A silent syndrome with serious side effects

For most women, infrequent menstruation might seem like a lucky break. For physicians, however, oligomenorrhea in a patient should set off warning bells.

That's because about 10% of all premenopausal women and 80% of women with irregular periods have polycystic ovary syndrome (PCOS), a condition that can cause infertility, diabetes and/or metabolic syndrome, and distressing physical symptoms like hirsutism and alopecia.

The good news about the syndrome is that it's often responsive to treatment, once it's successfully detected. But primary care physicians sometimes fail to detect the disorder, either because they downplay the importance of the symptoms, or don't know the patient has them to begin with.

"To be diagnosed, patients would have to report hirsutism or difficulty conceiving or irregular menstrual periods, which they often don't, and many doctors don't inquire about those things, either," said Marianne Legato, FACP, professor of clinical medicine at Columbia University in New York City and a specialist in gender-specific medicine. "Many of these women are also obese, so anything that's unusual just gets written off to their obesity."

Defining PCOS

A single symptom may lead an internist to investigate a patient for PCOS, but more than one symptom is needed to make the diagnosis, said Ricardo Azziz, MD, chair of the department of obstetrics and gynecology, and director of the Center for Androgen-Related Disorders at Cedars-Sinai Medical Center in Los Angeles.

"PCOS isn't simply the presence of one symptom [doctors] think is sort of critical," Dr. Azziz said. "It's not just the ovaries or the irregular periods, and it certainly isn't the complaint of unwanted weight gain. It's a combination, a syndrome that has a fixed definition, or rather, three definitions, in the literature right now."

Those three definitions for PCOS are hotly debated. The most basic, stripped-down version sprang from a survey of speakers and attendees at an international National Institutes of Health conference about the syndrome in 1990. To be diagnosed with PCOS, it states, a woman must have infrequent ovulation, and clinical or biochemical signs of androgen excess.

The other two definitions of PCOS expand on the NIH version. The Rotterdam criteria, created in 2003 at a joint conference of a U.S. and a European medical society, says women can be diagnosed with PCOS if they have two of three symptoms: infrequent ovulation, androgen excess, or polycystic ovaries on ultrasound. These guidelines are much more popular in Europe, though some physicians in the U.S. also use them, Dr. Azziz said.

"The Rotterdam criteria broaden the definition by adding two new kinds of patients to the mix: those who had evidence of androgen excess and polycystic ovaries with normal ovulation, and those who had no evidence of androgen excess but had polycystic ovaries and irregular ovulation," Dr. Azziz said.

In 2006, the Androgen Excess society issued the third definition, a position statement for which Dr. Azziz was the lead author, that agreed with the Rotterdam criteria on the first group of patients, but not the second. As the name implies, the society believes there needs to be some kind of evidence of androgen excess for a patient to qualify as PCOS.

"The truth is, we know the NIH criteria are the core, but we don't know for certain which criteria are best, or how broad the phenotype is," Dr. Azziz acknowledged. "It often depends on where you are coming from—whether you are an endocrinologist, a dermatologist, a gynecologist—and the types of patients you are most likely to see."

Diagnosing PCOS: anovulation

For a general internist's purposes, the basic NIH definition of PCOS is probably sufficient, several experts said. The first step toward catching patients, then, is to be sure to ask all female patients about their periods during routine visits.

"If you take a menstrual history and it's abnormal, there is something wrong that needs to evaluated," said Andrea Dunaif, MD, head of endocrinology at the Feinberg School of Medicine at Northwestern University in Chicago.

Doctors also should inquire about the patient's use of birth control pills, said John C. Marshall, MD, an internist and endocrinologist at the University of Virginia Health Sciences Center in Charlottesville, Va.

"You give a patient a list to tick off in the waiting room, and one of the questions is 'Do you have regular periods?' A woman on the pill might answer "yes," even though her periods were irregular before she started taking the pill," Dr. Marshall said. "So then you miss the symptom completely."

Physicians should ask about family history, as well—especially whether a sister or mother had irregular periods. About 40% of sisters of women with PCOS also have some form of it, Dr. Dunaif said.

