minimize the damage created by a mutation, mother nature has given us duplicate sets of chromosomes for each function — for each protein. Therefore, if one doesn’t work right, at least there is another copy that will do the job correctly.
Chromosomal abnormalities and genetic mutations are a lot more common than people realize. However, in the vast majority of instances, either they are of no consequence because the other chromosome is able to take over the job or the defect is so devastating that it never permits embryo development to take place and the woman has a miscarriage.
There are, however, various genetic mutations that fall somewhere in between and these often result in diseases that we can now recognize and often treat.
In many instances, a person will have two genes for the same characteristic and neither gene is harmful or dangerous — just different. Such a characteristic would be eye color. If there are two genes for the same characteristic and one predominates or takes over, that characteristic is called “dominant” and the other characteristic, which is suppressed, is called “recessive”.
In the case of eye color, brown is dominant over blue. Therefore, if a person has two brown-eyed genes, they would be obviously brown eyed. If a person had two blue-eyed genes, their eyes would be blue. However, if a person has one gene for brown eyes and one gene for blue eyes, their eyes will be brown.
To further confuse you, many genetic characteristics are not “all or none”, there can be what is termed incomplete dominance. In the case of eye color, your eyes might be hazel or green.
There is another important feature of the way your body functions that you must understand. All chemical steps within your body proceed in a very tightly controlled fashion and each step in each chemical process is controlled by what is called an “enzyme”. Enzymes are Mother Nature’s catalysts and determine that certain chemical reactions always take place in a certain manner and only in that manner.
Enzymes are proteins and you can now begin to appreciate that if there is a genetic mutation, a given protein was not formed properly. If that protein is an enzyme, then a given chemical reaction within the body may not proceed the way it should.
As with almost anything else in medicine, there is always going to be an exception. As I have already discussed, there is no such thing as idiopathic hirsutism - studies done many years ago clearly showed that if a woman has androgen stimulated hair on her body in areas that are not normal, such as the chin, front part of the neck, between the breasts, etc., then that woman is producing excess amounts of androgen. When most people think of excess androgen production, they think of either the ovary or the adrenal gland or the body fat as the source of that excess androgen production and in fact, for the vast majority of women, this is the source. There is, however, a small group of women where the actual problem is in the hair follicle itself. This problem is hereditary and is genetically determined. Hence, I have included it in this section.
As I have mentioned, the hair follicle itself is very metabolically active. Dihydrotestosterone is the hormone that stimulates the hair follicle and causes it to produce course dark hair. Dihydrotestosterone is produced in the hair follicle by the conversion of testosterone itself and the enzyme which controls this conversion is called the 5 alpha reductase enzyme.
The vast majority of women with hirsutism have increased production of testosterone. Therefore, there is an excess amount of testosterone available to the hair follicle which drives the reaction forward and results in the increased production of dihydrotestosterone.
However, there are a small group of women whose total daily testosterone production is normal - their problem is an excess level of activity of the 5 alpha reductase enzyme leading to an increased conversion of testosterone to dihydrotestosterone. In cases such as this, although therapies directed at reducing total daily testosterone production play a role in therapy, blocking the 5 alpha reductase enzyme also plays a significant role. This will be discussed in the section concerning treatment.
THE ADRENAL GLAND AND ITS HORMONES
There are many endocrine glands in the body. One of the most important and one of concern in women with hirsutism or other androgen problems is the adrenal gland. Primary adrenal abnormalities do exist. At one time, before we had a better understanding of the problem, it was felt that primary adrenal abnormalities were more common than they are. Now, we have come to realize that for most women, they have PCOS, which leads to abnormal adrenal function.
Your body has two adrenal glands - they are about the size of your thumb and they are found just above the kidneys.
The outer portion of the adrenal gland is called the adrenal cortex and the inner portion is called the medulla. For those of you who are interested in these things, the adrenal medulla is the site of epinephrine (adrenaline) production.
The adrenal cortex has three zones - outer, middle and inner. Although the same types of reactions take place in all three zones, the outer zone is concerned predominantly with the production of a hormone called aldosterone, which controls your body’s salt and water balance.
The middle layer of the adrenal cortex produces cortisol.
The inner layer of the adrenal cortex produces androgen.
The adrenal gland produces its various hormones (which are all quite similar to each other in terms of their biochemical structure) through a series of steps starting with cholesterol. Each step is very carefully and specifically controlled by a separate and distinct enzyme. Defects or abnormalities in any one of these enzymes means that the chemical change that it (the enzyme) controls does not take place properly (or may not take place at all).
When this occurs, the orderly progression from cholesterol to the various adrenal hormones is disrupted and the adrenal gland is not able to function properly. Even though the adrenal gland makes three distinct groups of hormones, the only one that is of critical importance for your life and health is cortisol. It is the regulation of cortisol production that determines the overall level of activity of the adrenal gland. This is an extremely important fact to keep in mind because it is the driving force behind many of the abnormalities in the adrenal gland that bring women into my office. It is especially important in pediatric endocrinology, particularly in babies born with “ambiguous genitalia” – i.e., babies whose genitals at birth are not normal and it may be impossible to determine initially whether the baby is a boy or a girl.
The adrenal gland has to make a certain amount of cortisol each day. Your life, health and well-being depend upon it. If the adrenal gland is unable to do this, mechanisms are set in motion to insure that adequate cortisol production occurs even if it means that other hormones may not be produced in normal amounts. In fact, they are often produced in excess amounts.
Think of the pathways within the adrenal glands for the production of the various hormones as if there were three parallel roads all going in the same direction with a series of bridges in each road and, furthermore, with a series of crossroads that link the three main roads.
Think of one of the enzyme deficiencies in the adrenal cortex as if one of the bridges on one of the roads was either completely gone (a complete enzyme defect) or the bridge was under repair and reduced to one lane only (a partial defect).
If you were traveling on one of the roads, and the bridge ahead of you was not carrying its full load, you would take one of the crossroads over to another main road to complete your journey. This is exactly what happens in the adrenal cortex. If one of the enzymes that controls cortisol production is either absent or defective, hormone synthesis in the adrenal gland is shifted into other pathways. Depending upon the nature of the enzyme defect and the degree to which the enzyme is defective, certain hormones will be produced in excessive amounts and other hormones will be produced in much lesser amounts than they ought to be.
