Polycystic Ovarian Syndrome (PCOS)
Polycystic ovary disease (PCOD) was first reported in 1935 by two gynecological physicians in Chicago, Drs. Stein and Leventhal, who noticed women with irregular cycles and facial hair had small fluid filled sacs in both ovaries, therefore coined the name polycystic ovarian syndrome.
Over time, and with the advent of new technologies, other defining abnormalities have been attributed to this disorder making the term polycystic ovary syndrome (PCOS) more accurate description. Women with this diagnosis have an increase risk for hypertension, cardiovascular disease, stroke, and type 2 diabetes. PCOS, is estimated to affect approximately 10 percent of women, which implies that approximately 3 million reproductive – aged women in the United States have PCOS.
Despite increasing recognition this condition is among the most underdiagnosed syndromes and the most common cause of infertility in this population. One major problem is the definition of PCOS is still being debated among the leading researchers in this field.
Definition
At the PCOS Consensus Conference in 2003, the National Institutes of Health – National Institute of Child Health and Human Development (NIH-NICHHD) expanded on the clinical definition of PCOS.
To be diagnosed with PCOS a women needs 2 of the following; multiple cystic areas on the ovaries by ultrasound, hyperandrogenism (elevated testosterone and androstenedione), and / or long term absence of ovulation in women that was not the result of a specific underlying disease of the pituitary or adrenal glands.
Clinical features
Clinically, women present with concerns regarding irregular menstrual cycles, hirsutism, or obesity. However, affected women may complain of profuse heavy vaginal bleeding without hirsutism and may be of normal weight.
By ultrasound the ovaries are increased in size due to enlargement of the cells that produce androgens (stroma cells). Around the periphery of the ovary multiple small, < 10mm, follicles are seen secondary to the hormonal imbalance that prevents the follicles from maturing normally.
Not all women with polycystic appearing ovaries have the complete syndrome. Approximately 20 percent of all reproductive aged women have multiple cystic areas on their ovaries but do not have PCOS. Therefore, polycystic ovaries are not a decisive criteria to diagnose PCOS, but it is a combination of laboratory, clinical, and ultrasound findings.
Clinical Criteria:
- Chronic anovulation
- Clinical signs of androgen excess
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Hirsuitism
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Menstrual Irregularities
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Virilization
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Infertility
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Acne
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Alopecia
- Polycystic Ovaries
- > 8 follicular cysts < 10 mm in diameter
- Exclude other causes for elevated androgens
Diagnosis
The diagnosis of PCOS is made by ruling out other causes for your symptoms. After reviewing your medical history and performing a physical exam, your physician will determine which tests are necessary.
If you have irregular or absent menstrual periods, the first concern is pregnancy. A pregnancy test would be ordered with the initial blood tests. Your height and weight will be noted along with any increase facial or body hair, loss of scalp hair, acne and acanthosis nigricans, which is a discoloration of the skin under the arms, nape of the neck, under the breasts and in the groin area.
Laboratory testing is needed to make sure you do not have other conditions such as Cushing's disease / syndrome (overproduction of a male hormone called androgens), thyroid problems, congenital adrenal hyperplasia or increased prolactin production by the pituitary gland.
Initial hormone testing includes TSH, prolactin, 17-hydroxyprogesterone, DHEAS, and testosterone. Based on these results would determine if further provocative testing is warranted. Elevated androgen levels (male hormones) such as androstenedione, DHEAS or testosterone can confirm the diagnosis of PCOS.
Hormones from the pituitary gland Lutinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) are disproportionate. The LH to FSH ratio is usually greater than 2:1, which causes menstrual irregularities and elevated androgens.
These values are not absolute because 30 percent of normally ovulating women have this finding. Therefore, we use this information along with the other test results to confirm this diagnosis.