None of the three PCOS guidelines gives a threshold for the number of periods per year that are considered irregular, but Dr. Azziz puts it at less than 8-10 per year. (The range allows for taking other symptoms into account.)

Some patients will have irregular ovulation but still get regular periods, Dr. Azziz said.

"About 30% of the patients with PCOS by the NIH criteria will actually have regular vaginal bleeding episodes, but they don't ovulate. So our recommendation is that if a patient comes in with other symptoms, like unwanted hair growth or very oily skin, assess their ovulation by measuring progesterone in the luteal phase," Dr. Azziz said.

Internists who see adolescent or pre-adolescent girls in their office should know that the common belief that women don't get periods for years after menarche just isn't true, several experts said.

"Something like 90% of women develop regular monthly cycles within a year of their first period. So if someone is now 3-4 years down the line and she is having 4-6 periods a year, that's not normal," Dr. Marshall said.

Diagnosing PCOS: androgen excess

The clinical signs of androgen excess include hirsutism, and to a lesser extent, alopecia, acne and very oily skin. In the case of hirsutism, or hair growth in a male distribution pattern, it can be difficult for physicians to know exactly how much hair is abnormal. It also can be difficult to detect hirsutism at all, because some women remove the hair, have light-colored hair and skin, or feel embarrassed to report this symptom to their doctor.

"In general, patients who complain of 'unwanted hair growth' should be listened to, because many of them have already taken care of it and you can't notice it easily," Dr. Azziz said.

Physicians also should use the Ferriman-Gallwey score, the gold standard for evaluating hirsutism, or have patients fill it out. The measurement comprises a series of pictures that show increasing levels of hair growth in various areas, including the chin, upper lip, sideburns and pubic region. The more dense the hair growth, the higher the score; a score of 6-8 or higher is abnormal. The instrument is available online via the Endocrine Society's new guidelines on evaluating and treating hirsutism.

If a patient has irregular menses but no apparent signs of androgen excess, internists still should order tests to try to detect elevated androgen levels. Dr. Azziz recommends ordering high-quality radioimmunoassay and column chromatography, or mass spectrometry, to measure total testosterone. To get free testosterone levels, he advises ordering an equilibrium dialysis or competitive binding test.

"Many labs use not-very-accurate methods of assessment; they use direct assays, which aren't very helpful or useful. You have to check the labs out to make sure you will get high quality assays," Dr. Azziz said.

Obesity and age

Patients who are heavy in the mid-section, and/or have major difficulties losing weight despite dieting and exercise, are also candidates for possible PCOS, said Orli Etingin, MD, an internist and director of the Iris Cantor Women's Health Center in New York City. So are women with hypertriglyceridemia and low HDLs, even if they have no physical signs, she said.

In more than half of PCOS cases, the women are obese, which can lead physicians to over- and under-treat patients based on their weight, experts said. Thin or average-weight women may be overlooked, for example, because doctors expect PCOS patients to be obese.

Conversely, physicians who aren't clued in to PCOS may see an obese person and immediately focus their efforts on helping the patient lose weight, rather than digging deeper for a potential cause or consequence of the obesity. (Researchers still aren't sure about the causal direction between PCOS and obesity, though most suspect the disease usually comes first.)

Other physicians who are aware of the PCOS-obesity connection can be too likely to assume an obese person has PCOS, Dr. Azziz said.

"Very often, patients who complain of unwanted weight gain, or who come in with irregular periods, are given the diagnosis of PCOS, but when you look through the data, the syndrome itself isn't supported," said Dr. Azziz.

Another issue: It can be difficult to diagnose PCOS in a woman after age 40, because her ovaries shrink and her periods become more regular as she ages, said Corrine Welt, MD, an endocrinologist and assistant professor of medicine at Harvard Medical School in Boston.

"If a patient is older, and there are indications she had PCOS in the past—irregular menses, hair growth, etc., maybe you would start looking at all the cardiovascular and diabetes risk factors earlier, and monitor more regularly," Dr. Welt said.

The differential diagnosis

In order to confirm the diagnosis of PCOS, doctors need to rule out a host of other possibilities.

