Polycystic Ovarian Syndrome (PCOS) Treatment | The Brandeis Fertility Center | New York Fertility

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POLYCYSTIC OVARIAN SYNDROME PCOS

The PCOS Center of New York
A division of the Brandeis Center for Reproductive Health

Is the America’s premiere website resource for patients seeking advice on PCOS and related androgen disorders.

The PCOS Center is the first center in New York devoted exclusively to the diagnosis and treatment of PCOS.

Dr. Vincent Brandeis, our faculty of renowned physicians offer patients immediate access to a multi-disciplinary team approach – recognizing that PCOS is a condition that affects the entire body and must be evaluated and treated with a holistic approach;

• we are the first center in the US to incorporate acupuncture and herbal    medicine as an integral part of diagnosis and treatment
• we are the first center in the US and possibly the world to offer patients    with    immediate phone contact 24 hrs a day 7 days a week to a physician    to answer    questions on matters relating to PCOS
• Our website includes a chat room, monthly email newsletter, monthly    discussion    groups on matters on PCOS diagnosis, new drug therapies and    nutritional    concerns
• We are the only center in the country which holds monthly clinical    meetings    where the charts of patients with PCOS are reviewed by a panel    of physicians    to allow for an integrated approach rather than the isolated    view of one    physician
• We have ongoing research efforts exploring the relationship of PCOS to    molecular genetics as well as diet strategies and various medication    protocols    for treatment.

TEAM OF PCOS EXPERTS

Out team of experts include specialists in the following areas of expertise:

• Reproductive endocrinology
• Dr. Vincent Brandeis board certified in the reproductive endocrinology is a medical    director and founder of PCOS New York
• Dr. Brandeis has over 20 yrs experience in his specialty and has written    numerous articles in his field
• Dr. Brandeis was a member of the first team to perform in vitro fertilization in    New York City and was also a member of the first team to perform in vitro in the    state of New Jersey – one of the first centers in the East Coast

Dr. Brandeis has achieved thousands of pregnancies and nationally-known and respected authority

Through his lectures and teaching appointments as the director of reproductive endocrinology at 2 major teaching hospitals as well as a consultant at 5 other hospitals in the NY area, Dr. Brandeis has devoted ongoing effort and devotion to educating physicians, residents, interns, and medical students as well as the general public on issues related to PCOS.

• Endocrinology
• General Medicine
• General Obstetrics and Gynecology
• Nutrition
• Diabetes
• Acupuncture
• Physical Therapy
• Complementary Medicine
• Pediatrics
• Genetics
• Reproductive Immunology

PCOS OVERVIEW

The term polycystic ovarian syndrome (PCOS) derives from the characteristic appearance of the ovaries in patients with PCOS – the ovaries are enlarged and contain numerous cysts (polycystic). Actually, each cyst is a really a follicle – a fluid–filled sac that contains immature egg cell that during the course of the monthly cycle, continues to grown in size and eventually ovulate or release the egg at the mid-cycle. In PCOS - there is a disturbance in the ability of the ovary to make these follicle sacs grow and ovulate.

PCOS is the most common hormonal disorder in women of reproductive age and is a major cause of infertility. Depending upon the criteria used to define PCOS, at least 5-10% of reproductive age women in the United States have PCOS and as many as 30% may have one or more characteristics of PCOS.

Patients with PCOS seek medical advice for one of the following:

1. The first sign of PCOS can be irregular and heavy periods that begin in     adolescence with the onset of menstrual cycles.
2. In some cases, there are no symptoms at all and PCOS is discovered in the     course of an infertility evaluation, through blood testing or ultrasound studies.
3. Counseling and evaluation for treatment of obesity and/or excess hair growth
    Counseling and evaluation for the treatment of abnormal cholesterol,     insulin/glucose levels and hypertension

Some patients will have the classic findings of irregular periods, excess weight and excess facial hair – but PCOS can affect different women in a variety of ways.

The early diagnosis and treatment of PCOS will reduce the risk of long-term complications – which include heart disease and diabetes.

PCOS affects the entire body and as such must be considered in the broader context of a woman’s overall general health. For many years, PCOS was underestimated in its relevance to overall health as well as the frequency with which it is actually found. Over the past several years, the medical community has achieved a better understanding of the true spectrum with which this disorder can present and its considerable frequency.

Ongoing research about PCOS has been advanced by many medical disciplines including gynecology and its sub-specialty of reproductive endocrinology, internal medicine, general endocrinology, experts in diabetes, genetics, radiology, pediatrics and perhaps most importantly, family medicine. As someone who has studied this syndrome for over two decades, I strongly feel that we have just barely scratched the surface as to the health implications long-term of PCOS.

In conclusion, it is my opinion that the most significant milestone in women’s health in the last decade is the awareness of the relationship between PCOS and general health which has allowed for the remarkable interdisciplinary approach to both diagnosis and treatment. Again, it is my further opinion that the next major milestone will be to achieve a holistic approach to PCOS with integration of both Eastern and Western medicine that allow women to have a full range of options in terms of treatment, prevention and hopefully one day a cure.

HISTORY AND TERMINOLOGY OF PCOS

In 1935, two esteemed physicians from John Hopkins Medical School in Baltimore – Dr. Stein and Dr. Leventhal - reported that there was an association between irregular menstrual cycles and the surgical finding of enlarged ovaries. By examining these ovaries histologically, microscopic analysis showed that the ovaries were enlarged because they contained many small cysts just beneath the outer capsule of the ovary. Because of this cystic appearance, these pioneer clinicians called this new syndrome Polycystic Ovarian Disease. For many years, what we call PCOS today was actually referred to as the Stein-Leventhal syndrome. Based upon their understanding, PCOS was considered a “disease” with a limited list of symptoms and characteristic findings on surgery. In their initial report of 7 women – all of their patients had long menstrual cycles and most had excess facial hair and obesity. As time went on, with better understanding of this condition, the word “syndrome” replaced the nomenclature of disease. In other words, clinicians recognized that there was actually a wide spectrum of symptoms, physical findings and laboratory results. In fact, there is a movement now to consider PCOS as a “spectrum” rather than a syndrome considering the wide variation of presentation in patients with PCOS.

