Polycystic ovary syndrome (PCOS) is a common endocrine disorder, but it remains shrouded in uncertainty due to its varying diagnostic criteria and its misleading name. This uncertainty, in turn, can affect the patient-physician relationship.
Women with PCOS, who commonly experience symptoms such as irregular or skipped menstrual periods, excess hair growth, acne, and weight gain, often go years without a diagnosis or go online to diagnose themselves. Given this, it may not be surprising that many are unsatisfied with their health care experiences.
In one survey of 1,385 women with PCOS, about 34% reported a time to diagnosis of more than two years, and about 47% reported seeing at least three clinicians in the process, according to results published in February 2017 by the Journal of Clinical Endocrinology and Metabolism. Overall, about 35% said they were satisfied with their diagnosis experience, and only 16% were satisfied with the information they received about PCOS.
Although the prevalence of PCOS depends on the diagnostic criteria used, it is the most common reproductive disorder in the world, affecting an estimated 8% to 20% of reproductive-age women, according to an article published in December 2013 in Clinical Epidemiology. As a PCOS researcher, Marla E. Lujan, PhD, noticed that many study participants had incorrect or uncertain diagnoses. “They were coming to us as researchers to learn about PCOS because they weren't getting sufficient information or information that they trusted from their primary care physicians, or specialists for that matter,” said Dr. Lujan, an associate professor of human nutrition at Cornell University in Ithaca, N.Y.
To quantify patients' trust in their doctors regarding the condition, her research group surveyed 332 U.S. women. Overall, having PCOS was associated with significantly greater distrust in the primary care physician's opinion and significantly more patient-clinician arguments compared to the control group of women with regular menses, according to results published in the September 2018 Journal of the Endocrine Society.
For Dr. Lujan, the results suggest two areas to target: building trust, often through candid conversations about what the practitioner is comfortable diagnosing or not diagnosing, and building social support by making time to listen to patients' concerns without judgment. “I think they're very doable if there's acknowledgment on the part of the practitioner that these areas are important to the patient-provider relationship,” she said.
To build trust and social support with patients, experts said frontline practitioners could focus on two simple characteristics of the syndrome, become familiar with the confusion around the condition's name, and keep a few pearls in mind along the way.
PCOS has several phenotypes, depending on the diagnostic criteria applied, but characteristics of the disorder generally include elevated androgen levels, ovulatory dysfunction, and “polycystic ovarian morphology” on ultrasound.
This last point is a major source of confusion. In fact, the term “polycystic” is a misnomer, as the multiple resting antral follicles commonly seen on the ovaries of women with PCOS are not technically cysts, noted Nicole Banks, MD, a reproductive endocrinologist and clinical geneticist at VCU Health in Richmond, Va. Yet, patients with PCOS will often say their doctor told them they have cysts on their ovaries, she said.
“A lot of the time, it's helpful … to explain that the term is a little bit misleading and that they don't have cysts on their ovaries,” Dr. Banks said.
In addition, changes in ovarian morphology are not essential to make the diagnosis. The diagnostic criteria established in 1990 by the National Institutes of Health (NIH) specify that patients must have chronic anovulation and clinical and/or biochemical signs of hyperandrogenism. PCOS is commonly associated with insulin resistance, glucose intolerance, and obesity, and there is expert consensus that the NIH phenotype is associated with the greatest metabolic risk, noted Andrea Dunaif, MD, professor of molecular medicine at Icahn School of Medicine and system chief of the division of endocrinology, diabetes, and bone disease at Mount Sinai Health System in New York City.
The broader Rotterdam PCOS diagnostic criteria, established in 2003, require any two of these three symptoms: 1) oligo- or anovulation, 2) clinical and/or biochemical signs of hyperandrogenism, and 3) polycystic ovaries, in addition to exclusion of other causes (e.g., congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome). Both the NIH and Rotterdam recommendations are based on expert opinion.
In 2012, an NIH evidence-based methodology workshop panel recommended maintaining the inclusionary Rotterdam criteria while specifying four phenotypes: 1) androgen excess and ovulatory dysfunction, 2) androgen excess and polycystic ovarian morphology, 3) ovulatory dysfunction and polycystic ovarian morphology, and 4) androgen excess, ovulatory dysfunction, and polycystic ovarian morphology. (The panel also recommended changing the name of the syndrome, calling it “a distraction and an impediment to progress.”)