ADRENAL ENZYME DEFICIENCIES AND ANDROGEN DISORDERS
Five principal adrenal enzyme abnormalities have been described. The most serious involves an absence of the enzyme that allows the adrenal gland to begin the conversion of cholesterol to the other hormones. With this deficiency, the most serious, no adrenal hormones can be produced and these babies will die almost immediately after birth. If the appropriate diagnosis can be made, it is possible to anticipate the problem in subsequent pregnancies and with appropriate therapy, these babies have the potential for survival. Sometimes this abnormality can be detected before birth and the baby can be saved.
The most common enzyme deficiency involves the inability of the adrenal to carry out the necessary steps for the production of cortisol. Because of this enzyme block, the adrenal gland is also unable to produce aldosterone, which is essential for salt and water balance in the body. As a result, on two of the three pathways in the adrenal (the three roads I talked about before), the principal enzymes are inactive or very much underactive. In other words, main bridges are out on the two roads.
Remember that the body is only interested in cortisol production and it is the production of cortisol that the body regulates very carefully. The other hormones are also regulated but to a much lesser degree.
When the body realizes that there is inadequate cortisol production, it increases ACTH production from the pituitary gland which stimulates the adrenal gland to work harder — the body is attempting to produce more cortisol.
With two of the three bridges out, hormone production is shifted onto the one remaining road open - the road that leads to androgen production.
Consequently, the following syndrome appears at birth. These babies develop adrenal insufficiency very soon after life because they cannot make adequate amounts of cortisol and will die if not promptly and accurately diagnosed. They also cannot produce an adequate amount of aldosterone so they cannot retain sodium. This is termed “salt wasting”. Lastly, these babies are producing tremendously increasing amounts of androgen.
Increase androgen production in a baby boy may be difficult to diagnose accurately. However, if the baby is a girl, then the excess androgen production will alter the baby’s external genitalia to the point where she will definitely not have the appearance of a normal girl but won’t look like a normal boy either. The external genitalia are “ambiguous” and this fact alone will immediately alert the pediatrician that this is a baby with a potentially serious problem.
Going back now to the previous discussion about genes and enzymes, it is important to understand that a person may be born with two normal genes for the enzyme in the adrenal cortex in which case that person will be totally normal since the normal gene is dominant. If a person is born with two abnormal genes for the enzyme, then that person is a pure recessive for that enzyme and it means that the enzyme cannot be produced at all. These are babies born with the disease who are severely affected. Fortunately this situation is fairly rare and occurs only once in about 15,000 deliveries overall.
Much more commonly than having 2 abnormal genes, a person may be born with one normal gene and one defective gene. Therefore, the enzyme is present in deficient amounts and, therefore, the adrenal gland is able to do what it has to but not as well. These “partial adrenal enzyme deficiencies” are fairly common in certain ethnic populations.
Approximately 3% of Jews of eastern European origin are carriers for the most common enzyme deficiency. It is also found with a fairly high frequency in people of Mediterranean origin such as Italians and Greeks. It is, therefore, not rare to see people from these particular groups who have evidence of abnormal hormone production but who are otherwise normal and who lead normal lives. There is a tribe of Eskimos where nearly one third have the defect.
These individuals with the partial enzyme deficiencies usually do not show a problem until puberty. Women with the partial enzyme deficiency often manifest menstrual irregularities, hirsutism, acne, obesity and infertility. These women resemble people with PCOS and it is sometimes difficult to distinguish between them. In fact, as has been discussed, we are beginning to realize that there is far more interplay between the ovary and the adrenal then we had previously appreciated.
It is becoming recognized with increasing frequency that men can have this problem as well. However, it is much more difficult to make the diagnosis. How do you determine that a man is producing too much male hormone? Where the problem is being searched for most diligently is men who are infertile and show evidence of decreased sperm production. This is probably the only area where the partial enzyme deficiency in men has any clinical significance. The only other possible area of concern to me would be those individuals with severe acne, particularly if it persists into adulthood.
Further complicating the problem is the fact that we now know that abnormalities in how the ovary functions affects the way the adrenal produces its hormones. It has been known for years that abnormalities in adrenal function significantly affect the ovary. The opposite is also true.
Therefore, it is not rare to see women with PCOS have increased levels of DHEAS — a hormone produced almost exclusively by the adrenal. This led to confusion as to which problem was causing which. Women with variants of Congenital Adrenal Hyperplasia can exhibit symptoms that are indistinguishable from classic PCOS. Since both problems usually begin at puberty, it can be difficult to determine which is the main problem and which is secondary. (Keep in mind that the most severe forms of Adrenal Hyperplasia manifest themselves at birth. It is only the milder forms that begin later in life.)
If you try to research this, you will come across many terms that have been given to it. One of the more common is “LOCAH” – Late Onset Congenital Adrenal Hyperplasia. It is really an inappropriate term since “congenital” means present at birth and therefore cannot be “late onset”. Again, it is one of those terms (like PCOS) that may not be correct but everyone knows what is meant by it.
Many times, especially in infertile women, it is necessary to treat both the ovarian and the adrenal abnormalities in order to achieve a pregnancy.
Regardless of what underlying hormone abnormality you may have, the bottom line is this – if you have hirsutism (the presence of hormonally stimulated hair in places where it should not be) you are producing or have produced excess amounts of androgen. It is critically important to understand that there is no such thing as “idiopathic hirsutism”. This is a term that you will frequently see in your various readings. It is a term that is frequently applied to women who do not appear to have a hormone problem. The fact is that all women who have hirsutism have a hormone problem. This was proven many years ago by Dr. Mortimer Lipsett and his colleagues at The National Institutes of Health. Dr. Lipsett put his patients through a series of tests that are for research purposes only - they are far too involved to carry out in a regular clinical practice.
What Dr. Lipsett did was to measure the total daily production rate of testosterone - the actual amount of testosterone that the woman produced in 24 hours. This has nothing to do with the serum level of testosterone. What he found was that in women who had hirsutism, there was invariably an increased daily production rate. These women were producing more testosterone than normal. I believe it is improper to label any woman with idiopathic hirsutism. However, it is also true that the tests that we use in clinical practice may not be able to demonstrate the problem but it is there.
One of the principal targets for androgen is the hair follicle - officially called the pilosebaceous unit. In addition to growing a hair, the pilosebaceous unit contains glands that produce an oily substance called sebum. Under the influence of androgen, the sebaceous glands produce this oily substance. If the hair follicle becomes plugged and the oily substance is forced into the surrounding tissues and becomes infected, you develop a pimple. If you develop many of them, we call it acne.
