Understanding and managing Polycystic Ovarian Syndrome (PCOS) 
by Sam Thatcher, M.D., Ph.D.

Polycystic ovarian syndrome (PCOS) is a complex hormonal disturbance that affects the entire body and has numerous implications for general health. For far too long, PCOS has been in the “closet,” underestimated both in prevalence and importance. Now, with a better understanding of the spectrum of the disorder and armed with new treatment options, PCOS is starting to receive the attention it deserves. Interest, research and most importantly, recognition are increasing in a number of medical disciplines including gynecology, reproductive medicine, internal medicine, endocrinology, dermatology, genetics, pediatrics, radiology, and family medicine. Still, it is quite possible that we are still at the tip of the iceberg as we look at the consequences of PCOS on long-term health and disease.

It has been said that PCOS is the most common hormonal disturbance of premenopausal women and certainly it is a leading cause of infertility. Depending on how the disorder is defined, from five to 30 percent of all women have some characteristic of PCOS.

There are three broad reasons why PCOS patients seek medical care: Menstrual cycle disturbance and infertility; problems of appearance and self esteem arising from obesity and excessive hair growth, and metabolic derangements, including abnormalities in blood fat (lipid) levels, insulin/glucose (sugar), and elevated blood pressure (hypertension).

Often gynecologists, the health care provider to whom many women turn for help, have concerned themselves with only the first of these concerns and have been relatively insensitive to the latter two. Generalists have often failed to make, or understand, the relationship of the different faces of PCOS. A more holistic approach to PCOS is certainly warranted and can have a significant effect in altering quality of life.

History & Terminology

In 1935, Drs. Stein and Leventhal reported that three problems 1) excessive male-pattern hair growth (hirsutism), 2) obesity, and 3) menstrual cycle disturbances leading to infertility were associated with larger than normal ovaries containing many small cysts.  They designated this condition “polycystic ovarian disease,” often since referred to as Stein-Leventhal syndrome.    The term “disease” indicates a specific set of symptoms, or constant physical findings. Even in this first report, not all of the patients treated had all three of the above problems. The term disease now has been abandoned in favor of syndrome to reflect a grouping of symptoms, physical and laboratory findings.  It must be realized that the term “syndrome” still might be too restrictive and that this condition is broad “spectrum” with a vast difference among patients.

Not all patients are obese. There seems to be a distinct group of thin PCOS patients that may have even more firmly entrenched hormonal and fertility problems.  Some patients with abnormal hair growth have been given the diagnosis of idiopathic (no known cause) hirsutism, but on close examination most will have subtle abnormalities of their hormones or polycystic ovaries on ultrasound scan. Some researchers make the distinction between “PCO-appearing” ovaries on ultrasound and PCOS. Not all PCOS patients are infertile or have menstrual cycle abnormalities. With pelvic ultrasound it has been found that approximately 20-30% of women of the reproductive age range will have polycystic appearing ovaries, some despite proven fertility and lack of other characteristic findings.  How all this fits together is really unknown. There may be a central, yet to be found problem that may be the root of PCOS. Alternatively, PCOS can be a symptom of a variety of problems; much like a fever is a consequence of a number of diseases. Despite the designation of PCOS, the ovaries may not be the primary source of the problem, but since the designation of PCOS is well entrenched in the literature and medical practice, no better name has emerged. It is much less important what the disorder is called than that it is appropriately recognized.

Making the Diagnosis of PCOS

In no other gynecological condition is the general medical history more important than in PCOS.  Once one is familiar with the common symptoms and physical appearance of individuals with PCOS, the diagnosis can be made in family members, coworkers and perhaps, even in the occasional passer-by. Despite this, it is surprising how often health care providers miss the diagnosis.  A concern remains in making the diagnosis of PCOS. While much less common, even rare, several serious diseases can masquerade with the same general symptoms as PCOS. Luckily the more serious disorders are often easily separated, once the physician is aware of their possibility. A key point in the history, and one that is especially important in the exclusion of more serious problems, is the rapidity of symptom progression. The more dangerous problems are usually of more rapid onset and do not tend to occur in other family members. Some of the less common diseases that have findings similar to PCOS include hyper- and hypothyroidism, Cushing’s syndrome, pituitary gland adrenal and ovarian tumors.  Virilization is a condition where male sexual characteristics emerge.  It is very rare, but not impossible for the individual with PCOS to be virilized. Virilization always warrants immediate attention and thorough evaluation. Characteristics of virilization include deepening of voice, balding, increased muscle bulk, increased size of the clitoris, or marked hirsutism.