THE HISTORICAL TRIAD OF PCOS

In the early literature, based on the early findings of Dr. Stein and Dr. Leventhal -PCOS was thought to be a triad consisting of;

1) irregular menstrual cycles,
2) facial hair and/or acne and
3) excess body weight.

We now realize that this classic triad does not always exist.

VARIABLE PRESENTATIONS OF PCOS

1. Many PCOS patients are actually thin and interestingly, these thin patients may     have more significant fertility and hormonal issues than patients who are     overweight with PCOS.
2. Additionally, patients with PCOS can sometimes present with just excess facial     hair and subtle slightly abnormal laboratory findings. This group of patients, for     many years, were classified by dermatologists to have hirsutism of unknown     ideology (idiopathic). Actually these subtle but nonetheless elevated hormonal     abnormalities are due PCOS in many cases, when studies with careful ultrasound     technique.
3. Some PCOS patients are fertile and have normal menstrual cycles. However on     ultrasound evaluation, these patients have the classic findings of many small     cysts in the ovary – thus suggesting that they are polycystic.
4. In fact, 20-30% of reproductive age women have polycystic-appearing ovaries     despite being fertile and having no excess facial hair or any other evidence to     qualify for the diagnosis of PCOS.

Therefore, the findings of polycystic ovaries, described by Stein and Leventhal, simply do not necessarily mean that PCOS is present. I strongly urge my readers to be aware that the more correct and current term polycystic-appearing ovaries (POA) should be adhered to differentiate these non-PCOS patients from patients with PCOS.

Finally, despite the fact that the ovaries are significantly involved in PCOS as will be explained later, the ovaries themselves may not always be the primary cause of PCOS.

MAKING THE DIAGNOSIS OF PCOS

There are three methods by which the diagnosis of PCOS is achieved:

1) clinically – through history, symptoms and physical exam
2) hormonal lab testing
3) ultrasound evaluation

MAKING THE DIAGNOSIS OF PCOS - CLINICAL HISTORY

Patients with PCOS experience their first period:

1) at the usual age of 12-13 years.
2) even earlier at the age of 9 or 10.
3) menses may not occur at all.

Following the first period, the menstrual cycle may be regular for the first several years. By high school, the number of days between cycles begins to lengthen and gradually progress to the point where menstrual cycles occur months apart.

Some PCOS patients do not have cycles and only menstruate if Provera or some other progesterone medication is given. Some PCOS patients do menstruate but have heavy bleeding and long periods of spotting between periods.

Some patients with PCOS have regular 28-day cycles - but they are the exception. Most patients with PCOS have irregular cycle lengths – specifically defined as cycles greater than 35 days in interval or less than 8 cycles per year. Therefore any young patient with long cycles should be evaluated for PCOS.

When these young patients are seen by gynecologists complaining of irregular periods, oral contraceptive pills are often used to regulate the menstrual cycle. Although the pill will regulate the menstrual cycle – it does so artificially - giving the patient the mistaken impression that her cycle has been “fixed”. Actually, nothing has been remedied – it is just that because of the cyclic use of estrogen and progesterone in the birth control pill, there is a cyclic predictable bleeding cycle – totally achieved through hormone therapy.

In addition to questions regarding menstrual cycles, patients with PCOS will often give a history of having facial acne and excess hair growth that begins in early teenage years.

In our experience, women who gain weight especially greater than 10 percent of their total body weight, or increase their carbohydrate intake will often be sufficient to provoke the onset of irregular periods.

MAKING THE DIAGNOSIS OF PCOS - HISTORY, SIGNS AND SYMPTOMS

Symptoms usually first appear during adolescence - about the time that menses first begins. However, some women may not experience any symptoms until their early or mid-twenties.

Although PCOS begins in adolescence and early in life, this condition persists throughout the reproductive years and beyond. Normally around puberty, there is a normal increase in the amount of androgens (adrenarche). Therefore in adolescence, we commonly find acne and seborrhea. Dermatologists, on a daily basis, are involved in the evaluation and treatment of androgen-related skin conditions that often occur at the time of puberty, when body image is a keen issue to start with.

Clinical judgment and compassionate caution must be used to evaluate skin problems in teenagers. There is a fine line between normal-occurring skin problems and increased amount of acne or facial hair that requires an evaluation in the teenager for PCOS.

It is well-documented that skin conditions in PCOS patients are related to the increase in the level of male hormones (hyperandrogenism). This increase in androgen levels may be

• An increase in the total amount of androgen levels present in the blood
• A relative increase in the ratio of male hormone to female hormone.
• Normal levels of male hormones but an abnormal response of the skin to normal levels of androgens.

Any of these three possibilities can result in excess hair growth (hirsutism), acne, balding, seborrhea and inflammation of the sweat glands in the arm pit and groin, acanthosis nigricans (described below)

MAKING THE DIAGNOSIS - ULTRASOUND FINDINGS

In patients with PCOS, there is characteristic ultrasound findings referred to as PAO or Polycystic Appearing Ovaries:

• Enlarged ovaries
• At least 8-10 small ( 5-10 mm) follicles around the outer border of the ovary

Follicles are tiny sacs found in the ovary which contain immature eggs that usually develop in size and maturity. When the egg is fully developed, it will ovulate. At the time of ovulation, the follicle usually measures around 20mm.

In patients with PCOS, these tiny follicles do not further develop. Rather, they remain small and hundreds of these follicles gradually accumulate just beneath the outer capsule of the ovary – giving rise to the poly (many) cystic (cystic-appearance under the ovary).

The ultrasound appearance of polycystic ovaries is very common and in fact is found in twenty percent of women in the reproductive age group.

The PolyCystic Ovarian Syndrome (PCOS) - polycystic ovaries and the clinical and hormone abnormalities listed above is found in 5 to 10 percent of women of reproductive age. Thus, PCOS is without a question the most common hormonal disorder in women of reproductive age.

HIRSUTISM AND OTHER SKIN DISORDERS FOUND IN PATIENTS WITH PCOS

1. Hirsutism (excessive hair growth on the face and chest and abdomen). Elevated hormones can oftentimes cause long course hair on the chest, face, lower abdomen, back, upper arms and or upper legs.