Insulin Resistance with PCOS
Insulin resistance is defined as the decreased ability of insulin to stimulate glucose transport into the target tissue. This is seen in approximately 50 percent of women diagnosied with PCOS. Of these approximately 40 percent of women will demonstrate some degree of diabetes mellitus by the third or fourth decade of life.
Therefore it is imperative to screen all women suspected to have PCOS for insulin resistance and diabetes mellitus. A fasting glucose to insulin ratio of less than 4.5 is predictive of insulin resistance.
Some women may have a normal ratio but produce higher levels of insulin to keep glucose levels in the normal range. Therefore, in those with high insulin levels a two hour glucose tolerance test is more sensitive in detecting impairment.
We do not fully understand why women develop PCOS. There are women who demonstrate polycystic appearing ovaries on ultrasound but have regular menstrual cycles and no signs of excess androgens while other women develop the entire syndrome associated with PCOS.
One major biochemical feature of polycystic ovary syndrome is insulin resistance which causes a compensatory hyperinsulinemia (elevated fasting blood insulin levels) state. There is increasing data that hyperinsulinemia produces the hyperandrogenism of polycystic ovary syndrome by increasing ovarian androgen production, particularly testosterone and androstenedione and by decreasing the serum sex hormone binding globulin concentration from th liver.
The high levels of androgenic hormones interfere with the pituitary ovarian axis, leading to increased LH levels, anovulation, amenorrhea, and infertility. Hyperinsulinemia has also been associated high blood pressure and increased clot formation and appears to be a major risk factor for the development of heart disease, stroke and type II diabetes.
Obesity
Obesity is known to be a risk factor for type II diabetes mellitus but is also a common characteristic of women with PCOS. Obesity has been reported in 35 percent to 80 percent of women with PCOS. Truncal obesity, identified by a high waist to height ratio, or a body mass index greater than 26, have a higher free androgen levels and higher degree of insulin resistance.
Genetics
Recent studies suggest a genetic basis for PCOS. Prevalence of PCOS these cases occur within families of affected women. These genetic abnormalities cause alterations in pathways involved in hormone production and steroid actions in the body.
In addition, the high prevalence of insulin resistance and abnormalities in insulin secretion suggests the gene for insulin and/or its receptor may be involved.
Treatment goals
Treatment should be tailored for the individual women’s needs. The therapeutic goals include:
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Reversing the symptoms of androgen excess and hirsutism.
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Establish cyclic menstruation.
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Addressing the metabolic problems such as insulin resistance with weight loss, exercise and medication.
Treatment options
Hirsutism/Facial Hair
The cosmetic problem of increased facial hair and acne brings many women to the doctor. This is due to an increased amount of androgens which affect the skin . Oral contraceptives have several clear benefits in treating this condition:
It usually takes 8 – 10 months to see an improvement. Oral contraceptives can also cause regular withdrawal bleeding which reduces the risk for endometrial hyperplasia, a precursor for uterine cancer.
If symptoms still persist then spironolactone, Aldactone, is added. This is a blood pressure medication but it also blocks the androgen hormone at the receptor at the skin level. We usually start off at a low dose and increase slowly over 1 month. Side effects include lightheadedness, dizziness and low blood pressure. Other anti – androgen medications have been used, flutamide or finasteride, but the side effects could be severe.
Fertility
Infertility treatments include weight loss diets, use of ovulation medications (clomiphene, Follistim, Gonal-F, Bravelle), ovarian drilling surgery and IVF.
Ovarian drilling can be performed during laparoscopy. Using an electrosurgical needle or a laser the ovary is punctured approximately 10- to 12 times. This treatment results in a dramatic lowering of the male hormones, androgens, within a few days.
Studies have shown that this is effective in helping PCOS women ovulate in up to 80 percent of cases. Many who failed to ovulate with medical treatment will respond when to these medications after ovarian drilling.
Ovarian drilling can cause ovarian failure or pelvic adhesions, which could affect the fallopian tubes. Therefore, this procedure is indicated in those who want conservative fertility treatment and avoid aggressive medical treatment.