It is important to understand that everyone has hair all over their body. The only exceptions are the palms of your hand and the soles of your feet. Hair follicles in different parts of your body are genetically programmed to produce different types of hair unless subjected to an outside influence.
Basically, there are two types of hair - vellus hair and terminal hair.
Vellus hair is thin and finely textured. It may be light or dark depending upon your own particular coloration.
Terminal hair is thick and course. It is usually dark - at least darker than a given person’s usual hair color. The hair on your head is terminal hair. Pubic hair is terminal hair.
It is a misconception that increased androgen makes you grow new hair. What is really occurring is that increased androgen takes a hair follicle that was originally programmed to produce a vellus hair and transforms it into a follicle that produces a terminal hair. No new hair follicle has developed. No new hair has grown. It is a transformation of existing hair.
This transformation occurs normally in boys when they go through puberty because of the significantly increased amounts of testosterone that they begin to produce at that time.
Women, because of their lower androgen levels, only begin to produce terminal hair at puberty in those follicles that are genetically programmed to respond to lower levels of androgen. This would include hair under the arms and pubic hair. If, however, a woman’s androgen levels are higher than “normal” hair that should have remained vellus is now transformed into terminal hair.
Hirsutism is defined as the presence of terminal hair on a woman’s body in locations where it should not be - hair that is the result of increased androgen levels. As a general rule, the closer to the midline of the body, the more significant the hair is.
The most common locations for such abnormal hair are the chin and the front part of the neck.
Another common location is the lower midline of the abdomen. In women, the top of the pubic hair pattern should be straight across. If there is any growth of the pubic hair up the midline toward the naval, this is abnormal.
Another common site for abnormal hair growth is the midline of the chest over the sternum (the breast bone). Less commonly, there may be terminal hair growth on the upper surfaces of the breasts.
Hair around the nipples, especially if that is the only location, is of little or no clinical significance.
As unsightly as it might be for some women, hair on the upper lip, if that is its only location, again, has no clinical significance.
Hair on the sides of the face in front of the ears is of some clinical significance but, again, some women will have this as their only location and no other. If that be the case, it is of lesser importance.
Other areas in which women may develop rather heavy excess hair growth involves the lower back and buttocks. Usually, hair growth in this area is associated with abnormal hair growth elsewhere.
Some women have excess amounts of body hair and if they are darkly complected, this hair will also be dark. It may be very cosmetically stressful to the woman. However, if there is no evidence of abnormal terminal hair growth, this abundant body hair is simply the way you were genetically programmed and there is nothing that can be done about it. Such excess body hair is termed “hypertrichosis”. Unfortunately, there is little you can do to treat this except bleach it.
The following is a description of how endocrine abnormalities lead to the development of hirsutism. It is a multi-step process.
In the majority of instances, there is an abnormality in the way the ovary functions (most commonly PCOS) or the adrenal gland (as in one of the inherited enzyme defects). As has been mentioned, women with PCOS frequently have an associated adrenal abnormality.
The bottom line is an increased production of either testosterone itself or hormones that the body will convert into testosterone. In women who are significantly overweight, conversion of the “pro hormones” will also occur in body fat. This may occur even if there is no underlying ovarian or adrenal abnormality.
As previously discussed, once the increased testosterone is produced, it circulates in your blood stream attached to its specific binding protein. The free or unbound hormone then leaves the blood and enters the cells. Cells that are genetically programmed to respond to androgens will have a receptor specifically for that androgen.
Testosterone then enters the cell and, in the hair follicle, the testosterone is converted to dihydrotestosterone. This process involves adding two hydrogen atoms to the testosterone molecule. Because of the way the testosterone molecule is described biochemically, the enzyme that causes this to occur is called the “5 alpha reductase enzyme”. The dihydrotestosterone then stimulates the hair follicle to change from producing a vellus hair to a terminal hair.
Treatment of hirsutism involves an attempt at modifying this change of events at one or more places. All the various therapies that we currently employ are directed at this sequence.
One of the most common ways of doing this is simply to suppress the increased production of testosterone or its pro hormones from either the ovary or the adrenal or both. This can be done directly. In the case of the ovary, oral contraceptives are a common drug that are used with great effectiveness. More potent suppressers of ovarian function, the GnRH analogs (Synarel or Lupron) may also be used.
Adrenal suppression is best carried out with the drug Prednisone. Although some physicians use Dexamethasone, I feel that this is not the best drug. It stays in your body too long and is associated with more side effects than is Prednisone. However, in some women, Prednisone is not potent enough to adequately suppress the adrenal gland and Dexamethasone has to be used.
Vaniqa is a cream that inhibits the 5 alpha reductase enzyme, thus lowering the concentration of Dihydrotestosterone in the hair follicle. Used in combination with other therapies, it helps reduce hirsutism. Unfortunately, since most insurance companies refuse to recognize hirsutism as a legitimate medical problem and consider it cosmetic, they will not pay for Vaniqa. (Funny they will pay for many acne treatments and both have the same cause in many people.)
At one time, prior to good drug therapy, ovarian wedge resection was the standard treatment for PCOS. We now understand that it worked simply by physically removing part of the ovary. The less ovarian tissue there is, the less testosterone is produced. We can accomplish the same thing less invasively by laparoscopy. An electric needle is used to burn multiple small holes in the surface of the ovary. This therapy is most effective in women who are trying to become pregnant and for whom the use of Clomid and other drugs does not result in normal ovulatory cycles.
The problem with any of these surgical procedures is the fact that their effectiveness is relatively short-lived. Since the surgery does nothing to address the underlying endocrine abnormality, within 6 to 9 months the problem has returned full force.
Another approach is to try to modify the way the ovary is functioning. In almost every instance where the ovary is the source of the increased androgen, the woman is either not ovulating or is ovulating very infrequently. If the woman has PCOS and is therefore insulin resistant, treatment with some of the insulin sensitizing drugs such as Glucophage or Actos will often allow normal ovulation to occur. Once normal ovulation begins to occur, the ovarian androgen production is significantly reduced. Problem - there is a Catch 22 in this scenario - namely, that the problem may be so well entrenched that these simpler measures do not work well.
Unfortunately, there is nothing that can be done to change the way the adrenal gland functions. It can only be suppressed.