Hirsutism is defined as the increase in the coarseness of the hair texture and/or male pattern hair distribution. For example, excess hair growth found between the umbilicus and the pubic hair line is also a form of hirsutism.

In addition to excess facial hair, there also can be male pattern hair growth (including sideburns, lower neck, and lower back and inner thighs).

A faint moustache is also a quite common but maybe more related to ethnic background or family trait.

2. Acne, comedones, whiteheads

With the rise in androgens, there is an increase of sebum. Sebum itself is a naturally-occurring combination of old skin tissue and various naturally occurring oils. As the amount of sebum increases - there will be a clogging of the skin pores. Bacteria grow in the sebum naturally. With the increase in sebum, we commonly see an inflammation of the skin pores called comedones.

Blackheads are comedones that are open . The black color is a result of the breakdown of keratin - a natural skin pigment. Closed comedones are referred to as whiteheads.

3. Seborrhea
Seborrhea is another result and sign of an increase in androgens.

4. Alopecia (Baldness)

With a significant rise of androgens, patients can actually experience balding (alopecia) and anterior hair line recession. These sites on the scalp are affected because these sites are the most sensitive to androgen levels.

5. Acanthosis nigricans (AN)

Acanthosis nigricans (AN) is a velvety dark patch closely adhered to the skin. Acanthosis nigricans has been described as an area that appears dirty. However AN has nothing to do with personal hygiene. Any patient with PCOS should be evaluated in the presence of acanthosis nigricans (AN) which is most often seen on the back of the neck, beneath the breasts, and on the axillae. AN is often seen in association with acrochordons – skin tags.

   AN can also be found in patients who are:
   • over weight
   • diabetic
   • have cholesterol problems
   • experience hypertension
   • have cancer

6. Hidradenitis suppurtiva
   In patients with PCOS, we also sometimes find Hidradenitis suppurtiva, which is a    hormonally related chronic disfiguring and painful condition. These boil-like    abscesses can be found in the axillae and groin and can be wrongly diagnosed as    a result of poor hygiene.

WHY DO ANDROGENS CAUSE SKIN PROBLEMS IN PATIENTS WITH PCOS?

Understanding the action of androgens

In order for androgens in the blood stream to cause an effect on the skin – the androgen molecules must bind with specific androgen receptors in the skin.

In order for androgens to cause an effect at the skin level Testosterone must be converted to dihydrotestosterone by an enzyme called 5a-reductase. 5a actually stands for 5-alpha. Alpha refers to the position of the hydroxyl radical that binds to the testosterone molecule. DHT is a much stronger androgen than testosterone itself. DHT binds to androgen receptors and causes the hair follicles to grow.

Evidence has shown the number of androgen receptor varies greatly from individual from individual and between different ethnic groups. Asian women in general have a lesser number of androgen receptors, and therefore have less facial and body hair then Italian women.

Therefore, from a clinical standpoint – the following observations can be explained with the information we know about androgens, receptors and DHT:

1. Women with PCOS of Northern Eastern background or Mediterranean origin are    likely to be much hairier then Asian women with PCOS because they have more    androgen receptors.
2. In some PCOS patients who have high levels of androgens, we sometimes find    no evidence of any skin problems. The reason for this could be:
   a. that if the androgen receptor is present in only very low numbers – despite        many androgen molecules in the bloodstream – there are simply a very small        number of receptors for these molecules to bind to and therefore no androgen        effect occurs.
   b. there may be a deficiency of 5a-reductase.
3. Some PCOS patients can have normal levels of androgens but still have hirsutism because they may have:
   a. very high numbers of androgen receptors.
   b. An increased response of the androgen receptors to normal levels of male        circulating hormones – perhaps an explanation of idiopathic (undetermined)        cause of hirsutism.

OBESITY AND PCOS

It is unclear whether obesity can cause PCOS or whether PCOS can cause obesity. In my experience, many patients are more likely to be overweight because of the sugar abnormalities that result from their PCOS.

• Women who are obese, especially if they have irregular periods, have the strong likelihood of having PCOS.
• Many women with PCOS are obese.
• Not every woman with PCOS is overweight
• Not every overweight patient has PCOS

Some physicians choose to distinguish between lean PCOS and obese PCOS patients. The distribution of fat affects the severity of symptoms found in patients with PCOS.

The medical literature suggests that women, in general, who have central obesity – fat in the trunk or midsection – have higher androgen levels, glucose and lipid levels, than women who have accumulated fat in other body areas.

The typical obese patient with PCOS is described as centripetal – which means that her fat distribution is primarily concentrated in the center of her body – as opposed to her hips and thighs.

Patients who are apple-shaped as oppose to pear-shaped have greater risk of diabetes, hypertension and lipid abnormalities.

It is important to know that although many metabolic problems may improve with weight loss – PCOS cannot be cured by weight reduction.

However, weight reduction is a primarily modality in the first line treatment of PCOS.

Patients with PCOS tend to gain weight extremely easily and lose weight very slowly and only with extreme effort. This fact is unfortunately over looked or not understood by some nutritionists and weight loss specialists. The diagnosis of PCOS must be factored in to any weight loss program - in order for it to be effective and relevant when dealing with patients with PCOS.

The classic diet approach of “less in-more out” simply does not work in itself with all patients with PCOS. Although in general we can advise calorie restriction and increased exercise for patients who must lose weight - when advocating weight loss to a PCOS patient, we must factor in that patients with PCOS use calories less efficiency and store fat far more easily than patients who do not have PCOS.

Insulin is a hormone that is produced by and released from the pancreas. Insulin is produced in response to the rise in glucose in the blood stream. Insulin also acts to facilitate fat storage to provide the body with a constant source of calories and fuel in times of “starvation”.

The PCOS is linked to abnormalities of insulin and glucose metabolism. It is possible that PCOS is a new phenomenon. In years past when people ate less and consumed fewer carbohydrates - it is likely that diabetes and obesity did not even exist. In the last century, as a result of our sedentary lifestyle, obesity has presented itself as a major health hazard and in fact may be thought of as a genetically related disease. Some individuals are more prone to weight gain than others.