There are 3 different ways to make the diagnosis of PCOS: 1) by symptoms and physical findings, 2) hormonal testing, and 3) ultrasound. Probably most individuals will have abnormalities in all three, some only in two, and possibly only in one. Some may argue that findings in only a single category may not constitute PCOS. But, until we have PCOS better characterized, or find a different diagnosis for these patients, the diagnosis of PCOS should remain. The most minor of apparent problems may have significant implications for future general health and well-being. 

• • Clinical findings
    

    The classic findings of menstrual cycle abnormalities; increased sexual hair growth and obesity that characterize PCOS will be presented in turn

    Menstrual disturbance

    Obviously, a detailed menstrual history including menarche (onset of periods), pattern of menses (periods) in the past and changes in the number of days of flow, amount of flow and number of days between menses should be recorded. Often in PCOS patients, the menarche occurs at the usual age of 12-13 years.  Some PCOS patients may start menstruating earlier. Not uncommonly, PCOS patients may first be seen by a physician for lack of menses. Any female who has not had menses by age 16 should be evaluated. The menstrual cycle may at first be regular, but by high school, cycles start to lengthen and may be skipped. Often during this time, oral contraceptives are started. The “‘pill” usually regulates the menstrual cycle and may give the false impression that all is well. Usually in the teenage years, the other symptoms of skin and weight problems also start to be seen. Some PCOS patients easily establish a pregnancy in these early years. Occasionally, birth control pills may even increase the chance of pregnancy by suppressing abnormal hormonal production. Often a gynecologist sees the PCOS patient when she is in her 20’s after stopping the pill, and her periods. Some PCOS patients have quite regular 28 days cycles, but the diagnosis should be suspected in individuals with cycle length over 35 days. Some patients have no bleeding unless some form of medication, usually a progestin, is given. In some there is excessive bleeding, or long periods of spotting. It is thought that the age of menopause in individuals with PCOS is about the same, age 50, as other women.

    While virtually never mentioned in medical publications, or recognized by physicians, it seems that chronic pelvic pain and premenstrual (PMS) symptoms are quite common. Given the chronically abnormal hormonal patterns, the capacity of hormones to alter body fluid and even the enlarged cystic ovaries, these findings should not be surprising.

     

    Hair and skin problems

    The skin manifestations associated with PCOS are possibly more common than either menstrual cycle irregularity, or obesity. Disorders of the skin in PCOS patients are related to an increase in level of male hormones (hyperandrogenism). This may be due to an absolute increase in androgen level, or an alteration in ratio of hormone levels.  A third possibility is an exaggerated response of the skin to relative normal androgen levels. The end result of all three of these possibilities is the same and includes: acne, seborrhea, balding, hidradenitis suppurtiva (inflammation of the specialized sweat glands in the arm pit and groin), acanthosis nigricans (see below) and hirsutism.

    Hirsutism is defined as an increase in amount and/or coarseness of hair distributed in the male pattern in a female. This is opposed to hypertrichosis, which is excessive growth of non-sexual hair. The issue of facial hair is usually self-evident, but a good screening test is the amount of hair between the umbilicus and pubic hair line. Other areas of male pattern hair growth include ‘sideburns,’ lower neck, lower back and inner thighs. A faint moustache is quite common and may be more related to family trait and ethnic group than hormonal imbalance. The same can be said for occasional ‘stray’ hair around the breasts.   Outside hirsutism, other manifestations of hyperandrogenism are often dismissed, or not recorded in the gynecologist’s evaluation.