Birth control pills have an added benefit- more than just simply suppressing the ovary and reducing androgen production. The estrogen in birth control pills increases the concentration of the testosterone binding proteins in the blood stream. The net effect of this is to reduce the free testosterone concentration. This ultimately results in less testosterone that is available to get into the tissues.
If you have had the opportunity to review your lab studies or have gotten on the internet (or both) you will frequently see a test called SHBG. It is a test that I always do and it is a test that should be done routinely.
SHBG stands for Sex Hormone Binding Globulin. You may also see it referred to as Testosterone Binding Globulin or Testosterone-Estradiol Binding Globulin. The terms all mean the same. The most common term is SHBG.
It is important to understand that hormones do not circulate in your blood stream by themselves - they are always attached to special proteins, usually of the globulin class. Albumin may also bind some hormones but not to the same degree. Each hormone has its own specific binding protein although some (as in the case of testosterone and estradiol) may share the same protein.
The concentration of these binding proteins is of critical importance if you are going to understand exactly what is going on and if you are going to interpret the tests properly. It is important to understand that the vast majority of each hormone is bound to its own protein (99% or more). Hormone that is bound to the protein is biologically inactive.
The active hormone is that small percent which is unbound or “free”. Thus, you will frequently see two tests in your results - the total testosterone and the free testosterone. Another synonym for free testosterone is “bioavailable testosterone”.
If there is a large amount of binding globulin circulating in your blood, there are more binding sites for the hormone to attach itself. Therefore, the free or unbound portion will decrease.
Conversely, if there is a lower concentration of binding protein, there are not enough binding sites for the hormone to attach to and, therefore, the percentage of the hormone that is free or unbound will increase.
Simply measuring the total testosterone is not enough. Unless you know the concentration of the binding protein, you cannot accurately interpret the testosterone concentration.
This same principle applies to other hormones as well, most commonly thyroid hormone.
Many things will influence the concentration of the binding proteins in your blood stream. In general, estrogen increases the concentration of the binding proteins and testosterone lowers the concentration. This compounds the problem. As a result, a woman may have a normal total testosterone level but if her SHBG level is low, her free testosterone level will be elevated. Failure to recognize this will often lead people to conclude that there is no hormone problem when in fact, there is.
However, in discussing androgen problems, one other hormone that must be mentioned is of critical importance and that is insulin. Studies have now clearly shown that insulin reduces the concentration of SHBG. This is highly significant for several reasons. First, if the SHBG concentration is low, the free testosterone level will be increased even though the total testosterone may be normal. Given this fact, I hope you can now appreciate that simply measuring the total testosterone without measuring the SHBG gives you an incomplete assessment of a woman’s true hormonal status and may lead you to conclude incorrectly that there may not be a hormone problem.
Of equal importance is the fact that a low SHBG level indicates an elevated serum insulin level. It now seems fairly certain that a low SHBG concentration in your blood stream is the biological equivalent of hyperinsulinemia and insulin resistance. We have known for some time that a low SHBG level is a risk factor for cardiovascular disease. We never knew why - now we do.
This is becoming even more important since it has been shown that if a woman has a low SHBG level early in pregnancy, she is at increased risk to develop Toxemia of Pregnancy. Studies have shown that Toxemia shares many features of the Metabolic Syndrome or Insulin Resistance Syndrome. Furthermore, women with PCOS and / or Gestational Diabetes (both of which are associated with and / or caused by insulin resistance) are at increased risk to develop Toxemia.
The association of low SHBG levels and Toxemia is especially significant in thin women, whom we would not usually consider to be at risk for Toxemia. Being able to predict toxemia is of great importance. It also suggests that treating the insulin resistance may prevent Toxemia. However, those studies have yet to be done.
It is a relatively simple calculation, using the total serum testosterone and the SHBG concentrations to generate a number that we call the Free Androgen Index or FAI. A normal woman does not have a FAI greater than 5. If the calculation shows that her FAI is in fact greater than 5, this indicates that she has elevated levels of circulating androgen even though the actual concentration may be “normal”. This is why I have seen a number of women over the years who were told that they did not have a hormone problem because their total testosterone level was “normal”. As I have discussed elsewhere, this, in part, may be due to the fact that the normal range given by the lab is incorrect. It may also very well be due to the fact that the SHBG concentration was never measured and, therefore, a true picture of that woman’s hormonal status was never obtained.
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 at least 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. Depending on how you define the syndrome, the incidence may be as high as 20-25%.
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 / Hyperlipidemic / 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 the result of the problem — not its 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 criterion that is necessary to make the diagnosis of classic 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.
Another subset may be those women with hirsutism or acne and “PCOS” ovaries on ultrasound who ovulate but who do not ovulate normally or consistently. This is discussed later.
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 majority of women with PCOS have 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 8 periods a year. (As I have said, in practice, there is no one universal definition of the syndrome although there is supposed to be. I have seen a number of articles published in various medical journals in which the authors have created their own criteria. Theoretically, the journal should not have accepted the article for publication but they did anyway. In part, this may be due to the fact that one of the criteria for PCOS is “menstrual dysfunction” — a term that is so nebulous that it can mean almost anything you want it to).
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. Over the past few years, it has become apparent that Avandia may be associated with a small increased risk of heart attack. Actos has been linked to the possible increased risk of bladder cancer. While there are some alternative drugs to disease, keep in mind that these are being used to treat serious medical conditions. Everything in medicine is a balance of risks. The risk of not using these drugs may be greater than the risk of taking them.
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.
As I have noted, the term “Poly-Cystic Ovary Syndrome” is over 75 years old. For many years, there was not a uniformity of opinion as to what this term meant. At least most people now agree what it is. Nonetheless, every one also agrees that it is not the best term since, as I have already mentioned, it is not an ovarian disease.
A recent consensus panel was formed by the national Institute of health whose job is to come up with a better term. At this time, there are 3 different sets of the criteria for what constitutes Poly-Cystic Ovary Syndrome. The first is from the National Institutes of Health and contained only 2 criteria-significantly irregular menstrual cycles and either clinical or laboratory evidence of increased androgen production.
The Rotterdam criteria again includes some degree of ovarian dysfunction, evidence of increased androgen production, and the appearance of the ovaries on ultrasound.
The Androgen Excess Group of the American Society of Reproductive Medicine basically goes back to two criteria -ovarian dysfunction and evidence of increased androgen production.
Implicit in all of these definitions is the understanding that other causes of excess androgen production have been ruled out. I’m sure you understand that I treat a lot of women with PCOS. I can tell you that other causes of excess androgen production are really pretty rare.
