Shahab S. Minassian, M.D.
IVF-Fertility Division, Women's Clinic, Ltd.
Section Chief, Fertility and Reproductive Endocrinology
The Reading Hospital and Medical Center
Clinical Associate Professor, Drexel University College of Medicine
The changes are gradual but no less frustrating. Weight gain, excessive hair
growth, acne and a steadily worsening irregularity of menstrual periods begin to
surface. Fertility, once thought to be a natural process, is impaired. After its formal
reports in the medical literature and for decades in modern times, the diagnosis, treatment and
health risks of Polycystic Ovarian Syndrome (PCOS) have afflicted patients and perplexed their
physicians. However recent advances in the knowledge of this common syndrome, especially in the
area of insulin resistance, have helped everyone involved to better understand the problems PCOS
causes and turn to newer, more effective treatments to combat them. It is hoped that this will
serve as an overview to our readers and offer them hope that was not available until recently.
Women have most likely been affected by PCOS as a disease for a very long time. However,
it wasn't until a French physician reported the appearance of polycystic ovaries in the mid 1800's
that brought it to the attention of the medical community. Gradually more reports surfaced
including surgical recommendations for treatment, most notably the “wedge resection”, in which
wedge-shaped portions of the ovaries were removed. In 1935 Stein and Leventhal, two gynecologists
from Chicago, described the symptoms of PCOS (immediately named the Stein-Leventhal Syndrome), and
noticed that they disappeared, at least for a while, after the wedge resections were done. These
patients were for the most part overweight, infertile, hirsute and had a lack of periods. Since
those reports many if not most physicians, until recently, have thought of PCOS in this way. There
are, however, a significant number of patient who are not overweight, or may have one or a few of
these symptoms. In 1990, an NIH consensus conference defined PCOS as the finding
of elevated androgens and impaired (irregular)
ovulation when the hormonal diseases of congenital adrenal hyperplasia (an
inherited enzyme disorder), elevated prolactin, thyroid disease and Cushing's syndrome were
excluded. Later on, in 2003, a conference of specialists in the field held in Rotterdam, Netherlands
proposed a modification of the definition. They supported the finding of polycystic ovaries during
ultrasounds as part of the criteria to diagnose PCOS. They also proposed that PCOS can be
diagnosed even if a woman has regular periods. This definition is accepted by many PCOS specialists
worldwide, as is the NIH definition. Needless to say there is a great worldwide controversy going
on about the definition of PCOS.
Not all patients have all of the symptoms of PCOS. Hirsutism (90%), menstrual
irregularities (90%) and infertility (75%) are the most common. Polycystic ovaries can be seen on
ultrasound in many (84%). Excessive weight is commonly seen but not exclusive (50%). Insulin
resistance is a rather newly found problem (up to 70% of PCOS patients have proven insulin resistance, but
many more – if not all - probably have it as well). Insulin resistance can be so serious in some patients
that Type 2 (adult-type) diabetes has been found in up to 7% of PCOS patients. How common is PCOS? Much
work has been and continues to be done in this area. The answer may depend on many factors, including
how it's diagnosed or who is being diagnosed. If ultrasound is the only way used, over 20% of all
women have polycystic ovaries. If only irregular periods are used about 10% have PCOS. Ethnicity plays
a major role. For example, Caucasians and African-American women have a 4% incidence, but certain Native
American groups have an over 20% incidence. Greek women (9%) and perhaps certain Latino groups have a
higher incidence. There is emerging evidence that PCOS may be transmitted in some families themselves
through genetics. These facts lead many researchers to suggest that PCOS may be an inherited problem in
some women. Insulin resistance appears to be inherited too. Can this be a partial answer?
In an effort to confirm a PCOS diagnosis, and to locate a possible source of the
problem, doctors will turn to physical exams, laboratory tests and imaging tests. Women with PCOS
and excessive weight tend to have more fat tissue at the waist and upper body. In addition to the usual
weight and height measurements, the waist-hip ratio and body-mass index are then excellent tools to
evaluate excessive weight. Common blood tests include androgen levels (testosterone, DHEA-sulfate,
17-hydroxyprogesterone, androstenedione for example). Many women have increased LH (luteinizing hormone)
levels compared to FSH (follicle-stimulating hormone), resulting in an elevated LH to FSH ratio. However
the elevated LH to FSH ratio is not a definitive way to diagnose PCOS. Vaginal ultrasound is an
increasingly popular test. The ovaries are seen to have a polycystic appearance, a bit enlarged and with
collections of small follicle cysts lining the outer edge, just under the surface. This finding is called
the “pearl necklace”, “string of pearls” or “necklace” sign. Ultrasound alone, however, is not a
definitive way to diagnose PCOS.