    Acne and seborrhea occur quickly as androgens rise.  Androgens increase sebum, which is a combination of skin oils and old skin tissue. Increased sebum causes plugging of skin pores.  Bacteria that thrive on sebum are increased, resulting in inflammation. The inflamed skin pore is called a comedon. Closed comedones are “whiteheads,” while ‘‘blackheads” are open comedones. The black color comes not from dirt, but from the breakdown of keratin, a natural skin product. Increased male hormone levels also cause seborrhea. A particularly common skin condition and one not usually associated with hormonal alterations is dandruff.  Contrary to what is generally believed, dandruff is caused by oily, not dry skin and is a variety of seborrheic dermatitis.

    Many women complain of skin problems that wax and wane with during the menstrual cycle. In regularly cycling women, the second half of the menstrual cycle is characterized by increased progesterone levels. Progesterone is a weak androgen and may create a situation of relative hyperandrogenism.  Around the time of menstruation estradiol is decreased.  Low levels of estrogen (hypoestrogenism) also create a situation of relative increase in androgens with resultant increased oiliness and inflammation of the skin. 

    One of the most distressing of hyperandrogenic skin disorders is alopecia (balding). The most androgen sensitive area of the scalp is the vertex, the highest point of the head.  Frontal balding and anterior hairline recession is seen only in the more severe cases of androgen excess.  As can be an imagined, the mechanism for hair growth (and loss) has been extensively studied, but no unified theory has emerged.

    A search for acanthosis nigricans (AN) should be a part of every physical exam of the PCOS patient.  AN is usually described as a velvety, raised, pigmented skin changes, most often seen on the back of the neck, axillae and beneath the breasts. AN is often seen in association with skin tags (acrochordons). Possibly the best description is that it looks like the affected area is ‘dirty’ and would benefit from scrubbing.  Obviously this is not the case.   There is an association of this finding with simple obesity as well as other endocrine disorders.  AN should always alert the clinician to a risk of diabetes, major lipid abnormalities, and hypertension. Although less common, it may be a warning signal of cancer.

    Elevated androgen levels may be only a part of the problem. For androgens to have an effect on the skin they must bind together with an androgen receptor in the skin. There may little, or no, physical evidence of hyperandrogenism despite very high androgen levels, if the androgen receptor is lacking or present in relatively low numbers. The number of androgen receptors varies among different ethnic groups and individuals. Northern European women with PCOS are more likely to be hairier than Asian women. A third requirement for androgen action in the skin, besides androgens and receptors, is a specific enzyme called 5a-reductase. Testosterone must be converted to dihydrotestosterone (DHT) by this enzyme to exert its effect. Only sexual hair follicles contain the necessary enzymatic machinery for conversion of circulating androgens to DHT.  A fair skinned individual may have little excess hair growth despite high levels of testosterone, due to absence of the specific androgen receptor, or enzyme converting capacity, in the hair follicles.  Another individual may be quite hirsute with no apparent abnormality in circulating hormones. 
    
    

    Laboratory Testing

    Virtually all patients with PCOS will have at least subtle laboratory abnormalities. The reported results may be only on the upper limits of the ‘normal range,’ showing only a tendency, not a discrete abnormality. Often a pattern will emerge after considering a group of tests together. These subtleties may reveal dysfunction in the control mechanisms of the hypothalamus, pituitary, ovary and adrenal (HPOA axis) working collectively. In distinction, serious pathology may be more evident by a marked elevation, or suppression of a single test. Though the value of repeated blood testing for the same hormones could be questioned, it is recommended that each PCOS patient have an initial, relatively comprehensive evaluation and interpretation by an individual familiar with this testing. In the following list, normal levels will not be given because of the marked variations between laboratories and techniques. Any level that is twice the upper or lower limit of normal is particularly important and may indicate a serious problem. The marginally elevated test is almost always dysfunctional, rather than pathologic. As a rule, endocrine testing, other than a pregnancy test, is probably best performed in the morning, soon after a spontaneous or induced menses. The days around ovulation or mid-cycle should be avoided.  Hormonal evaluation in patients on oral contraceptive will often give misleading results with suppression of gonadotropin, ovarian steroid and SHBG levels. It is of limited value to determine these hormone levels in patients on the pill. Glucose and lipid evaluation should be in the morning after fasting (no food or drink after midnight the night before).

