"Polycystic Ovary Syndrome "

By: Michael Mersol-Barg, MD

Polycystic ovary syndrome (PCOS) is a medical condition that occurs in about 5% of women in the general population and 15-20% of women with infertility. Drs. Stein and Leventhal first described this syndrome in 1935 among women who had no menstrual periods, excessive hair growth and obesity. For many years PCOS was known as the Stein-Leventhal Syndrome. Women with PCOS have enlarged ovaries containing multiple small cysts, which has led to the descriptive term “polycystic ovaries”. A specialized cyst on the ovary is a follicle which is a fluid filled sac containing an egg (oocyte). As it turns out, the term polycystic is misleading. In fact, each cyst, commonly very small at 4-8 mm is a follicle containing an egg. The problem is that the eggs within the follicles are in different phases of disrupted development- some eggs are immature andsome are past peak maturity. These follicles are in constant turnover with few having normal growth and development that would lead to ovulation at a follicle size of 26 mm and result in normal conception.

After nearly 70 years of observation, we now recognize that Drs. Stein and Levanthal described the most obvious variety of PCOS. However, women do not need to be obese nor do they need to have excessive hair growth to have PCOS. PCOS has many appearances and can lead to uncertainty in making the diagnosis. An analogy I often think of is that PCOS comes in many varieties similar to tomatoes: Stein and Levanthol described the Beefsteak tomato, but the Roma variety also exists. The number of women with PCOS is likely to be grossly underestimated in the current population estimates. The minimum criteria to establish the diagnosis of PCOS until recently were anovulation and androgen excess. The recent Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop of May, 2003 published a change in the consensus of diagnostic criteria for PCOS in January, 2004 Fertility and Sterility Journal: that irregular menstrual cycles and/or anovulation no longer need be necessary to establish the diagnosis of PCOS. In fact, a woman can have regular cycles. There is great hope for successful treatment of this disorder. Early detection and therapy can result in a high probability of successful pregnancy and a reduction in risk of many lifetime diseases related to PCOS such as diabetes, cardiovascular disease, and diseases of the lining of the uterus: the endometrium including cancer.

It is important that women with PCOS symptoms or those suspected of having PCOS should be tested for disorders of their thyroid, pituitary and adrenal glands prior to establishing the final diagnosis of PCOS. If these conditions have been tested and they are found not to be present, then the diagnosis of PCOS may be made.

HOW DO YOU KNOW YOU HAVE PCOS?

PCOS is diagnosed by observing physical evidence of menstrual irregularities and androgen hormone (testosterone) excess such as acne and/or hair growth in male pattern such as face, back, chest, upper arm abdomen and buttocks. The diagnosis made by such physical signs is called a clinical diagnosis. Although laboratory tests can add to the characteristics of this disorder, it is the clinical signs presented upon which the diagnosis is made. Conventional wisdom has required that menstrual cycles be prolonged to 35 days or greater. However, women with PCOS may have nearly regular menstrual cycles or regular menstrual cycles with a history of some cycle irregularity. Some women with PCOS ovulate regularly. PCOS in these women may only reveal itself under adverse health conditions of increased weight gain, emotional stress, or even during their response to fertility medications taken for reasons other than to treat an ovulation problem. PCOS has been confirmed among women with regular menstrual cycles, yet during infertility therapy with ovulation induction medications such as clomiphene or FSH, the ovarian response may be abnormal exposing the underlying disorder. Since the mid-1990s, we have recognized a connection between PCOS and abnormal glucose/insulin metabolism. Signs or hypoglycemia or the opposite- hyperglycemia (diabetes mellitus) are common. High carbohydrate dietary consumption is also common.

WHAT CAUSES PCOS TO OCCUR?

Currently, we do not have a clear understanding of the cause. The root cause is most likely genetic. That is, there is a gene or several genes in various combinations that are not normal. The genetic abnormality may be as varied and unique as each person’s fingerprint. This may be the reason why women experience such a wide variety of physical signs and symptoms, all of which are recognized as polycystic ovary syndrome. These genes may also make some women vulnerable to develop PCOS if their conditions of good health are altered. Examples of changes in health include weight gain, diet changes, stress and anxiety, medications, and other hormone diseases that can lead to not ovulating.