The current opinion of many PCOS researchers is that it is a syndrome with more than
one cause. Two have been most often proposed: (1) insulin resistance and (2) some type of abnormality in
the way the ovary produces hormones (androgens and estrogens). Insulin resistance is strongly linked to
PCOS. In this problem the cells of the body cannot process insulin, to keep the blood sugar normal, very
efficiently. Excessive weight further aggravates the insulin resistance. The body will compensate by
making more insulin. The excessive insulin stimulates the ovary to make androgens. Additionally, it's
difficult to lose weight when insulin levels are elevated, further compounding the problem. At least one
third of patients with PCOS can have insulin resistance. In the second case, some researchers have
proposed that a gene defect may force the ovary into making the excessive androgens. Either way, the
androgens will cause follicles, normally trying to mature and ovulate, to stop growing. The follicles
collect in the ovary (making it appear polycystic), and eventually degenerate. The androgens also may
create excessive hair and/or acne. One area that is much less studied, but may be important, is the
effect of stress on PCOS. There have been some older and more recent reports that PCOS patients score
higher on anxiety or other psychological testing. Adding stress reduction techniques seems to help with
PCOS treatments.
PCOS is a syndrome with both short and long term risks to women. In the short term, it
can cause infertility and/or uncontrolled or irregular vaginal bleeding (dysfunctional uterine bleeding)
with the possibility of anemia. The infertility results from as obvious a problem as a lack of ovulation
to as subtle a problem as sub-optimal ovulation (such as luteal phase defect). Irregular bleeding,
spotting or staining, which can plague women for weeks or months, is due to a lack of ovulation which
would ordinarily cause a regular monthly shedding of the uterine lining (endometrium). The endometrium
continues to grow in thickness despite the lack of regularity eventually breaks down in a disorderly
way. Many of the longer-term risks of PCOS have been known for years, but others are just recently being
discovered and studied. Women who have PCOS with insulin resistance (most if not all do) will have a much
higher risk of Type 2 (adult type) diabetes later in life. These women also have a higher risk for
“dyslipidemias”: high blood levels of cholesterol or other lipid substances. High blood pressure is more
common. For this reason, most PCOS researchers feel that there is a higher rate of heart disease and
atherosclerosis in women with PCOS. There is also increasing evidence that women with PCOS have a higher
risk for “fatty liver”, a metabolic disease which increases risks for liver failure later in life. Cancer
of the endometrium is a long-term risk that has been known for decades. Women with PCOS do make enough
estrogen to grow their endometrium (much of it from their body fat) but without regular shedding of the
lining it can grow uncontrollably. Without ovulation there is no progesterone (hormone of ovulation) to
oppose this effect of the estrogen. After many years this “unopposed estrogen” may lead to a precancerous
condition of “hyperplasia”, which may eventually lead to cancer. Some studies have suggested that PCOS
may be linked to a slightly higher chance of ovarian cancer but more work needs to be done. It was
previously thought that PCOS may lead to a higher breast cancer risk but this evidence is not quite
solid. One new area of research has looked at the risks for pregnancy complications in women with PCOS
once they conceive. Miscarriage rates seem to be higher and may be related to their higher androgen or
LH levels. Gestational diabetes risks can run up to 30%, and a recent report has studied a possible PCOS
link to pre-eclampsia during pregnancy.