    There have been a large number of tests and procedures used in the past for evaluation of PCOS. Listed below are a number that may be seen and should provide sufficient data for a very comprehensive investigation. All may not be useful in all patients.

     

    Hormone assays:

    While androstenedione may be the steroid most often elevated in PCOS evaluation, its lack of specificity in determining the source of hyperandrogenism, or modifying its treatment, probably make measurement of this hormone unnecessary.  Androstenedione is almost totally and equally produced from the adrenal gland and ovary. 

    Dehydroepiandrosterone (DHEA, DHA) and Dehydroepiandrosterone sulfate (DHEAS) are relatively weak androgens and are almost exclusively of adrenal origin. Although produced in relatively large amounts, they have little potency. They can be converted in the ovary and peripheral sites to more potent androgens. Adrenal tumors often produce very large amounts of DHEAS and are seldom associated with only modest elevations. A DHEAS measurement can be used to determine whether there is an adrenal component to PCOS and whether the patient may benefit from a trial of low dose corticosteriods.  Women with 21-hydroxylase deficiency (described below) may not have an elevated DHEAS.

    Follicle Stimulating Hormone (FSH) Luteinizing Hormone (LH) FSH and LH are gonadotropins, hormones made in and released from the pituitary gland that control the function of the gonads, the testes and ovaries, The absolute level of each, as well as the LH:FSH ratio, can offer significant insight into the PCOS patient. Clearly increased LH is related to, if not diagnostic of, PCOS. Traditionally, the diagnosis of PCOS has been made when the LH:FSH ratio is over three. A relatively recent change in the type of assay used to measure LH has resulted in lower reported LH levels.  Still, finding a higher LH than FSH in the early part of the menstrual cycle is a hallmark of PCOS.  The alteration in the LH: FSH ratio is more likely to be evident before, rather than after, a progestin challenge.  Some PCOS patients, especially those who are markedly obese, may have gonadotropin levels that are suppressed rather than elevated. Some experts suggest that measurement of LH and FSH is of limited value. It would seem that confirmation of an elevation in LH is very diagnostic of PCOS. The measurement of FSH will also permit the diagnosis of an occult ovarian failure where the FSH levels are particularly elevated. This is a diagnosis, which is important not to miss in therapy planning.

    17-Hydroxyprogesterone (17-OHP4)  is a hormone produced by the corpus luteum formed from the follicle after ovulation and by the adrenal gland. A clinical picture virtually identical to PCOS can be caused by an isolated, inherited disorder of the adrenal glands where an enzyme responsible for interconversion of steroids is missing. This results in a build-up of androgens and thus, PCOS findings.  A measurement drawn at 8-9 AM in a fasting state in the follicular phase will identify most cases of 21-hydroxylase deficiency.  Levels should be over twice the normal range. While not as sensitive as dynamic testing using synthetic ACTH, it is much easier.

    Insulin is discussed elsewhere. Insulin levels should be obtained fasting and possibly after a glucose challenge (see GTT below).  Insulin resistance may be present in advance of or without, elevated glucose level. There is controversy about what levels constitute hyperinsulinemia and what the diagnosis of insulin resistance. Most with fasting insulin levels above 20 are hyperinsulinemic and may be candidates for insulin altering drugs depending on the clinical situation. 