The hormone problems in PCOS are very complicated. The challenge in trying to understand where the problem starts in PCOS is like trying to figure out which came first, the chicken or the egg. Perhaps a more apt analogy in this case is the brain or the ovary. The brain and the ovary signal each other by using chemicals called hormones. Hormones from the brain, follicle stimulating hormone (FSH) and luteinizing hormone (LH), direct the ovary to develop and release an egg each month. The problem is that FSH and LH are produced and released by the brain in an abnormal way. The actual engineering of the hormone may not be normal. The actual timing of hormone release and the amount released is also abnormal. The ovary is also functioning abnormally. This occurs in part, due to the abnormal hormone signals from the brain. Another part of the problem is the ovary itself. The ovary may contain eggs of varied quality. The cells in the ovary that produce hormones such as estrogen, progesterone and testosterone may manufacture and release these hormones in the wrong amounts and at the wrong time.

WHAT HAPPENS TO THE EGGS WITHIN THE POLYCYSTIC OVARY?

In a normal ovary, about 4-6 follicles, each holding one egg, compete within the first 5 days of every menstrual cycle. Only one egg wins and becomes dominant. This follicle will then grow much larger and releases its egg (ovulates) about 8 days later. The other follicles and the eggs within dissolve. In PCOS, the early competition never ends and there is no winner. This means there are always small follicles either in the very early development phase or fizzling out ready to dissolve. No one follicle becomes dominant. No egg is released. Ovulation does not occur. Menstrual cycles are prolonged or may not occur at all.
The term polycystic ovary is really describing these small follicles in constant turnover. The prefix “POLY” means many. The term “CYST” describes a fluid filled sac with an inner lining of cells. A follicle is a special case of a cyst with an egg in it.

HOW DOES OBESITY PLAY INTO PCOS?

Obese women with PCOS may also have an imbalance in their sugar metabolism. Some women with PCOS have high levels of the hormone insulin circulating in their blood stream. Insulin is a hormone produced in the pancreas. Insulin is released in response to eating carbohydrate foods that in turn raise your blood sugar levels. Women and men who are obese have an increased proportion of their total body composition made up of fat. Greater fat composition in our body makes it more difficult for the tissues like our muscle and liver to allow insulin to push the sugars from our blood stream into these tissues. This is termed increased insulin resistance by our tissues. The pancreas can detect higher than normal blood sugar levels; therefore the pancreas compensates by releasing higher than normal amounts of insulin into the bloodstream to overcome the insulin resistance and push the sugars from the blood stream into the tissues. This condition of higher than normal blood insulin levels is termed hyperinsulinemia. A glucose/insulin challenge test is done to determine if you have hyperinsulinemia. If insulin resistance is too great, the pancreas may not be able to compensate enough to overcome the insulin resistance. This can lead to diabetes. Another side effect of the hyperinsulinemia is that insulin passes from the blood into the ovary and stimulates the ovary to produce extra testosterone hormone. The extra testosterone hormone can block follicle development, block ovulation and lead to excess hair growth in areas usually found only in men: for example, the face, back, chest and abdomen. You can see how the insulin story can cause or worsen the condition of PCOS. This also explains why women with PCOS are at greater risk for diabetes during pregnancy (gestational diabetes) and diabetes in their lifetime. Treatment for this condition will be described below.

Women with PCOS have normal reproductive organs (such as the uterus, fallopian tubes, cervix and vagina). Their ovaries each contain multiple small cysts around the periphery. Each ovarian cyst generally measures less than eight (8) mm diameter and will be easily seen by pelvic ultrasound. These cysts do not appear to grow and usually remain small. They do not require surgical removal and are not associated with an increased risk of ovarian cancer.