There is a general consensus (I believe) that PCOS is, basically, a disease of excess androgen production in women. However, I believe it is far more complex than that because of all the evidence that insulin resistance leading to increased insulin production is as important, if not more important, than the increased androgen. In fact, when you stop to think about it, it is the increased insulin that leads to the increased androgens.
The clinical manifestations of the excess androgen production is what leads many women to seek help but that is mainly cosmetic. It is the increased insulin production that causes the damage.
As I have discussed elsewhere in this pamphlet, it is a complex disease and not everyone has every feature of it. I have many women in my practice with some of the features of PCOS, but not all. My philosophy is that it is not necessarily what label you put on a woman but what are the actual problems that she has because that is what needs to be addressed.
Part of the problem is the fact that determining who is in fact insulin resistant is not always easy. The tests that we use in the office are rather crude and imprecise. In order to really know who is or is not insulin resistance, you need to carry out certain tests that are basically designed for research purposes. Nonetheless, the studies that have been done clearly show that women with PCOS are, almost always, insulin resistant and women with hirsutism are also insulin resistant although not to the same degree as women with full-blown PCOS.
Because the term Poly-Cystic Ovary Syndrome has been around for so many years and because it is so entrenched in our vocabulary, I am not sure where that changing the name is going to make that much of a difference. There will still be controversy as to who does or does not have this syndrome.
In the previous section of this pamphlet, I discussed the diagnosis of PCOS and pointed out that it is a clinical diagnosis based upon the woman having two out of three criteria - abnormalities of ovulation, evidence of increased androgen production and the appearance of the ovaries on ultrasound. The classic PCOS woman would either not ovulate at all or very infrequently. However, when it comes to treating a woman, especially if she is trying to become pregnant, significant abnormalities of ovulation could also be a criteria.
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 or the appearance of the ovaries on ultrasound. 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 carefully, 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.
There is a school of thought that hyperandrogenic women can be diagnosed with PCOS even if they have normal menstrual cycles. I do not agree but there is one thing to always keep in mind. At one time it was believed that the vast majority (90%+ in some studies) of women with regular cycles were ovulatory. In fact, for those women who have other features of PCOS, the actual incidence of ovulatory cycles is only about 40%. Therefore, such women need to be evaluated carefully since in fact they may be anovulatory (i.e., they do not ovulate) even though their cycles are regular. Such women would therefore be properly diagnosed as having true PCOS.
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 extremely 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. Also, women with hirsutism are insulin resistant, just not to the degree seen in women with classic PCOS. The problem is that many of these women cannot be diagnosed as being insulin resistant by the standard tests we do in the office. It often requires a research tool to diagnose it. Therefore, even though we would not have automatically diagnosed them as have a mild form of PCOS, these studies have shown that in fact they do have it. It would therefore be appropriate to label them as having a “PCOS” variant.
It reinforces what we have known for a long time — namely that women with hirsutism have a hormone problem. There is no such thing as “idiopathic hirsutism”.
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.
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. Most women with increased androgen production do not have one of the 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:
Bioavailable or free testosterone
17 hydroxy Progesterone
Sex Hormone Binding Globulin (SHBG)
You can also calculate the “Free Androgen Index” or FAI. The formula is: T(estoserone) X 3.47 / SHBG.
If the FAI is 5 or above, it is abnormal.
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. However, it is more reliable if done fasting.
If the woman happens to be fasting at the time of her office visit (or has not eaten anything for at least 8 hours) then a fasting blood sugar and insulin level is also measured. If the fasting insulin level is over 18, 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. This is especially true if the woman is overweight.
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 100 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 OF ADRENAL PROBLEMS
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 it was taken off the market 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.
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 was usually the next step to remove the hair permanently. The concomitant hormonal therapy would prevent the hair from regrowing. Using this 2-pronged approach, women could be helped to achieve a satisfactory solution for their problem.
Unfortunately, electrolysis treatments usually don’t work very well. It probably has no place in modern therapeutics. Most of the women I have seen who went through electrolysis had less than perfect results and often went through years of treatment to achieve whatever success they did.
In today’s world, LASER hair removal has replaced electrolysis. It requires far fewer treatments, it is much less painful and the results are better. It may seem as if it is more expensive but think of how much several years of electrolysis would cost.
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.
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.
EVALUATION OF WOMEN WITH ANDROGEN DISORDERS
Women who fit into one of these syndromes need to be thoroughly examined to make a specific diagnosis. Initially, full laboratory tests will be drawn to measure the various androgen in the blood. An ultrasound is also done to evaluate the ovaries and the lining of the uterus. It is important to understand that women with these syndromes, if not treated appropriately, are at increased risk to develop pre-malignant and even occasional malignancies in the lining of the uterus.
In addition, you will be brought into the office fasting to measure your insulin levels to determine whether or not there is any degree of insulin resistance.
At the same time, if the baseline tests drawn at the time of your initial visit do not yield definitive answers, a rapid one hour ACTH stimulation test will be carried out. The purpose of this test is to detect abnormalities in the adrenal gland that are not apparent on baseline testing.
The one hour ACTH stimulation test can be thought of as a “stress test” on the adrenal gland. Just as many people with heart disease feel fine if they are sitting down but develop cardiac symptoms when they are put on a treadmill, so too there are many people (both men and women) with androgen disorders that are only apparent if the adrenal gland is “pushed”.
The ACTH stimulation test is easy to carry out. Blood is drawn, you are then given an injection of ACTH and additional blood is drawn one hour later. While this is certainly an annoying thing to go through, in the overall scheme of things, it is relatively minor.
Women who have an obvious adrenal abnormality based upon either the baseline testing or following the ACTH stimulation test are treated with adrenal suppression using Prednisone or occasionally Dexamethasone.
Women who do not have an adrenal abnormality are treated with one of several medications, either oral contraceptives or occasionally one of the GnRH agonists.
Women who have evidence of insulin resistance should undergo a 2 hour glucose tolerance test with insulin levels to determine the severity of the problem and to detect a state called “Impaired Glucose Tolerance” — not yet diabetes but on its way. Early intervention may delay or prevent the onset of overt diabetes.
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 ALSO 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 100 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 officially be classified as being Diabetic. However, the evidence is that little or no damage would be occurring to your eyes, kidneys, and blood vessels. However, you would still be at significant risk for cardiovascular disease. 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.