    Prolactin  is a hormone produced by the pituitary gland level that assists in milk production for lactation. The hormone is, by necessity, elevated in pregnancy and during breastfeeding.  Prolactin suppresses ovulation and is one of the reasons why breastfeeding women are relatively infertile.  Prolactin levels maybe elevated outside these times (hyperprolactinemia) and associated with breast secretion (galactorrhea). Hyperprolactinemia, regardless of PCOS, is a relatively frequent cause of infertility and usually can be easily and successfully treated. Hyperprolactinemia has been associated with increased production of DHEAS, which is reversed after treatment with bromocriptine (Parlodel). While a direct effect is possible, another mechanism may be indirect from conversion of DHEA into estrone in the periphery. Estrogens are known to elevate prolactin levels through a mechanism in the central nervous system. Despite this fact, it is still not clear that the findings of PCOS and hyperprolactinemia, both relatively common disorders, are not coincidental.  Potential functional causes of mildly elevated prolactin levels are drug use, anesthesia, stress, blood drawing, recent breast stimulation, breast examination and blood sampling around the time of ovulation. Hyperprolactinemia can be a sign of a prolactin producing pituitary gland tumor (prolactinoma). These are benign and usually easily treated with oral medications. Less often, hyperprolactinemia may be an indication of other structural abnormalities of the brain. Hyperprolactinemia is often found in patients with hypothyroidism and a TSH level should be obtained.  Patients with over marginally elevated prolactin levels on repeat examination should be referred for magnetic resonance imaging, MRI.

    Testosterone  is the principal male hormone. Over 75% of circulating testosterone is derived from conversion of other steroids by the liver and skin.  The remainder comes equally from the adrenal gland and ovary.  Either the free or total testosterone level can be determined. The decision on which to obtain should be based on availability and cost of the test and personal preference of the physician.  Total testosterone is more likely to be related to overall metabolic status and is less specific than free testosterone.  Marked elevation of either free or total hormone is equally worrisome and warrants complete investigation.

    Thyroid Stimulating Hormone (TSH) is the single most important measurement of thyroid function. Except in the relatively uncommon disorder of central suppression, where both TSH and free thyroxine are suppressed, TSH is diagnostic of both hyper- and hypothyroidism. A free thyroxine level may be added to a repeat TSH measurement when the initial TSH measurement is low. There is no clinical utility in the “thyroid panel,” or total thyroxine measurement, and these tests should be abandoned. TSH is the method of choice to monitor thyroid replacement therapy. It should be noted that a 4-6 week period is necessary for equilibrium to be reached.  Patients on replacement should be titrated to the mid-normal TSH range.  Overly supplemented patients are at risk for osteoporosis and heart disease.

     

    Other useful laboratory determinations

    Comprehensive biochemical profile The designation for a group “panel” of blood tests that evaluate the body’s overall metabolism, salt and fluid balance. Various electrolytes (salts), fats, glucose and liver enzymes are measured.  Overall these tests are used to evaluate the function of the liver and kidney. Some therapies use to control PCOS potentially have adverse effects and their use needs to be monitored periodically. This relative inexpensive test obtained form a single blood sample. It is best to be obtained after fasting.

    Glucose and Glucose Tolerance Testing (GTT) A GTT may be considered on PCOS patients, especially those over 120% of ideal weight, have first degree relatives with diabetes, have elevated serum lipid levels, or those having delivered over a 9 pound infant. The American Diabetic Association (ADA) has designated individuals with fasting glucose levels over 126 mg/dl, as diabetic. A new category is used to describe individuals with fasting levels 110-126 mg/dl, as having impaired glucose tolerance. The term “Type 2 diabetes” is used to describe insulin resistance that has resulted in elevated glucose levels and has replaced the older terminology of “late, or adult onset”. No distinction is made for insulin dependency. The ADA recommends a 2 hr. screening after a 75 gram glucose load, as definitive testing, but a one hour 50 g. test is often used in most obstetric practices and will probably yield similar results. 

    Hemoglobin A1c This blood test is a unique marker of how well diabetes is controlled. There is usually no reason to measure this in a PCOS patient unless diabetes or glucose intolerance is confirmed.