THE SYMPTOMS AND RISKS OF PCOS

Menstrual irregularities—either no menses or very heavy bleeding.
Risk of endometrial cancer- if menstruation is too infrequent, intervals greater than three months, then the endometrial lining of the uterus can build up. Abnormal growth of this tissue can lead to abnormal precancerous changes to the lining of the uterus. Eventually this can lead to frank cancer of the endometrium. This can be prevented easily by inducing periods at least every three months with progesterone. If progesterone is taken for 5-10 days then stopped, there will be a well-timed complete shedding of the lining of the uterus. The abnormal cells are likely to be shed or not have time to initially develop. A biopsy of the lining of the uterus may be necessary to assure that substantial precancerous or cancerous cells are not present prior to use of progesterone withdrawal. This would most likely be necessary for women with prolonged abnormal uterine bleeding. In some cases a D&C of the uterine cavity may be necessary.
Impaired fertility, usually due to the woman’s inability to ovulate regularly.
Miscarriage rates are higher due to the effect of elevated LH levels on egg development and uterine lining.
Hair and skin problems—increased hair growth and acne from elevated testosterone levels.
Obesity—about 50% of women with PCOS are clinically obese.
Heart disease—It has been assumed for years that women with PCOS may be at a long-term increased risk of heart disease due to the unfavorable serum lipid profile produced by elevated androgens. However, recent clinical studies have followed women with PCOS for about 15 years. The reports show no increase in cardiovascular disease among women with PCOS. These women have been followed for about a decade into their postmenopausal years. Longer term follow up is still needed. However this is good news.
Abnormal insulin action—PCOS patients have a greater long-term risk of developing diabetes mellitus. The same long-term studies following women with PCOS have verified the increased risk of diabetes.
Breast milk secretion—30-40% of PCOS patients have an elevated serum prolactin level.

Prior to initiating fertility treatment, other factors which impact fertility are usually evaluated. These factors include tubal patency, pelvic anatomy, assessment of semen and sperm function, cervical mucous quality, presence of immunologic causes of infertility, and uterine anatomical abnormalities. In women with PCOS, failure to ovulate is the most common reason for not achieving pregnancy.

THE TREATMENT OF PCOS

In cases where ovulation is irregular or absent, medication can be used. The most common medication is clomiphene citrate (Clomid, Serophene), which is generally taken daily from days three through seven (3-7) or days five through nine (5-9) of a cycle. Ovarian follicle development is monitored with a combination of blood estrogen, blood progesterone, and office ultrasound examinations. hCG injectable medication may be used to control the timing of ovulation to coordinate with intercourse or artificial insemination. Intrauterine inseminations (IUI) are frequently advised because of clomiphene’s adverse effect on a woman’s cervical mucous quality. There is a mildly increased rate of multiple pregnancy with clomiphene (4-7%), but studies show that there is no increased risk of birth defects. The majority of women who conceive on clomiphene will do so in the first four (4) cycles. If clomiphene fails to successfully induce ovulation and/or pregnancy, then a group of injectable hormone preparations, known as gonadotropins, may be employed.

Metformin (Glucophage) is a medication Dr. Mersol-Barg may prescribe for women who have a polycystic ovary syndrome (PCOS). Some women with PCOS have high levels of the insulin hormone circulating in their blood stream known as hyperinsulinemia. A glucose/insulin challenge test will be done to determine if you have hyperinsulinemia. Women with PCOS and who are overweight are at risk for insulin resistance and hyperinsulinemia. The condition of hyperinsulinemia may impair the effectiveness of clomiphene to induce ovulation. Metformin reduces hyperinsulinemia. This reduction in hyperinsulinemia reduces the resistance to clomiphene, which enhances the effectiveness of clomiphene to promote ovulation. Some women with hyperinsulinemia may ovulate while taking Metformin without the need for clomiphene. If you have hyperinsulinemia, Dr. Mersol-Barg may recommend that you take Metformin with a low carbohydrate diet for 4 to 6 weeks before starting clomiphene therapy. You would continue Metformin therapy until you are pregnant.