Most recently, in July 2018, an international panel of experts released 166 clinical practice points and recommendations about PCOS, published in Fertility and Sterility, and endorsed the Rotterdam criteria in adults. When both oligo- or anovulation and hyperandrogenism are present, an ovarian ultrasound is unnecessary but can identify the complete PCOS phenotype, they wrote.
One of the authors, Anuja Dokras, MD, PhD, said the new recommendations will help standardize care throughout the world, especially in nonspecialty centers. “I think [PCOS] can be very competently addressed in primary care. … It's so common that our patients need to see a physician locally,” she said.
However, there are very little data on how to best manage PCOS-related metabolic complications, Dr. Dunaif added. “For example, it is not known whether metformin and lifestyle modification are as effective at preventing diabetes in women with PCOS as these modalities are in the general population,” she said.
Most women with PCOS commonly present with symptoms by the end of their teenage years or early 20s, said Dr. Dokras, professor of obstetrics and gynecology at the Perelman School of Medicine of the University of Pennsylvania and director of the Penn PCOS Center in Philadelphia. “It's very rare that somebody's going to present for the first time in their 30s or 40s,” she said. “In fact, a lot of the symptoms of PCOS get better by the late 30s and 40s.”
The new guidelines outline the myriad health concerns in women with PCOS, such as a fourfold increased risk of type 2 diabetes in the U.S. “Indeed, PCOS is a leading risk factor for prediabetes and type 2 diabetes in adolescent and young adult women,” said Dr. Dunaif. “Women with PCOS are also at increased risk for other disorders associated with insulin resistance, such as gestational diabetes and metabolic syndrome.” Ovulatory dysfunction in PCOS is associated with infertility and an increased risk of endometrial cancer, she added.
In addition to its metabolic and reproductive risks, PCOS is associated with clinically significant depression and anxiety. Compared to women without PCOS, those who have the syndrome have more than three times the odds of depressive symptoms and more than five times the odds of anxiety symptoms, according to a systematic review and meta-analysis of 18 studies published in March 2017 by Human Reproduction. The association persisted when researchers restricted the analysis to moderate and severe depression and anxiety scores.
The recent recommendations state that clinicians should consider women with PCOS to be at increased risk of cardiovascular disease if screening reveals relevant risk factors (e.g., obesity, cigarette smoking, dyslipidemia, hypertension, impaired glucose tolerance, lack of physical activity). Indeed, no strong evidence shows that women with the condition have an increased risk of cardiovascular disease, per se, according to a paper published in the May 2018 British Journal of General Practice. The small cardiovascular risk that may exist in women with PCOS seems to be confined to those with too much androgen, said coauthor David Taylor, MD, a general practitioner in Birmingham, England.
Broader criteria are making it easier to label people with PCOS while ultrasounds are gaining more definition, which make any phenotype-specific associations with long-term outcomes “all the more pertinent,” he said. “And never forget the harm of turning a person into a patient.”
At the same time, the lack of evidence regarding the link between PCOS and cardiovascular disease is due to a lack of studies, Dr. Dunaif noted. “Whether women with PCOS are actually at increased risk for cardiovascular events has not been established because there have been no prospective longitudinal studies of affected women into the seventh and eighth decades of life, when such events become common in women,” she said.
Dr. Lujan felt that PCOS was underdiagnosed in the past but now views it as an overdiagnosed condition, particularly because women are self-diagnosing. “I'm concerned about labeling individuals with PCOS unless they have a more severe presentation, particularly because … in this country, that could affect their access to insurance and other types of social services,” she said.
Others, however, say PCOS is underrecognized. “There's no question it's underdiagnosed,” said Katherine Sherif, MD, professor of medicine, director of Jefferson Women's Primary Care, and vice chair of the department of medicine at Jefferson University in Philadelphia. “The reason it's underdiagnosed is because we work in silos, and internists typically do not ask about the menstrual periods.”
She said it is not uncommon for her to see a first-time patient in her 40s with prediabetes and nonalcoholic fatty liver disease with a history of gestational diabetes and irregular periods, but not a PCOS diagnosis. “If we could stop diagnosing at this end, when you have the end-organ complications, and diagnose it at the beginning, we could keep women healthier,” Dr. Sherif said.