    Lipid panel  This is a useful test for the general evaluation of health risks in all patients, but is of special importance in PCOS. These individuals have a distinct tendency toward abnormalities. When abnormalities are found, treatment can be prescribed which may alter significantly the risk of heart attach and stroke. The panel includes tests that measure the concentration of cholesterol, triglyceride and relative concentration in lipoproteins (the good and bad cholesterols).

    Sex Hormone Binding Globulin  (SHBG) This is a useful but not commonly used marker of PCOS. Low levels are a relatively good indicator insulin resistance. Age, weight, diet, steroid and thyroid hormone levels, all affect the concentration of SHBG. Hypothyroidism is associated with a decrease in SHBG. There is an inverse correlation between body mass and SHBG in women, but not men. Women with high waist-hip ratios have lower SHBG, possibly relating to correlation with hyperinsulinemia. While there is a clear direct dose related effect of estrogen administration, it is much less clear what effect concomitant use of progestational agents has on SHBG levels. 

     

    Ultrasound

    Sonography of the pelvis is warranted in virtually every potential PCOS patient. Evaluation should be performed by individuals experienced in judging ovarian and endometrial function.  The finding of greater than ten (some say 8) cystic structures less than 10 mm in either ovary meets the generally established ultrasound criteria of PCOS. Often cysts of PCOS are located in a peripheral subcortical ring leading to the reference of a “string of pearls.”  The PCOS ovaries are typically 1.5 to 3 times normal size. In some cases the ovary is virtually filled with small cysts.  In other cases, it is heterogeneously dense with hardly detectable microcystic changes. It must be remembered that any hyperandrogenic state may be manifested by the PCO-appearing ovary. Diffusely enlarged ovaries without discrete mass on ultrasound are often associated with insulin resistance

     

     

    CAUSES of PCOS

    In short, the cause of PCOS is unknown. However, the story is starting to unravel and several important lines of evidence have emerged that offer clues about a central mechanism. The central question remains whether PCOS is a single entity. Is there only one, or are there many causes of PCOS? PCOS is a “final common pathway” of a variety of disorders and the diagnosis PCOS itself remains one of exclusion. Still, an important principle of medicine is that we always first attempt to link all physical complaints and clinical findings into a single disorder.  Although thus far, we have not been able to do this with PCOS, it does not mean that we can not do so in the future, 

    Let’s first look at several characteristics those individuals with PCOS universally tend to share–what binds not separates. We know that PCOS is inherited (see further explanation below).  For the present, it also means that a cure is unlikely, so we must stick with trying to control, or correct, the abnormalities of PCOS. Elevated levels of male hormones (hyperandrogenism) also characterize PCOS. Hormones are natural chemicals that are released by the body into the bloodstream and in very small quantities and have dramatic effects on distant sites throughout the body. As such, and the case of PCOS, the entire body is affected by relatively small hormonal abnormalities. There is also the important observation that surgical removal of a portion of the ovary, wedge resection, restores menses and fertility in many PCOS patients. For this reason, it has been suggested that the ovary is the origin of the abnormality.

    All estrogens, the female sex hormone, are made from androgens.  It is only when androgens are present in abnormally large quantities, or the balance of estrogens to androgens is disrupted, do the unwanted effects of hyperandrogenism appear. A large percentage of the androgens circulating in the bloodstream are produced in fat cells. A larger number of fat cells create a greater potential for androgen production. The remainder of androgen production normally is divided about equally between the adrenal gland and ovary. There may be adrenal and ovarian forms of PCOS depending from where the greater portion of androgens arise.  In the ovary, androgens are produced in the smaller size follicles that characterize PCOS. That the ovary is filled with increased numbers of smaller follicles, 4-10 mm, has led some to postulate that some factor blocking follicle development is the key to PCOS.  The cells surrounding these follicles (theca cells) are sensitive to the higher amounts of LH, also a characteristic of PCOS. LH stimulates androgen production.  The smaller follicle has not developed the enzymatic machinery capable of converting these androgens to estrogens.  Whether this is a specific block in the ovary, or a consequence of other factors outside the ovary is not known.  A genetically acquired abnormality in steroid steroidogenesis, insulin resistance (see below) and/or hypothalamic-pituitary- ovarian axis abnormality probably act in concert as in the etiology of PCOS. The degree of participation of each of these etiologies varies between patients. Regardless, the ovaries are arrested in a relatively static situation, a grid-lock, log-jam that prevents the eventful maturation of the follicles. 