Following a low carbohydrate diet under the supervision of an experienced nutritionist maximizes the treatment for women with PCOS and hyperinsulinemia. Women who strictly follow this program lose substantial weight. About 15 to 20% of women will resume their regular periods and ovulate on the Metformin/low carbohydrate diet combination therapy alone—no fertility medicines are necessary.

There are two types of gonadotropin preparations available. One contains both FSH and LH, and the other has only FSH. Although both types of gonadotropins work well in women with PCOS, many physicians prefer to use the products that contain primarily FSH. Therapy includes daily injections, with careful monitoring of ovarian follicle development by serum estradiol and progesterone hormone measurements and pelvic ultrasound examinations. When optimum growth and development of the follicle(s) has occurred, administration of human chorionic gonadotropin (hCG) is performed to stimulate release of the egg(s) from the follicle(s). The risk of multiple pregnancy is increased with gonadotropin therapy (15-20%). Women with PCOS who take gonadotropins are at an increased risk of an uncommon but potentially serious condition known as Ovarian Hyperstimulation Syndrome (OHSS). OHSS arises if an excessive number of follicles respond to the medication. Avoidance of OHSS is best achieved by careful monitoring of ovulation induction. This is the reason that virtually all fertility specialists are available 365 days a year for office ultrasound and clinical monitoring for their patients. There has been no clear evidence demonstrating that fertility drugs cause breast or ovary cancer. However, this question needs to be studied further to gain complete assurance that there is no cancer risk related to these medications. It is always wise to be as conservative as possible as to the number of treatment cycles in which a woman is exposed to these medications.

Laparoscopic laser drilling of the ovarian capsule is another treatment for PCOS. This usually results in resumption of regular ovulatory function. In some cases, regular ovulation persists for some time, whereas in other patients, irregular or absent menstrual function recurs. There is concern that this surgical treatment may cause scarring around the ovaries. This scarring (adhesions) can create a physical barrier that impairs the movement of the egg away from the ovary and prevents it from entering the fallopian tube. Thus fertility could be impaired by formation of adhesions.

In vitro fertilization (IVF) may also be an option for women with PCOS who wish to conceive after other treatment strategies have failed. Success (pregnancy) rates with IVF in PCOS patients are generally excellent, although a higher risk of OHSS exists, especially in IVF patients who become pregnant. Some women with PCOS do not respond to clomiphene and overrespond to gonadotropin therapy. These women who are overresponding to gonadotropins in the midst of a treatment cycle may choose to convert to IVF therapy at that time. IVF therapy allows for collection of all of the eggs produced that cycle. The eggs are then inseminated in the laboratory with her partner’s sperm. Although many embryos may form in the laboratory incubator, only a limited number (up to 2) are returned to the uterus. This allows for couples to avoid cancellation of their treatment cycles. They can continue their treatment cycle while substantially reducing their risk of high order multiple births (more than twins) and reducing their risk of severe ovarian hyperstimulation syndrome.

There is a cautionary note for women with PCOS considering fertility therapy. The ovaries are very unpredictable in nature. There are usually many follicles in constant turnover as previously described. With clomiphene or FSH fertility medications, an all or nothing response of the ovaries is more common in women with PCOS. “All” can mean 20 or more eggs are recruited. This means that there is a greater risk of an excessive number of eggs being recruited that could lead to adverse conditions that include:

High order multiple gestation and birth (more than twins).
Ovarian hyperstimulation syndrome with substantial health risks.
Cancellation of the treatment cycle to avoid the above listed risks.

Most women with PCOS respond very favorably to these fertility medications. There is good reason to have hope that treatment will result in having a baby—preferably one at a time.

SUMMARY

PCOS is the most common cause of menstrual irregularity in reproductive-age women and its occurrence may be associated with a variety of clinical symptoms, including infertility. There are known long-term health risks associated with PCOS. As a result, patients with this condition are advised to seek medical assistance because current therapies and treatments exist which may prove very beneficial.

PCOS is a lifelong disorder. The main focus of these medications is to enhance fertility, The Metformin/low carbohydrate diet combination therapy should be considered for women with PCOS regardless of their reproductive choices.