All the data clearly demonstrates that weight gain involves not only consuming fewer calories but also genetic, metabolic, and environmental influences all impact on both the likely hood of weight gain, as well as the successful achievement of temporarily or permanent weight loss. PCOS is no exception to this.

INFERTILITY AND PCOS

Women with PCOS experience increased infertility because of irregular cycles which makes it more difficult to determine when exactly to have intercourse. However, even in cases where cycles remain regular, there may be an increase in male hormone levels within the follicle fluid – and this will interfere with the ability of the egg to fertilize the sperm or develop further after fertilization to form a healthy embryo.

DIAGNOSING PCOS - LABORATORY TESTING

All patients with PCOS can have either an obvious or subtle laboratory abnormality. In some cases, the result may be in the upper limits of the normal range, showing perhaps only a tendency – not a significant abnormality. In some cases a pattern will be obvious when considering several tests together.

The blood testing that we do for PCOS patients - is done to distinguish between problems of the hypothalamus, pituitary, ovary and adrenal (HPOA axis). All of these organs must work well both individually and in concert with the other organs. The proper balance and interaction between them is necessary to have a normal cycle.

It is recommended that all patients suspected to have PCOS should have an initial comprehensive laboratory evaluation, which should be interpreted by a physician or a group of clinicians who are familiar with the laboratory findings in patients with PCOS.

PCOS Patients should be aware that normal levels vary between laboratories and the specific manufacturer of testing kits used by laboratories to evaluate blood specimens. Obviously if a level is two times the upper or lower limit of normal, this will undoubtedly indicate a significant problem. Many endocrine levels will vary during the course of the day – so we recommend as a rule to do testing best in the morning, and soon after the first few days after the period. Additionally patients who are using the birth control pill will often have misleading results especially for ovarian steroids and SHBG levels.

I recommend that for the best diagnostic value, we obtain the blood sample in the first 2-5 days after a period begins and to avoid any food or beverages after midnight the night before.

THE FOLLOWING TESTS ARE NECESARY FOR PCOS EVALUATION:

• Fasting comprehensive metabolic profile including glucose and electrolytes    evaluates:
   • The overall state of metabolism
   • Salt water balance
   • Electrolytes (salts)
• Lipid Panel –evaluates cholesterol and triglycerides.
• 3 hour glucose tolerance test (GTT) with insulin levels.

The GTT can detect diabetes and impaired glucose tolerance.

UNDERSTANDING THE GTT

The GTT is a more sensitive test than a single measure of glucose. The GTT should be considered in all patients with PCOS especially if they are/have:

• 20% above of their ideal body weight
• A first degree relative with diabetes (Have elevated lipid levels, or delivered a child weighing an excess of 9 pounds.)

According to the American Diabetic Association (ADA)

• A fasting glucose over 126 mg/dl is considered diabetes.
• Fasting levels 110-126 have impaired glucose tolerance.

The term “Type 2 diabetes” is used to describe the presence of insulin resistance that results in elevated glucose levels. Type 2 diabetes has replaced the older terminology of “late, or adult onset diabetes”.

The ADA recommends a 2 hr screening testing following a 75-gram glucose drink (load). Patients who demonstrate a single high fasting insulin level may have insulin resistance, but the diagnosis of the insulin resistance can only be made with certainty by measuring insulin as a part of a glucose tolerance test where the blood level of insulin is done on a fasting test and then for one, two, or three hours after in combination of glucose levels.

• The Ratio of luteinizing hormone to follicle stimulating hormone (LH: FSH ratio) is a measure of the balance of stimulation from FSH and LH.

In patients who have PCOS the level of LH is much higher than the level FSH. Most physicians agree that when the LH: FSH ratio is greater than 2 to 1, this indicates PCOS.

For example, if the value for LH is 18, and the value of FSH is 6, that is a 3:1 ratio. If the value of LH is 12 and the value of FSH is also 12 – that is a 1:1 ratio and the likelihood of PCOS is less.

At this point, I must interject a word of caution. The value of LH to FSH ratio is only significant when one also includes on the same day the value of estradiol.

If the estradiol is high – that will cause the FSH to go down and it may be wrongly implied a LH to FSH imbalance. This point is absolutely critical in evaluating the results of LH and FSH testing.

ANDROGENS

1. Total Testosterone and Sex hormones binding Globulin (SHBG) are used to    measure the free Androgen Index, which helps to determine whether the source    of the androgen is from the ovary or the adrenal gland.
2. Dihydroepiandrosterone sulfate (DHEAS) is a hormone produce primarily by the    adrenal gland.
3. 21-hydroxyprogesterone. In patients with congenital adrenal hormone excess,    there is a increased level of 21-hydroxyprogesterone.This condition is found in    certain ethnic groups.

Thyroid-Stimulating Hormone (TSH) Many symptoms of thyroid disorders either under active or over active resemble those in patients with PCOS.

Prolactin is a hormone that causes milk production from the breast during pregnancy and women who are breast feeding. In some women with menstrual problems, we find an elevation in the level of prolactin. Therefore, prolactin should be measured to exclude this as a cause of irregular cycles of women who are expected to have PCOS.

HEMOGLOBIN A1C
This is an excellent marker of the level of the average level of blood glucose over the past three months. Hemoglobin A1C level is a reliable measure to say whether diabetes is well controlled. It is advised to obtain a Hemoglobin A1C level in patients where diabetes or glucose intolerance is found by the GTT test.

ULTRASOUND
A pelvis ultrasound should be obtained in every patient suspected to have PCOS. The sonogram should be done by the individual whose is experienced in carefully evaluating the ultrasound findings specific to patients who have PCOS.

A word of caution when a person is sent for a sonogram to a radiologist and the purpose of the sonogram is to determine whether or not the ultrasound appearance is consistent with or supports the diagnosis – the technician and the radiologist must both be aware that we are interested in;

1. The number and size of various small follicles that are found on the surface of the ovary.
2. The size of each ovary – in particular their volume.
3. The presence or absence of large cysts.
4. The thickness of the endometrium – the inner lining of the uterus

DIAGNOSIS OF PCOS - SONOGRAM FINDINGS

If a sonogram is done by someone who is not experienced - then the value of the ultrasound is limited in its usefulness.