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 METABOLIC SYNDROME OR
THE INSULIN RESISTANCE SYNDROME
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 all 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 50. A man is said to be dyslipidemic if his HDL cholesterol is less than 40.
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. Hypertension is caused by insulin resistance and the resulting elevated insulin levels.
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. However, many women with PCOS have significant metabolic abnormalities which would put give them major 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.
Men whose sister or mother has PCOS should also be evaluated.
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.
PCOS UPDATE – FALL 2003
I know this pamphlet is rather lengthy. However, PCOS and related issues constitute one the leading health problems in the United States. It is critically important that women and their families affected by this disease understand it fully. However, it is difficult to edit such a pamphlet and even more difficult to keep my website updated based upon any changes or newer information. I have discovered over the years that simply presenting new data as it appears is often easier and less confusing.
Although there have been no major breakthroughs in our understanding of PCOS, the accumulation of knowledge has allowed us to better understand exactly what is going on. From such understanding comes better therapy.
It is now apparent that all women with PCOS are insulin resistant. PCOS is in fact one of the subsets of the Insulin Resistance Syndrome (IRS). The IRS is perhaps the leading health issue not only in the United States but in all of the western world and certainly in many so-called underdeveloped countries, although many of them have more pressing issues such as AIDS.
The basic underlying cause of the IRS is insulin resistance. Although I have explained it previously, a quick review never hurts.
In order for insulin (or any other similar hormone) to act, it must attach itself to a special protein on the surface of the cell. This special protein is called the receptor. If there is some abnormality in the way the receptor functions, your body has to produce additional insulin to keep your blood sugar normal. This is what we mean by “insulin resistance”. People who are insulin resistant have higher levels of insulin in their blood stream - they are hyperinsulinemic. It is the hyperinsulinemia that creates all the problems that we associate with the IRS such as high cholesterol, high triglycerides, low HDL cholesterol (the good guy), hypertension, and either impaired glucose tolerance or actual diabetes.
Recent studies have indicated that perhaps as many as 50% of hypertensive people are in fact insulin resistant and this may be the cause of their hypertension.
Although PCOS is one manifestation of the IRS, it is unique insofar as it is an inherited genetic abnormality. There is an actual biochemical defect in the action of the insulin receptor that leads to the insulin resistance.
For the majority of people who are insulin resistant, it is an acquired disease brought on mainly by obesity. However, there are also undoubtedly inherited genetic factors at work insofar as certain racial and ethnic groups are much more likely to have the IRS. These groups include African-Americans, Hispanics, Native Americans, and Orientals.
As a result of all this, it is now apparent that many women with PCOS have a double insult. Two-thirds of women with PCOS are overweight. These women are insulin resistant because of their inherited genetic abnormality and they are also insulin resistant because of their obesity.
Dr. Andrea Dunaif - an Endocrinologist long recognized for her work with PCOS - has shown that the least insulin resistant women (i.e. the most insulin sensitive) are those without PCOS who are of normal body weight — just what you would expect.
Thin women with PCOS have about the same degree of insulin resistance as obese women who do not have PCOS.
The most insulin resistant are obese women with PCOS.
At one time, we believed that many thin women with PCOS did not always have to be insulin resistant - we now know that this is not the case.
There is now very compelling evidence that PCOS may actually begin in early childhood. There is a condition called “premature pubarche”, in which a young girl begins to grow pubic hair at a much earlier age than she ought to. Studies have now clearly shown that these girls are very frequently insulin resistant. They respond to treatment with Glucophage and, in view of all this, it is now believed that premature pubarche is in fact a manifestation of PCOS.
As I have read all the information concerning PCOS, one thing is becoming increasingly clear - most physicians have a very poor understanding of what PCOS really entails. As a result, although many women are given the diagnosis of PCOS, it is often not properly evaluated and not properly treated. As an example, based upon all the data that is now becoming available, all women with PCOS should undergo a glucose tolerance test. Anywhere from 30% to 50% of women with PCOS will show some abnormality and up to 10% may be diabetic and not even know it!
If a woman with PCOS goes to a General OB/GYN, she is most likely to simply be put on oral contraceptive therapy. Everyone is happy. The woman is happy because she is having regular menstrual periods. Oftentimes, she does not realize that this is artificial. The underlying problems have not been addressed. The physician is happy because his or her patient is not bothering them.
Unfortunately, oral contraceptives are a therapy with both positive and negative effects. The positive effect is that they do reduce excess ovarian androgen production. However, treating the insulin resistance directly will also accomplish the same thing although perhaps not to the same degree. Oral contraceptives also reduce the risk of uterine cancer which is known to be increased in women with PCOS. Oral contraceptives also reduce the risk of ovarian cancer. One of the principal risk factors for ovarian cancer is infertility. Women who have never had children are at greater risk for ovarian cancer and PCOS is one of the leading causes of infertility.
The down side to oral contraceptives is the fact that they actually increase insulin resistance. It is the insulin resistance and its resulting hyperinsulinemia that causes most, if not all, of the problems that we associate with the IRS. Although oral contraceptive therapy does have its role in the treatment of some of the problems associated with PCOS, they should probably not be used as the sole therapy.
I would like to summarize the information that I have just discussed.
The diagnosis of PCOS is a clinical diagnosis. It is based upon two criteria - ovulatory dysfunction and either clinical and/or laboratory evidence of increased androgen production characterized by either acne, hirsutism, or elevated serum androgens. It is unusual for a woman to have elevated serum androgens without clinical evidence of increased androgens unless she is of Oriental or Native American ancestry.
Ovulatory dysfunction in its most extreme form simply means that the woman does not ovulate at all or very infrequently. However, particularly for an infertile woman, an ovulatory abnormality accompanied by increased androgen production could be included under the broad umbrella of PCOS, particularly if it helps treat her problem.
A woman suspected of having PCOS should undergo a complete endocrine and metabolic evaluation including all of her hormone levels and a two hour glucose tolerance test to assess her degree of insulin resistance.
A full lipid panel should also be performed as well as any other endocrine and metabolic parameters since PCOS can affect many different bodily functions.
Always keep in mind that the various tests are designed to establish a baseline from which a woman’s response to therapy can be gauged. Except for those occasional women who did not exhibit acne or hirsutism, measuring the various hormones does not make or break the diagnosis of PCOS.