     

    PCOS and insulin resistance

    Insulin resistance (IR) is a condition whereby the body steadily becomes less responsive to the actions of insulin.  A primary action of insulin is to regulate, lower.  sugar, glucose, level in the blood. In IR, blood sugar levels rise despite high levels of insulin and eventually type 2 diabetes results. This is in contrast to type 1 diabetes where the pancreas does not make sufficient insulin. Although the relationship of diabetes to other endocrine disorders is not new, only recently has the high preponderance of patients with PCOS with IR been recognized. It appears that hyperinsulinemia causes hyperandrogenism, rather than the reverse. The obese PCOS patient is more likely to have both IR and hyperinsulinemia, while the thinner individual does not show IR as often. In terms of general metabolism, insulin facilitates storage of calories and increases fat stores.  In addition, hyperinsulinism and IR have been suggested as a root of many unrelated disorders, such as chronic fatigue syndrome, defects in the immune system, eating disorders, hypoglycemia, gastrointestinal disorders, depression and anxiety. Presently, there is considerable investigation on Syndrome X (Metabolic Syndrome) which is characterized by insulin resistance and hypertension.  Insulin resistance and hyperinsulinemia are considered to be significant risk factors in the development of atherosclerosis, hardening of the arteries.  This predisposes PCOS individuals to increased risk of high blood pressure and stroke.

     Hyperinsulinemia results in an increase both LH release and androgen production with subsequent alterations in follicle growth.  Hyperinsulinemia is associated with androgen excess and a depressed level of sex steroid binding globulin (SHBG) IR has been associated with development of type 2 diabetes.  In contrast to type 1 diabetes (previously called juvenile diabetes) where there is a pancreatic abnormality and low insulin production, with type 2 diabetes there is a strong family tendency to develop the disorder that is reminiscent of PCOS.    

     

    It’s in the genes

    It is a near universal finding that PCOS is genetic, but the heritage is complex. This genetic predisposition is not as simple as brown eyes or blue, but has a complex heritage. The tendency to develop PCOS may be of be inherited from either the mother’s side, maternal origin, from the fathers side, paternal origin, or from both sides. A paternal origin is equally likely, but often is overlooked. Also, various characteristic traits of PCOS may be passed down with varying degrees of severity. It is quite possible that PCOS is inherited as a small group of genes in which some are involved in glucose regulation and others in ovarian hormone production. Both groups may be necessary for an individual to develop PCOS.  In addition, there may be the interaction of diet and other environmental factors that may worsen or improve the problems associated with PCOS.  A particularly important point in the PCOS patient’s history is whether family members have had similar problems. While PCOS is inherited, the more serious diseases that may masquerade as PCOS, such as tumors of the pituitary, adrenal, and ovary, are not.  It is often distressing when a woman with PCOS learns that she may pass on the condition to her daughters, or through her son, to her granddaughters. Hopefully, with our new tools made available by molecular biology there may be significant advances in the genetics of PCOS during the next several years and in the future, PCOS may become a problem of the past.

     

    PREGNANCY and PCOS

    There is evidence that PCOS patients had a larger birthweight and were products of pregnancies in which their mother had gestational diabetes. It is clear that the risk of gestational diabetes and probably, pregnancy induced hypertension (PIH, toxemia, preeclampsia) is increased in pregnant women with PCOS. Some of this risk may be independently related to increased pre-pregnancy weight. There is no evidence that babies born of PCOS mothers, or the mothers themselves have any long term complications. Often pregnancies are achieved in the early reproductive years without medical assistance. Pregnancy has a positive health benefit on breast and reproductive cancer. Spontaneous pregnancy sometimes follows a pregnancy that was achieved after a prolonged wait, or aggressive fertility therapy.