• The finding of greater than eight cystic follicles less than 10 mm in either ovary is    consisted with the generally accepted criteria for the ultrasound diagnosis of    PCOS.
• Follicle cysts in patients with PCOS, are usually located in a ring that encircles the    outer periphery of the ovary often referred to as a “string of pearls.”
• PCOS ovaries are particularly two to three times normal size. The normal ovarian    volume is about 8-12 ml. In some cases with PCOS, the ovary is entirely covered    by small cysts. In other patients, the ovary itself may appear to be solid in    appearance without microcystic changes.

Any patient who has elevated androgens can have ovaries that have the characteristic appearance of polycystic ovaries – with numerous small cyst found along the surface of the ovary. Therefore one cannot make the diagnosis of PCOS just on the basis of the appearance of the ovary findings.

CAUSES OF PCOS

The ovary is thought to be the origin of the PCOS disorder because by removing a portion of the ovary (wedge resection) we can restore regular menstrual cycles and fertility in medications with PCOS.

The exact cause of PCOS is not known. The specific central mechanism is still a matter of debate. Additionally, it is possible that there is not one but several causes for PCOS all of which may share common features of a variety of disorders.

Most patients with PCOS have elevated male hormones which cause the characteristic findings of excess facial hair and acne.

Hormones are natural chemicals released from organs into the bloodstream in very small quantities. Hormones, by definition, cause effects at distant sites.

Thus PCOS patients have signs and symptoms throughout their body.

Female sex hormones (estrogens) are actually made from androgens (male hormones). When the amount of androgens present in the bloodstream are increased or when there is a relative imbalance (less estrogen than androgen), the unwanted effects of androgens become apparent.

The androgens produced in the body and released to the general blood circulation come from several sources:

1. the fat cells - Therefore patients who are overweight and have a larger number of fat cells than normal – have increased androgen production.
2. Ovary
3. Adrenal gland

PCOS may be of adrenal or ovarian forms depending upon where the greater amount of androgen comes from – the ovary or the adrenal.

IN THE OVARY OF PATIENTS WITH PCOS:

• Androgens are produced in the small follicle cysts that are seen on ultrasound.
• The ovary in some patients with PCOS has had multiple follicles that all measure under 10mm

It is possible that the key to understanding the cause of PCOS is a factor that prevents follicles from developing from larger size, and instead causes them to remain as small cysts that contain immature eggs, that do not further develop.

The follicles are tiny sacs that contain egg cells. The theca cells are cells that surround these follicles and are very important in providing nutrients to the developing egg cells. Theca cells contain an intricate network between themselves that allow substances in the blood to be transferred from a blood stream to the interior of the developing follicle. Without theca cells there would be no way for the hormones from the pituitary to reach the developing follicle and egg cell.

THE FOLLICLE UNIT PRODUCES ESTROGEN:

• The way this happens is that first androgens are produced by the theca cells.
• Androgen is converted to estrogen in the theca cells through an enzyme called aromatasa that is present in the theca cells.

In patients with PCOS - the theca cells are very sensitive to LH and because of this, there is increased production of androgens. This is one mechanism by which PCOS patients are different than non-PCOS patients and explains why they have higher levels of androgen production. Another possibility that there is possibly a deficiency in the ability of patients with PCOS to convert androgens to estrogens. Additional considerations are that insulin resistance and/or disorders involving hypothalamic-pituitary-ovarian axis are involved as causes for PCOS. It is further possible that each of these etiologies may vary between patients in their level of severity. Nonetheless the ovary remains in a steady state that prevents the follicles from progressing to mature large egg cells that are able to obviate and fertilize with sperm.

PCOS AND INSULIN RESISTANCE

Insulin resistance is a condition in which the body becomes increasingly less responsive to the actions of insulin.

The primary action of insulin is to decrease the glucose level in the blood. In patients with insulin resistance the blood sugar level rises despite even high levels of insulin. Eventually these patients will develop type two diabetes. In patients with type one diabetes, the pancreas does not make sufficient amount of insulin.

In patients with insulin resistance, there can be very high level of insulin, its just not as effective in making the level of glucose lower.

The clear relationship between PCOS and insulin resistance is well established. Additionally, the high level of insulin causes the androgen level to increase.

PCOS patients who are over weight, is more likely to have both insulin resistance and hyperinsulinemia (elevated level of insulin).

PCOS patients who are thin are less likely to be insulin resistant.

It is important to remember that insulin facilitates the storage of fat Thus, this explains the relationship between insulin resistance and abnormal lipid levels, and hypertension (and the metabolic syndrome.)

Insulin resistance and hyperinsulinemia are significant risk factors for the development of hardening of the arteries (atherosclerosis). This explains why patients of PCOS are in increase risk of stroke and high blood pressure.

Hyperinsulinemia causes an increase in LH and the production of androgen. Because of androgen elevated levels act to limit follicle growth and therefore cause disorders in ovulation in regular menstrual periods.

Elevated levels of insulin is also associated with where they decrease in sex steroid binding globulin (SHBG) – which then causes a increase in the “free or unbound androgen” which is more potent then bound androgen (androgen bound to SHBG.)

Finally IR is associated with the development of type two diabetes. The strong family tendency to develop PCOS may be linked to the strong family tendency to develop diabetes.

GENETICS OF PCOS

Women with PCOS appear to have a genetic tendency and often have male and female relatives who suffer from diabetes, obesity, hypertension, elevated triglycerides, infertility, and menstrual problems.

The genetic tendency to develop PCOS may be inherited from the mother or the father. When taking history of PCOS in the family, it is therefore imperative that one ask whether PCOS and/or diabetes was found on the father side as well.

Another area of interest currently under investigation is that the specific traits of PCOS may be inherited with variable degrees of severity from one’s parents. In other words, there may be a distinct tendency to develop facial hair that may not be passed on with the same severity to the next generation or with greater or less severity.