For anovulation, the alternative diagnoses include thyroid dysfunction, prolactin excess and late-onset congenital adrenal hyperplasia. If there are signs of virilization, physicians should consider an androgen-secreting tumor; Cushing's Disease should be ruled out as well, said Richard Legro, MD, professor of obstetrics and gynecology at Penn State University in State College, Pa.

"Frequently we do a TSH, a prolactin level, a 17-Hydroxyprogesterone to rule out adult onset adrenal hyperplasias, and testosterone levels, as much to make the diagnosis as to exclude very high testosterone levels, which would probably not be PCOS but another cause like a tumor," Dr. Legro said. "Another test I tend to send is an FSH level to rule out ovarian failure, though that is relatively rare."

Physicians who decide to look at the ovaries via ultrasound should know that "polycystic" means at least one ovary with a volume greater than 10 mm, or 12+ follicles that measure 2-9 mm in diameter.

Treating PCOS

The main treatment for women with PCOS is weight loss for those who are overweight and obese, and reducing the degree of insulin resistance, usually with metformin, Dr. Legato said.

Some physicians tend to prescribe metformin to every single patient who is diagnosed with PCOS, which is not a responsible use of the drug, Dr. Azziz said. In fact, the majority of patients will require combination therapy of some sort, including lifestyle changes and cosmetic treatments for appearance.

"Metformin is not the answer-all. It's particularly helpful for patients who want to reduce their long-term risk of glucose intolerance, but it is not a weight loss medication. It acts by reducing insulin levels somewhat, and indirectly lowers androgen levels somewhat, which indirectly lowers hair growth and ovulatory dysfunction," Dr. Azziz said. "But these are all indirect, which is why metformin isn't always as helpful as we'd like."

Internists will treat most patients for complaints like excess hair growth, irregular periods or obesity, as well, Dr. Azziz said.

Treating hirsutism usually requires a combination of hormonal suppression using either birth control pills or metformin plus an antiandrogen like spironolactone or flutamide or finasteride, he added.

Because of the apparent link between PCOS, diabetes and cardiovascular disease, one should test and re-test a woman with PCOS for lipids, fasting glucose levels and body mass index (BMI), experts said.

If glucose and lipid levels appear normal, they should be re-tested every year and five years, respectively. For abnormal levels, it depends on the person's profile—the levels, family history, etc., Dr. Dunaif said. Since PCOS appears to be heritable, family members should have these markers tested, too, she added.

Thin women with PCOS are less likely to be insulin resistant, Dr. Welt said. For those who aren't looking to get pregnant, the treatment would be to prescribe birth control pills to regulate the periods, encourage a good diet and exercise, and monitor lipids and glucose levels regularly.

When to refer

Opinions differ on the point at which a general internist should refer a PCOS patient to a specialist, such as an endocrinologist or an OB-GYN. A few believe it should be done as soon as the diagnosis is made, but most think a general internist can handle many elements of treatment.

"An astute internist should be able to recognize PCOS in all its forms and presentations, and diagnose it. From that point, for most women with PCOS, care should be in tandem," Dr. Etingin said. "Internists can take care of the diabetes and high cholesterol and weight issues, but the patient belongs in the hands of a gynecologist for fertility issues."

Others believe an internist is the ideal physician to diagnose and care for a patient with PCOS, because the syndrome is life-long and involves different systems.

"To manage PCOS, you need to be an astute clinician who takes a complete history and physical, and follows up on your patients," said George Sarka, FACP, associate clinical professor of medicine at University of California-Los Angeles and ACP Governor for Southern California, Region II. "Practically speaking, it also helps build your practice, because the syndrome is not rare, and involves following a young person through the course of her life."

For Dr. Azziz, it is a matter of whether the internist has the time and motivation to care for patients with a complex disease.

"It's no different than diabetes. You need to understand the medical and dietary options, the long-term impact of the disease, etc.," Dr. Azziz said. "If an internist is going to keep up with the latest literature, and understand that the field is changing rapidly, and understand how to assess and treat the disease, I think he or she can take care of PCOS."