From the February ACP Internist, copyright © 2009 by the American College of Physicians
By Jessica Berthold
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.”
PCOS poses serious associated risks to women
Diabetes. A woman with PCOS has at least twice the
risk of developing diabetes if she's thin, and four times the risk if
she's obese, experts said.
Coronary heart disease. There is some evidence
that women with PCOS are more prone to heart disease, perhaps due to
higher androgen levels. A prospective cohort study of 82,439 female
nurses found that those who reported menstrual irregularity in 1982,
when they were age 20-35, had a higher risk of coronary heart disease 14
years later, even when controlling for body mass index. (Journal of Clinical Endocrinology and Metabolism, May 2002).
Endometrial cancer. Reduced ovulation leads to
deficient progesterone secretion. Chronic estrogen stimulation without
progesterone may then lead to breakthrough bleeding, dysfunctional
uterine bleeding and endometrial hyperplasia. “Women with PCOS also
often have additional risk factors for endometrial cancer, like chronic
high levels of insulin, increased serum insulin-like growth factor
called IGF-1, high androgen levels and obesity,” said Marianne Legato,
FACP, professor of clinical medicine at Columbia University in New York
City.
Infertility. Anovulation is better discovered
sooner rather than later, said George Sarka, FACP, associate clinical
professor of medicine at University of California-Los Angeles and ACP
governor of southern California, region II. “I've had women in their 30s
cry in front of me because they wished they had been told about their
PCOS sooner. They would have tried to have kids before getting their
PhDs.”
What's in a name?
Experts debate the precise definition and characteristics of PCOS,
but many agree on one thing: It's less about polycystic ovaries than
about other markers, like insulin resistance, menstrual cycles and
androgen levels. Indeed, a growing number of researchers are arguing that PCOS
should either have a new name, or at least, a second name should be
added to the first.
“I routinely spend 10 minutes with recently diagnosed women
explaining that they do not, in fact, have cysts in the ovaries, just
normal follicles that are arrested in their early stage of development,”
said Andrea Dunaif, MD, head of endocrinology at the Feinberg School of
Medicine, Northwestern University.
Dr. Dunaif proposes calling the disorder either “Female Metabolic
Syndrome” or “Syndrome XX”, because Syndrome X was the former name for
metabolic syndrome. Changing the name of a disorder that's been around for awhile is a
steep hill to climb, however, said Richard Legro, MD, professor of
obstetrics and gynecology at Penn State University. “Over the years,
people have tried to come up with a better name for it, but it is just
hard to change a name once it has been established.”
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