Recently, using insulin lowering medications such as metformin, (Glucophage 500 or 850 mg three times per day or 1000mg twice daily with meals), pioglitazone (Actos 15-30 mg once a day), rosiglitazone (Avandia 4-8 mg once daily) or a combination of these medications have been shown ameliorates hyperandrogenism, by reducing ovarian enzyme activity that results in male hormone production. These medications have been shown to reverse the endocrine abnormalities seen with polycystic ovary syndrome within two or three months.
This results in decreased hair loss, diminished facial and body hair growth, regulation of menses, weight loss and restores normal fertility. We have seen pregnancies result in approximately 3 months after initiating these medications.
Literature suggests that women with PCOS and Insulin Resistance can develop medical problems that can affect them in the future. The metabolic consequences include high blood pressure, elevated triglyceride / cholesterol levels, elevated blood clotting factors, heart problems, and arteriosclerosis which is associated with strokes and heart attacks. Treating this condition early may help ameliorate future health problems.
Metaformin (Glucophage)
Metformin improves insulin sensitivity by significantly reducing sugar production from the liver. When you start taking this medication, you may experience an upset stomach or diarrhea. This usually resolves after the first week but could take up to one month.
The side effects can be minimized by taking metformin with a meal and starting with a low dose. We recommend our patients start with one 500 mg pill daily for the first week and increase to twice a day during the second week, followed by one pill three times a day. If needed, after two months we can change the dose to 850 mg twice daily.
When beginning metformin we obtain blood work that evaluates liver and kidney function. Women with reduced kidney (renal) function are at a higher risk for a rare side effect called lactic acidosis, and should not be used.
Pioglitazone, (Actos), Rosiglitazone, (Avandia)
These medications belong to a class of medications called PPAR gamma agonists. They enhance peripheral glucose utilization in smooth muscle and pancreatic function. This improves metabolic abnormalities, decreases androgen production, increases sex-hormone binding globulins, and reduces the ability for blood clotting problems.
Monitoring therapy
With metformin, you will return to our office in three months after initiating therapy. Women taking rosiglitazone or pioglitazone will be seen at two month intervals for monitoring liver function tests.
If you have had regular cycles within three months therapy you may continue this treatment for an additional three months, or you could elect to proceed with fertility medication. If you have not become regular, we would discuss adding fertility medication to facilitate ovulation.
The type of fertility medication used is dependent on your age, baseline blood work, prior history, and your desire for aggressive fertility methods.
Pregnancy
Metformin has been shown to reduce the incidence of first trimester losses in women with PCOS and Insulin Resistance. Continuing this medication throughout the pregnancy has reduced the risk of developing gestational diabetes.
To date, there have not been any reports of abnormal babies in women who conceived using metformin or continued this medication throughout pregnancy. Metformin is a category B medication, meaning that insufficient human data is available but no animal data suggesting a risk for birth defects.
PCOS and Miscarriages
Women with PCOS who conceive either spontaneously or after ovulation induction with fertility medication have an increased risk of miscarriage. The cause for this is still unclear. Hypersecretion of LH and high androgen levels appear to be the contributory factors. The high LH level could potentate the production of immature eggs and poor embryos. The elevated androgens could adversely affect the uterine lining and implantation
Hyperinsulinemia may also be a contributing factor in the higher rate of miscarriage. Elevated levels of insulin interfere with the normal balance between factors promoting blood clotting and those promoting breakdown of the clots.
Increases in plasminogen activator inhibitor activity (PAI-Fx) associated with high insulin levels may result in increased blood clotting at the interface between the uterine lining (endometrium) and the placenta. This could lead to placental insufficiency and miscarriage.
There have been several studies to indicate pregnancy outcomes are improved in pregnancies conceived while on insulin-lowering medications. These medications lower androgen and LH levels and therefore potentially improving egg quality and the uterine environment.