The treatment of PCOS depends upon many factors including whether or not the woman is trying to become pregnant. If the woman is trying to conceive, Glucophage is the treatment of choice. Six to eight weeks of Glucophage therapy is necessary. Following this, Clomid is almost always required. However, pre-treatment with Glucophage makes the Clomid therapy more effective.
For the woman attempting a pregnancy, other abnormalities such as elevated cholesterol, etc. must be ignored. The drugs used to treat high cholesterol are contraindicated in pregnancy.
For the woman who is not interested in becoming pregnant, treatment with a drug such as Actos is preferred. Actos also helps correct the insulin resistance but it is easier to take. Actos should only be used in women trying to become pregnant if Glucophage has failed for whatever reason.
For the woman who is not trying to become pregnant, treatment of any various lipid disorders is also necessary as well as any other endocrine or metabolic abnormalities that may be detected during the initial evaluation.
(IT IS USUALLY EASIER TO ADD UPDATES THAN IT IS TO RE-WRITE THE PAMPHLET)
At a recent consensus panel meeting, the criteria for PCOS were changed. Formerly, a diagnosis of PCOS was made if the woman was either totally anovulatory or ovulated very infrequently and had either clinical and/or laboratory evidence of excess androgen production.
The new criteria still incorporate some of these principles. However, a third criteria has been added. This new criteria is the “Poly-Cystic Ovary” appearance of the ovaries on ultrasound exam. The new diagnostic criteria for Poly-Cystic Ovary Syndrome now requires any two of the three criteria (abnormalities of ovulation, excess androgen, and the PCO appearance of the ovaries).
Many patients come to me having been told they have PCOS because their serum LH level is too high compared to the FSH level. While this is sometimes seen in PCOS, it is not always present and neither makes or breaks the diagnosis of PCOS.
The classic PCO ovary has what is called the “string of pearls” sign. The ovary is usually top normal in size or perhaps somewhat enlarged with multiple small cysts (immature follicles) arranged around the periphery of the ovary while the central portion of the ovary is free of any follicles. It is a very classic appearance when present. Not all ovaries in women with PCOS have this appearance (even with the most typical forms of the disease) but when it is present, it is very striking and easy to diagnose.
This seems reasonable since we know, as I have mentioned earlier in this pamphlet, that if you “backtrack” women whose ovaries have a PCO appearance, a significant percentage of them will be found to have many of the endocrine and metabolic abnormalities we associate with PCOS even though they may not, at first glance, have the typical syndrome.
I wish they had included any ovulatory abnormality in the list of criteria. I have many women in my practice who are hyperandrogenic, have PCO ovaries, and yet ovulate fairly regularly. However, when these women are carefully examined, they frequently do not ovulate “normally”. I believe these women also have PCOS, just a more subtle version. I will often treat them as if they have true PCOS, especially if they are trying to become pregnant or if they have the other endocrine or metabolic features of the disease.
My career in Reproductive Endocrinology started at the same time the subspecialty of Reproductive Endocrinology as we now know it also began. It was only a few years before I finished my Fellowship that we acquired the technology to measure hormone levels in blood - something that today we take for granted. The techniques of microsurgery were also developed at this time. These events (plus a few more) set the stage for what had been a relatively primitive area of medicine to become the sophisticated field we now know.
I was privileged and fortunate enough to be involved in a research project early in my career dealing with women that we would now unquestionably label as having PCOS. However, you must understand that, at that time, it was an extremely confusing area. For many years, I would not even use the term PCOS because there was no precise definition and everyone had their own criteria.
The research I did clearly showed that in women with these syndromes, the adrenal gland was playing an extremely important role (although we did not understand exactly what that role was).
The research I did clearly showed that Prednisone therapy was extremely effective in helping to treat these women. Although this is a standard therapy in today’s world, at the time, it was highly controversial.
The papers which I published were not universally accepted even though when I presented my work at the annual meeting of the American College of Obstetricians & Gynecologists, I was awarded first prize for having presented the best scientific paper at the meeting.
In the mid-late 1990’s, we had accumulated enough information to be able to step back and see what was going on. Prior to that time, the situation was comparable to the old Indian parable of the three blind men with the elephant - one had a hold of the tail, one had a hold of the trunk, and one had a hold of a leg. Each could only describe the animal by the part he was holding - none of them could step back and see the entire animal.
Once we could see PCOS for what it truly was, some universal definitions finally were put in place and everything began to make more sense.
As I indicated earlier in this pamphlet, the accepted definition of PCOS is as follows:
The woman must have either chronic anovulation (failure to ovulate) or very irregular periods. She must have either clinical or biochemical evidence of excess androgen production or she must have the typical PCOS appearance of the ovaries on ultrasound. Any two of these three criteria is sufficient to make the diagnosis.
However, over the years, I have seen many women who did not fulfill the criteria for PCOS and yet had many of the features of this disease. In many instances, I would treat these women as if they had PCOS because it enabled me to help them for whatever problem they had originally come to me. Now, however, thanks to some very elegant work done by some Italian Endocrinologists, we are beginning to see that PCOS is, first of all, a far more common disease than we had originally appreciated and, secondly, it may turn out to be far more complex.
As I discussed earlier, the classic patient with PCOS will be a woman who is significantly overweight. She will have very irregular periods or perhaps no periods at all. She will have significant facial hirsutism although, occasionally, she may have severe acne. Her ovaries will have the classic PCOS appearance. Her serum androgen levels will be significantly elevated and, even on simple office testing, she will be found to be significantly insulin resistant.
However, there are many women with significant hirsutism who have normal, regular, ovulatory menstrual cycles and whose ovaries look quite normal on ultrasound. At one time, these women were labeled as having “idiopathic hirsutism”. Idiopathic simply means that we don’t understand what’s going on.
This term gained widespread acceptance even though it had been shown many years ago that virtually all women with hirsutism are producing too much testosterone. The problem is that no one knew what was really going on.
As a result of the research done by the Italian physicians, it is now quite apparent that PCOS represents a broad spectrum of disease. The classic teaching on PCOS says that anywhere from 5% to 10% of all women have it. I have seen reports that claim that as many as 33% of women are affected. It is certainly far more common than had been formerly appreciated.
At one end of the spectrum are those women with classic PCOS in whom everyone would make the diagnosis and there would be no debate.
As I mentioned earlier in this pamphlet, it is now fairly well accepted that the underlying cause of PCOS is insulin resistance. The Italian researchers quite clearly showed in their studies there are two other conditions that are also associated with insulin resistance and which I, therefore, feel are certainly part of the PCOS spectrum. They have called these other conditions “ovulatory PCOS” and “idiopathic hyperandrogenism”.