The workup for PCOS should include a thorough physical and pelvic examination, laboratory
testing, perhaps imaging studies, and definitely counseling as to the risks and treatment choices (which
may be different for individual patients). Of course, excessive weight (women with PCOS tend to gain
weight in the upper body and trunk more than in the hips and thighs) excess hair growth and acne are
looked for. Noticeable skin problems that are suspicious for insulin resistance are acanthosis nigricans,
a brownish, raised skin discoloration in the body folds (neck, armpits, groin) and “skin tags” scattered
over the skin. If the woman has a long history of irregular bleeding an endometrial biopsy may need to be
performed to check for the above endometrial changes. Hormonal testing for other hormonal diseases that
can mimic PCOS must be drawn. Diabetes screening is critical. The 2 hour glucose tolerance test (GTT) is
the most effective office-based test available for diabetes screening. It is recommended by the AE-PCOS
Society that all women diagnosed with PCOS have this test done. This test “stresses the system” to
uncover the diagnosis by drawing a fasting glucose level, then having the patient drink a “glucola”
solution and drawing a glucose level 2 hours later. Some doctors will order insulin levels with these
glucose levels to help diagnose insulin resistance. Another way to check for insulin resistance has been
the fasting glucose:insulin ratio. This one time fasting blood test checks the baseline levels of the
patient's blood sugar and insulin. However, this test seems to be only 85% effective and is not reliable
enough to screen patients for prediabetes and diabetes. A fasting lipid profile (cholesterol, LDL, HDL,
triglycerides) should also be drawn. Liver enzyme blood tests are useful for fatty liver screening.
The treatment of PCOS has been noticeably changed in recent years. Medications for
insulin resistance, the “insulin sensitizers”, have helped many patients. These medications lower
insulin levels; androgen levels drop and menstrual cycles return. The most studied and prescribed is
metformin. It is at least 75% effective for the return of cycles in recent studies, in women with PCOS
and insulin resistance. Many patients will report some weight loss initially on this drug, however it is
usually short-lived unless lifestyle modification (see below) is done. Side effects of metformin can
include gastrointestinal distress (diarrhea, loose bowels, bloating). Newer sensitizers include
pioglitazone (Actos) and rosiglitazone (Avandia). These are less well studied but can provide an
alternative to metformin if needed, and are known to cause some weight gain and water retention. Liver
and kidney problems are extremely unlikely in a non-diabetic but blood pre-screening and occasional
monitoring for these problems while should be done while taking these medications. PCOS treatment really
does depend on the individual medical circumstances, and goals, of the patient. If she wants fertility
treatment clomiphene citrate (Clomid, Serophene), the oral fertility drug, is usually prescribed. If she
is insulin resistant, taking metformin or another insulin sensitizer alone is now becoming an option. Some
specialists will even give both drugs together. As a last resort ovarian drilling, a same day surgery
laparoscopic procedure that is a new version of the old wedge resection, has been shown to at least
temporarily make periods regular. However, this approach does lead to scarring of the ovaries in at least
20% of women, has not been proven to help against insulin resistance, and many will return to irregular
periods eventually. Women who are not currently interested in fertility have many options too. Whether
insulin resistant or not, oral contraceptives can regulate bleeding to prevent dysfunctional bleeding and
uterine cancer risks, and treat acne. If they are insulin resistant, insulin sensitizers can be given to
allow for regular periods and prevent the long-term effects of PCOS. The sensitizers will let ovulation
occur so sexually active women must use care to avoid unwanted pregnancies. In fact, some specialists are
using oral contraceptives and sensitizers together to prevent this. Metformin treatment can help in
reducing hirsutism, which also can be very well treated with oral contraceptives alone or together with
the drug spironolactone, which lowers androgens. Vaniqua, a new prescription cream, looks about 50%
effective for excessive facial hair. Of course, whether wanting to conceive or not, a great way to treat
PCOS is by lifestyle alterations including diet, exercise and stress reduction. Weight loss in women with
excessive weight can help their response to medications, or for some may even eliminate the need for them.
Low carbohydrate (probably more effective) or low calorie diets can be very useful for weight loss in
insulin resistant women. Exercise is essential for weight loss, and diet and exercise must be used
together for the best results. Cardio exercise is most effective, although adding a smaller percentage of
resistance to exercise regimens is also beneficial. Stress reduction can be accomplished in many
ways. “Western” methods like biofeedback have been advocated, as well as “Eastern” methods like
meditation, tai chi, chi kung and yoga. Anything to reduce stress that is enjoyable, and therefore can be
counted on for long-term use, is advisable. In the complementary medicine area, acupuncture has been shown
in some small Mainland Chinese and European studies, and one from our group that was the first report in
North America, to allow ovulation and regular periods to occur. The treatment options for women with PCOS
have certainly increased!
The diagnosis of PCOS results in a lot of questions, frustrations and anxiety for many
patients. Through the ongoing efforts and partnership of physicians, researchers and patients, the
syndrome of PCOS has and will continue to become less of a mystery. The goals of fertility and good health
are now within reach for women with PCOS.
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