Given that insulin resistance is such an important component of PCOS – there are geneticists that claim PCOS to be passed on by a discrete number of genes that are involved in glucose regulation and perhaps by other genes involved in the production of hormones from the ovary. Possibly, both genetic groups may be necessary to develop classic or full-blown PCOS. Additionally, it is entirely possible that diet and environmental factors such as stress and exercise may either strengthen or improve the manifestations of PCOS. Patients with PCOS should be counseled that it is possible to pass the PCOS condition to one’s daughter, son or granddaughters.

As we enter a new era of molecular biology where corrective gene alteration will be a therapeutic modality, conditions like PCOS may eventually be remedied at the molecular level early in life.

PREGNANCY AND PCOS

Patients with PCOS experience an increase in first semester miscarriage. The primary cause for this is probably related to poor egg quality that is commonly found in patients with PCOS. In performing in vitro fertilization on hundreds of patients, I’ve had the opportunity to evaluate personally the quality of eggs seen at the time of egg cell harvesting. The two things which are constant that I’ve observed is that PCOS typically produce many follicles. Unfortunately, many of these eggs are immature and simply do not do well in the laboratory environment.

Another cause of increased miscarriage in patients with PCOS is likely to be the fact that especially in patients with long cycles, there is a poorly developed lining of the uterus. Remember that if someone has 40-day cycles, that means the endometrium is not receiving the usual benefits effects of progesterone for 2 weeks out of a 4-week cycle. This over time will influence the quality of the lining of the uterus. Therefore, there will be a higher rate of miscarriage.

PCOS patients experience the following pregnancy-related complications:

1) pregnancy loss
2) gestational diabetes
3) pregnancy-induced hypertension

In patients with PCOS, the beneficial effects of increased exercise and weight loss are to increase the chances of a successful pregnancy.

PCOS THERAPEUTIC OPTIONS

WEIGHT LOSS

Weight loss will often improve lab findings and often results in the return of regular predictable menstrual cycles.

Unfortunately, weight loss does not predictably affect hirsutism to cause a lessening of the amount of facial and body hair. Diet plans recommended by the American Diabetes Association (ADA) are highly effective in patients with PCOS.

The most effective weight loss plans involve behavior modification and group involvement. Patients with PCOS should therefore seek out support groups with other PCOS patients – because their needs are different.

In terms of exactly which diet should be used, avoid simple sugars and try to maintain a low-carbohydrate, low saturated fat, with a focus on vegetables and fruits with low-glycemic index.

High protein diets have been used effectively in patients with PCOS but there is no data to say which is best.

PROGESTINS

A progestin is a medication that has similar actions to progesterone. Progesterone is a hormone produced by the corpus luteum which forms from the ovarian follicle after ovulation. The corpus luteum prepares the uterus for implantation during the last 10-14 days of the cycle. The corpus luteum has a limited life span of 10-14 days, and as the corpus luteum begins to break down, there is a decrease in progesterone level.

The menstrual episode of bleeding is a result of the loss of the lining of uterus which occurs as the progesterone level falls. Again, due to the withdrawal of the progesterone at the end of the cycle, the lining breaks down and the menstrual flow begins. When patients do not ovulate, there is minimal production of progesterone from the surface of the ovary. When progesterone is given, it will strengthen the lining and prevent menstrual flow. Progestins have little effect, if any, on hair growth or the metabolic abnormalities in patients with PCOS.

In order for progestins to thicken the lining of the uterus, the uterus must first have been stimulated or exposed to estrogen. This is referred to as estrogen-priming. In the normal 28-day cycle, there are sufficient amounts of estrogen for 40 days as the follicle and the egg within it grows. In patients with PCOS who do not ovulate for sometimes months at a time, the estrogen levels may be typically low and therefore progestin may not have an effect at all.

Patients with PCOS have follicles that remain for months or for years in the very early stages of egg cell development. Basically the eggs are suspended at a fixed early phase of egg cell maturation and do not go on to further growth and ovulate. The small follicles (cysts) found in patients with PCOS produce very limited amounts of estrogen. This low amount of estrogen is often not sufficient to stimulate the proliferation of growth of the lining of the uterus. Thus, the lining of the uterus is constantly exposed to low levels of estrogen that is not opposed by progesterone stimulation after ovulation. This constant exposure to low levels of estrogen over the course of years can lead to hyperplasia – overgrowth of the lining of the uterus and in some cases, cancer of the uterus.

The role of progesterone in patients with PCOS is to cause regular predictable withdrawal uterine bleeding and help prevent hyperplasia.

ORAL CONTRACEPTIVES

Oral contraceptives are an important treatment modality in patients with PCOS who do not want to conceive at this time yet. The estrogen portion of the oral contraceptive increases the amount of sex steroid binding globulin (SSBG) which binds to androgens and because they are neutralized, the effects of androgens can be decreased.

With the increase of SSBG, there is less free testosterone because free testosterone is bound and not unbound active. The progesterone portion of the pill reduces the amount of LH secreted by the pituitary gland. Therefore most testosterone production will come from the ovary. It is important in choosing the oral contraceptive to remember that some progestins are androgenic (have the action of male hormones) and may also adversely affect the glucose tolerance test results.

Corticosteroids

Corticosteroids have been useful in the treatment of PCOS because they are able to suppress the production of androgens from the adrenal glands. However, their use is limited because they have no effect on hirsutism and there are complaints of side effects. The recommended dose of steroids is 0.25 mg of dexamethasone.

ANTI-ANDROGENS

Spironolactone (Aldactione)

This group of medications should only be used on patients who are not trying to conceive. Spironolactone (Aldactione) is a diuretic that is used to treat hypertension. Spironolactone can produce excess hair growth by blocking the effects of anti-androgens. Spironolactone blocks the cytochrome P-450 system that helps regulate the production of androgens from both ovary and the adrenal gland. Spironolactone interferes with dihydrotestosterone (DHT) by 5a-reductase enzyme.

Cyproterone acetate

Cyproterone acetate (CA) is a potent anti-androgen and a weak progestin. This medication is available outside the US and is popular in Europe. Some patients who use CA claim to have had hair loss and some patients become amenorrheic.