     

    THERAPY for PCOS

    Weight Loss

    While dieting is certainly valuable, it is the most difficult of therapeutic regimens to administer.  With weight loss there is often an improvement in endocrine parameters and sometimes return of menses. Plans that focus on behavioral modification and group involvement, for example “Weight Watchers” have been the most effective. Weight loss may improve general health and menstrual regularity, but may have little effect on hirsutism. Diet plans approved by the American Diabetes Association (ADA) all excellent for PCOS. They are well balanced and a number of plans are available. Books containing these diets are available in most book stores. All women contemplating a pregnancy should use folic acid supplements. Regular exercise is encouraged. Fad diets are discouraged. The emphasis must be on life- long changes if the tendency toward development of type 2 diabetes and abnormal blood lipid levels is to be avoided.

     

    Progestins

    A progestin is a medication that mimics the action of progesterone. Progesterone is an ovarian hormone produced by the corpus luteum, the structure that forms from the ovarian follicle after ovulation and prepares the uterus for implantation. Unless a pregnancy intervenes the corpus luteum has a finite lifespan of 10-14 days. As it fails, progesterone levels fall. Menses, which is the bleeding accompanying the loss of the uterine lining, is the consequence of the withdrawal of progesterone support. As such, it is not the progestin, but its withdrawal, which results in menstruation. In the absence of ovulation, minimal progesterone is produced form the ovary and the interval between menses is lengthened (oligomenorrhea).  While progestins may be used to regulate the menstrual cycle and blood levels of LH may be reduced by progestins, they appear to be of little use in reduction of hair growth, or possibly metabolic derangements.

    The most commonly used agent is medroxyprogesterone acetate (MPA) (Cycrin, Amen, and Provera).  A regimen of 5 to 10 mg for 10-14 days monthly is used for normalization of cyclic bleeding.  Some prefer therapy every three months. It is unclear whether this is effective in reducing the risk of hyperplasia. Alternatively, norethindrone acetate  (Aygestin) can be used at 5 mg. daily in a similar regimen. Some patents report better tolerance of norethindrone. In 1998, a standardized oral progesterone preparation (Prometrium) was introduced. While progesterone therapy is not new, it has required a compounding chemist, has been relatively difficult to obtain and expensive. While less potent, a natural preparation may have theoretical benefits over the synthetic progestins. Prometrium may be given in the same fashion as the progestins with 100 mg equal to approximately 2.5 mg. of MPA.

    For a progestin to work, the uterus must first be “primed” with estrogen. In some PCOS patients the estrogen levels are not sufficient for the progestin to have an effect. If a progestin alone does not induce bleeding, a regimen first using estrogen then progestin may be tried.

    Because of the nature of PCOS, there are the early stages of follicle development, but ovulation does not occur.  The small follicles (cysts) of PCOS, while not producing near the amount of a pre-ovulatory follicle, do usually produce enough estrogen to stimulate the proliferation of the uterine lining. In absence of ovulation, the uterus is subject to unopposed estrogen stimulation.  Left unchecked, this can lead to an overgrowth of the lining of the uterus (endometrial hyperplasia) and if unchecked, even uterine cancer.  While uterine cancer is rare under age 40, most cases will occur in associations with PCOS.  Progestins do little for the overall body health, but are used to cause regular withdrawal

Editor’s Note: Sam Thatcher, M.D., Ph.D., former director of the Center for Applied Reproductive Science in Johnson City, Tennessee, was the author of PCOS: The Hidden Epidemic (Perspectives Press). In addition to serving on INCIID’s Advisory Board, Dr. Thatcher moderated INCIID’s PCOS Forum and contributed a regular column, Thatcher’s Thoughts. His book remains essential reading for anyone seeking to better understand PCOS.

Dr. Thatcher passed away on Friday, December 18, 2009, following a battle with leukemia and related complications. He was a valued friend to INCIID, an exceptional clinician, and a globally respected authority on PCOS. His contributions continue to shape patient education and care, and he is deeply missed.