These researchers were able to clearly show that women who appear to have PCOS but who ovulate are in fact insulin resistant although not to the degree as would be seen in a woman with classic PCOS.
The researchers also showed that women with hirsutism (who are obviously making too much androgen) are also insulin resistant although, again, not to the same degree as would be seen with classic PCOS or with ovulatory PCOS.
Because these later two groups are less insulin resistant, they may not appear to be so on regular office testing. It requires special research techniques to prove that they are in fact insulin resistant but the data is indisputable.
Hopefully, as a result of their research, the term “idiopathic hirsutism” will finally be relegated to the history books. As I have been telling my patients for many years, if a woman has facial hair, she has a hormone problem. We may not understand exactly the underlying abnormality that created that excess hair but it is unquestionably a hormonal problem.
The question that still needs an answer is why some women show the full-blown classic PCOS disease whereas other women may only show facial hirsutism or other problems in between. It has been known for a long time that approximately two-thirds of women with classic PCOS are overweight. Some newer information suggests that it in fact may be a woman’s weight that tips her over into the classic PCOS pattern. In other words, many women may be born with the genetic predisposition to PCOS. If a woman is also destined to be overweight, she will be the more classic PCOS. If a woman maintains a relatively normal body weight, she may be one of the in between stages. This is only conjecture at this point but it does seem to fit some of the known facts. However, because there is still much to be learned about the various fat hormones such as lepton and the role that they play in reproduction, it will be a while before this puzzle is completely sorted out.
This newer information represents a great advance in our understanding of PCOS and its wide spectrum of manifestations. It is only by understanding the underlying mechanisms of a disease that we can come up with effective therapies.
This section is specifically directed at the mother’s of women whom I am treating for PCOS. There is very compelling evidence that the mothers of women with PCOS whom themselves fit the criteria for PCOS if they are pre-menopausal or, if they are post-menopausal, based upon their history probably had PCOS, are at significantly increased risk for cardiovascular disease when compared to women who do not have these features.
Women who are the mothers of PCOS daughters but who do not themselves exhibit the features of PCOS seem to be at lesser risk.
Has this been definitively proven – no. However, when you look at all the data that is currently available, there is a very strong argument in its favor.
As a result, I would encourage any woman who falls into this category to be fully evaluated. If they show any of the abnormalities that we know are frequently associated with polycystic ovary syndrome such as diabetes, abnormal glucose tolerance tests, insulin resistance, or abnormal cholesterol profiles, treatment should be initiated to reduce your risk of cardiovascular disease in the future.
PCOS – THE NATURAL HISTORY
Over the years, I have seen many women in their forties and fifties, who had I seen them at a younger age, would have been diagnosed as having classic polycystic ovary syndrome(PCOS). These women give a history, when they were younger, of having had significantly irregular periods, significant facial hirsutism or acne, difficulty becoming pregnant, often requiring infertility therapy, etc. However, by the time I see them in their forties or fifties, their periods are regular, their facial hair may have diminished somewhat, and they often really don’t look like a PCOS patient.
After I had seen a number of women like this, I came to the realization that this is something that women with PCOS tend to do with time. However, I did not know the reason (and we may never know it).
Now, a study has been published that followed a large number of women with PCOS for over twenty years and kept good careful records on them. This study confirmed what I have already observed-namely that the natural history of PCOS is one of improvement, at least for some of the clinical features, with the passage of time.
What this study showed was that as women get older, their periods become regular when they had been irregular in the past. Their serum testosterone decreases. Many of the clinical features of PCOS diminish. The only thing that seems to worsen was their waistband.
Just because the clinical features of PCOS may improve with time, many of the underlying metabolic and biochemical abnormalities of PCOS do not. Even when I see a woman in her forties or fifties whose PCOS symptoms have significantly diminished, these women very often have high cholesterol, pre diabetes or even overt diabetes and other serious problems.
Very often I am asked by these women-“do I have PCOS”? The answer, based upon my clinical experience and now the results of this study clearly shows that even though your periods have become normal and your serum hormone levels have returned to normal, you still have PCOS and need to be constantly monitored because of the serious implications of this disease.
PCOS AND OVARIAN CANCER
A study was published in 2014 that examined the link between menstrual irregularity and ovarian cancer. Menstrual irregularity is one of the hallmark features of polycystic ovary syndrome.
This was a large study and more importantly, it was a prospective study. In other words, the study was begun many years ago and then the women were followed over the course of many years. This makes it a far more accurate study than if they had simply taken a group of women with ovarian cancer and ask them to recall what their periods were like 30 or 40 years previously.
The study included women with any type of irregular periods-either too many periods (polymenorrhea) or very irregular and infrequent periods-oligomenorrhea.
What this study showed was that women with a history of a irregular periods were over twice as likely to develop ovarian cancer as women with normal menstrual cycles. This is a statistic that really cannot be ignored given the way the study was done.
We have known for many years that polycystic ovary syndrome is a leading cause of infertility and we have known for many years that there is a direct link between the number of children a woman has had and her subsequent risk for ovarian cancer. The more children you have had, the less likely you are to develop ovarian cancer. Women who never had children have the highest risk.
In the report of the study which I read (I good did not see the original paper) it did not discuss whether any of the women in the study had become pregnant despite their underlying polycystic ovary syndrome or menstrual irregularity. This would be an important piece of information to know.
Furthermore, the study looked at menstrual irregularity-not polycystic ovary syndrome itself. The reason for this is the fact that the study was started in 1959 at a time when the term polycystic ovary syndrome was used very loosely. There were no official criteria for it. Therefore, even though we know that menstrual irregularity is very often associated with polycystic ovary syndrome, not every case is. Nonetheless, it does add one more risk factor for the future development of ovarian cancer and therefore women with polycystic ovary syndrome need to be aware of this.
This might influence your decision for future therapy. For example, no one is yet suggesting prophylactically removing your tubes and ovaries just because you have polycystic ovary syndrome, the same way we would do if you were carrying one of the BRCA gene mutations. However, in today’s world, if a woman needs a hysterectomy for whatever reason, we usually recommend that she keep her ovaries. However, if you are a woman with polycystic ovary syndrome and need a hysterectomy, you may wish to reconsider that option.
© Michael D. Birnbaum, M.D. 2014