Flutamide (Eulexin)

Flutamide (Eulexin) is a non-steroid anti-androgen first developed for the treatment of prostate cancer. Similar to Spironolactone and Cyproterone acetate, Flutamide is an anti-androgen which works by blocking androgen at the site of the androgen receptor. The advantage of Flutamide over Cyproterone acetate is that it does not have steroid like activity. The advantage of Flutamide over spironolactone that is does not affect kidney function.

Many patients complain of dry skin when using flutamide. Other side effects include an increase in appetite, fatigue, headache, nausea, and occasional hot flushes.

Flutamide is cleared from the body by the liver. Nonetheless, there have been only rare reports of liver toxicity. Studies differ as to whether flutamide works better than spironolactone. Understandably, researchers who have found that they are of similar effectiveness advocate using spironolactone because it is less expensive and theoretically there is less likelihood of liver toxicity.

Finasteride (Proscar or Propecia) acts by inhibiting 5a-redutase activity – therefore it is not a true anti-androgen which acts at the receptor level. The original use of Proscar or Propecia was to manage benign prostatic hypertrophy. Finasteride is now FDA-approved to treat male pattern baldness in men.

I am optimistic that Finasteride will prove to be highly effective in the treatment of hirsutism. Its action is specific to the site of production of the potent androgen dihydrotestosterone.

Recent studies suggest that Finasteride:

• is equally as effective as spironolactone
• appears to be safe
• extremely well-tolerated
• should not be used during pregnancy
• is more expensive than spironolactone.

Not withstanding the expense, in my opinion It may soon in my opinion Finasteride will one day be the medication of choice for many patients.

Vaniqa (Eflornithine) acts by interfering with ornithine decarboxylase - an enzyme critical for hair growth that is found in the hair follicle. I advise patients to use Vaniqa cream twice daily after the face has been thoroughly cleaned and dried.

Reports on Vaniqa indicate:

• Marked improvement in a third of patients
• Some improvement in another third
• Mild to no improvement in the remainder.

My guidelines to patients using Vaniqa are:

• The change will be gradual - and may not be seen for 2-6 months
• If there is no improvement after 6 months, consider an alternative medication
• Stop Vaniqa once pregnancy is documented because the safety during pregnancy has not been documented

Only a very small amount (less than one percent) of the active ingredient in Vaniqa is actually absorbed into the body. Therefore, side effects with Vaniqa are very rare and are usually limited to local skin sensitivity.

FERTILITY ENHANCING DRUGS

In patients with PCOS, there is a disorder in the normal mechanisms of hypothalamic-pituitary-ovarian (HPO) axis. PCOS has an adverse effect therefore on follicle development and ovulation.

In patients with PCOS, fertility medications are useful to at least temporarily correct disorders in ovulation - so pregnancy can be achieved.

THE TRADITIONAL FERTILITY MEDICATIONS USED TO TREAT PCOS ARE:

• Clomiphene citrate or serophene
• Injectable gonadotropins – such as Pergonal, Repronex, Fertinex, Menopure, Bravelle.

All fertility medications act to stimulate the follicles which contain the eggs on the surface of the ovary. Giving these medications accomplishes a ready mix of FSH and LH which are the gonadotropins that stimulate the eggs to grow every month during the reproductive years.

Clomid – is an oral medication that causes the pituitary to release high amounts of FSH and LH and therefore Clomid will indirectly stimulate the follicles and the ovaries to grow.

Injectable gonadotropins actually contain FSH and LH – and therefore directly stimulate the follicles and the ovaries to develop and release eggs during ovulation.

The limitation of all fertility drugs is that they only work for the cycle that they are given.

For PCOS patients who want to become pregnant - Clomiphene citrate is the most common first-line therapy. Clomiphene citrate:
• Is safe
• Rather inexpensive,
• Easy to use
• Can be taken orally

successful for many patients often within the first few cycles.
Clomiphene citrate (Clomid) is not a hormone - rather it is a synthetic anti-estrogen.

Clomiphene citrate (Clomid) – Understanding its mechanism of action

• Tricks the body into perceiving that there is an deficiency in estrogen.
• Accomplishes this by binding to the estrogen receptors in the pituitary so that estrogen can no longer bind its own estrogen receptors.
• Because the pituitary is not receiving a signal from its estrogen receptors, the estrogen has bound its receptor – the pituitary thinks that there is deficiency in estrogen and releases increased amounts of FSH and LH to try and speed up the number and size of follicles.

In patients with PCOS - there is an imbalance in the amount of LH to FSH. In other words, in patients with PCOS there is a tendency to produce more LH than FSH – especially when one gains weight. This results in the higher amounts of LH compared to FSH when these 2 hormones are measured during the menstrual phase of the cycle.

CLOMID IS USEFUL IN PATIENTS WITH PCOS BECAUSE:

• It is an oral tablet and rather inexpensive and requires little monitoring
• It acts to produce more FSH
• Herefore at least temporarily correct this imbalance
• This allows for orderly development of the follicles and ovulation so pregnancy    can hopefully be achieved

The disadvantage of Clomiphene citrate is that it is an anti-androgen:

• The lining of the uterus is normally stimulated by estrogen during the first half of    the cycle until ovulation to become thick and therefore receptive to implantation    of the embryo.
• Clomid will decrease the lining of the uterus and therefore may decrease the    likelihood of implantation of the embryo.
• Clomid decreases the quality and the amount of the cervical mucus, by making it    thicker and scant. This obviously makes it more difficult for sperm to move    through the cervical mucus at the time of ovulation.
• Some investigators are concerned about a potential harmful effect on the egg,    and possibly the embryo.
• Nonetheless many patients on Clomiphene citrate do ovulate and get pregnant    despite these drawbacks.

Additional Facts about Clomiphene citrate

• Is currently recommended to try a maximum of six months.
• 70% of pregnancies occur in the first three months
• the pregnancy rate after 6 months is 5-30% depending upon the couple’s age and    their fertility problems such as blocked tubes or sperm factor
• Twins occur in 5-10% of pregnancies.
• Triplets occur in less than 1% of pregnancies
• Ovarian hyper-stimulation is not common.
• Some reports indicate a increase in pregnancy rate if the birth control pill is used    for several months before starting Clomiphene.

Before the first cycle of Clomid - it is extremely important to have a base line ultrasound scan to be certain that:

• There are no ovarian cysts that may decrease the effectiveness of Clomid
• There’s no other pelvic abnormalities

I personally recommend that an ultrasound be performed every month before starting another cycle of Clomid

Insulin altering drugs

Metformin can improve ovarian function and increase fertility outcome in patients with PCOS.

Metformin can be used before Clomid or other fertility medications are tried. Metformin can also be used in combination with Clomid and other injectable preparations.

Letrozole (Fermara)

Letrozole is an aromatase inhibitor that has been used for many years for breast cancer.

In patients with PCOS, Letrozole can be effective in promoting normal cycles because of its beneficial effects on follicle development and ovulation.

Important Facts about Letrozole

1) can be taken as a normal tablet and is very affordable
2) low risk of hyper-stimulation – usually only several follicles develop
3) cleared rapidly from the bloodstream
4) proven to be a safe medication with minimal side effects

Advantages of Letrozole over Clomid

1) less side effects
2) does not have the adverse effects on the cervical mucus and uterine lining

There is ongoing research to determine in patients with PCOS if:

1) Letrozole is as effective as Clomid
2) Letrozole should be used in patients who have not been successful with Clomid

GONADOTROPIN INJECTIONS

Clomid is an oral medication used to stimulate egg cell development. Clomid is an anti-estrogen which stimulates the pituitary to produce both FSH and LH which are the gonadotropins that stimulate egg cell development within the follicles on the surface of the ovary.

Gonadotropins are combinations of FSH and LH. Originally FSH and LH were derived directly from the urine of menopausal women isolated, purified and produced in a powder preparation called Pergonal.

Currently, these medications are produced by a process called recombinant technology. Therefore, through artificial means, these medications are biologically perfect molecules that provide an immediate source of FSH and LH that can be given by injection to cause multiple egg cells to develop.

The disadvantages of gonadotropins are:

• Great expense ($1,000-2,000 per cycle)
• Can only be given by injection
• Require frequent monitoring, sometimes daily
• Twinning rate is 20% and triplets 5%
• Risk of hyper-stimulation syndrome – where the ovaries are enlarged and may leak fluid. This can cause abdominal enlargement and considerable discomfort

IN VITRO FERTILIZATION FOR PCOS

In Vitro fertilization was first developed as a treatment method for patients with blocked fallopian tubes. IVF was then recognized to be a solution for patients with low sperm counts, severe endometriosis, and unexplained infertility. Over the past several years, IVF has been offered increasingly to patients with PCOS.

The advantage of IVF for patients with PCOS is:

• Higher success rate than just using fertility medication
• Gives the couple information on the quality of their eggs and the ability of the eggs to be fertilized

PATIENTS WITH PCOS WHO UNDERGO IVF

• Higher chance of fertilization failure – the eggs do not fertilize with the sperm because the egg quality in PCOS patients is sometimes suboptimal
• Oftentimes either over-stimulate or under-stimulate
• Have a higher rate of miscarriage
• Have a higher rate of hyper-stimulation syndrome

Our understanding of PCOS in the last decade in regards to the role of insulin and the inescapable presence of androgen excess both in the bloodstream as well as within the follicle unit has allowed for new treatment strategies in medication protocols when stimulating patients with IVF.

Some of these innovative approaches that have been introduced include the use of:

1. Birth control pill for several months before the IVF procedure
2. Preparations such as follistin that contain only FSH rather than FSH and LH. Patients with PCOS already have an excess of LH so FSH preparations alone are recommended primary agent to be used in stimulation protocols
3. Metformin for several months prior to starting the IVF stimulation

SURGICAL THERAPY FOR PCOS

PCOS was first described by Dr. Stein and Dr. Levanthal to be ovarian disease. For many years, the treatment for PCOS was surgical - because the problem was erroneously thought to be purely the ovary.

For patients with PCOS, ovarian wedge resection, in which a significant portion of the ovary was surgically removed, was the primary treatment.
With Wedge Resection – we observed:

• significant decrease in androgen production
• decrease in LH to FSH ratio
• return of regular menstrual cycles in over 75% of patients.
• Pregnancy rates of 50%

However, pelvic adhesions occurred in 30% of patients who have undergone wedge resection– oftentimes severe. Additionally, the improvement in regular cycles was only temporary - lasting three to six months.

In current medicine, there is almost no indication for performing a traditional wedge resection through laparotomy. Laparotomy is a major surgery where a C-section-like incision is used to open the abdomen. Laparoscopy is an out-patient procedure where a small incision is made just beneath the bellybutton and the recuperation time is days or weeks rather than in months.

For patients with PCOS who require a surgical method of treatment, we currently perform ovarian drilling. A fine cautery needle or a laser is used to create between 10 and 20 punctures on each ovary. The cautery needle is attached to a surgical current. The laser beam is generated by a laser unit and allows for a highly precise and focused incisions. Laser and cautery have similar success rates. Ovarian drilling is currently recommended for patients who fail to respond to conventional medications.

The exact mechanism by which wedge resection or ovarian drilling work is still a matter of debate. It is possible that by reducing the ovarian mass, there is therefore less production of androgens. Additionally, by making holes in the thin cortex (surface of the ovary), it may be easier for follicles to ovulate.

A theoretical risk for wedge resection or ovarian drilling is earlier menopause due to destruction of the oocytes that are in the area that is removed.

COSMESIS

Medical therapy can significantly slow down hair growth, but it will not completely stop it. Permanent reduction of unwanted hair can be accomplished by physical removal with electrolysis or laser therapy – which actually destroy the re-growth mechanism of the hair. However, there is a risk of infection, inflammation, scarring in addition to the pain involved.

Plucking and shaving are only temporary fixes. They do not cause hair growth to come back faster or with coarser hair growth.

For these reasons, medical therapy is the first line therapy of choice.

Laser is preferred over electrolysis and works especially best on patients who have fair skin and dark hair.

INSULIN ALTERING AGENTS

The association of insulin resistance and PCOS is well established. PCOS can be treated and possibly one day cured by effective management