When considering a diagnosis, internists should be sure to take into account the various PCOS phenotypes, as they correspond to different long-term metabolic risks, said Richard S. Legro, MD, professor of obstetrics and gynecology and public health sciences at Penn State University College of Medicine in Hershey, Pa. He was lead author of a 2013 Endocrine Society clinical practice guideline that suggested using the Rotterdam criteria for diagnosing PCOS.
“The more severe phenotypes are almost always associated with the combination of irregular menses and androgen excess, and the less severe phenotypes are when you subtract one of those out and you add in polycystic ovaries,” Dr. Legro said. “I do think that the Rotterdam criteria overdiagnose PCOS and give patients a label that they don't necessarily need because they're not really suffering from the endocrine disorder of PCOS.”
Dr. Dunaif has proposed using two names for the condition: “metabolic reproductive syndrome” for the phenotypes that include both androgen excess and ovulatory dysfunction and “PCOS” for the reproductive phenotypes, which are diagnosed by ovarian morphology. The distinction among phenotypes is important, since PCOS may go undiagnosed in primary care due to a misconception that ovarian ultrasound is required, she said.
“[Ultrasound] is not needed for the diagnosis of the  NIH subtype, which is the metabolic high-risk subtype,” said Dr. Dunaif. “I call it internist PCOS.”
Dr. Legro, an ob-gyn, agreed that an ultrasound might not add anything to an internist's diagnosis if irregular menses and androgen excess are present. “You should obtain that test where it would change your management plan,” he said.
From a reproductive endocrinology standpoint, the size and appearance of the follicles would change the management plan for infertility “because I know that will be an additional risk factor for ovarian hyperstimulation,” Dr. Legro said. In general, though, PCOS is “a diagnosis that falls under the saying that 90% of things can be diagnosed by history and physical,” he said.
Pearls to remember
Internists diagnosing “internist PCOS” may not need to know the string-of-pearls sign of 20 antral follicles on ovarian ultrasound, but they may find it useful to keep some pearls in mind when taking a patient's history and ordering lab workup.
First, menses should be considered a vital sign, just like height, weight, and blood pressure, in any woman of reproductive age who is not on hormonal contraceptives and has a uterus, said Dr. Legro, who is also interim chair and vice chair of research for the department of ob-gyn at Penn State. “Whenever anything involves a menstrual cycle and vaginal bleeding, it scares off a lot of people,” he said.
And when asking about menstrual periods, dig deeper, said Dr. Sherif. “Patients will say, ‘It's regular: It's red, it's about five to six days, and it comes whenever it wants to,’ so ‘regular’ is meaningless,” she said. “What we're really talking about is menstrual intervals.”
To take a menstrual history, Dr. Dunaif recommended asking the patient a set of basic questions: At what age did your period start? When was your last period? When was your period before that? Are you having menses every month? If not, how frequently over the last year did you have menses? Most women with PCOS are going to have cycles much longer than 35 days, she said.
Internists who ask for a menstrual history, focus on patients who are having eight or fewer menses per year, and identify those at risk for PCOS “would be doing a huge benefit to women because those women need diagnosis and treatment,” said Dr. Dunaif.
One wrinkle is the beneficial yet troublesome effect of hormonal birth control: If a woman is on the pill for five or 10 years, of course she'll say her periods are monthly. “But what you don't know is that she started at age 15 because the intervals were so irregular,” said Dr. Sherif.
The other criterion for high-risk PCOS, elevated androgen levels, also can require a bit of detective work. While some women will have clinical signs of hyperandrogenism, such as hirsutism, acne, and alopecia, others may not. Asian patients, for example, tend to have less body hair than patients of other ethnicities and are less likely to present with facial hair, said Dr. Sherif.
In addition, picking up signs of hyperandrogenism can be tricky because so many women wax, pluck, or use laser hair removal, which can hide any signs of excess hair growth, said Dr. Banks. “But just asking the question would be very helpful in identifying these patients,” she said.
When clinical signs do not suffice, blood tests can provide biochemical verification of hyperandrogenism. However, lab tests for elevated androgen levels tend to be inaccurate in women because of sex-based differences, Dr. Legro noted.
Although women with androgen excess have on average twice the androgen levels of a normal woman, “That's still a fraction (probably a third or half) of what the normal male assay would be,” he said. “The problem with our androgen assays is that most of them are calibrated towards the lower end of the male assay and not the higher end of female.”
So in addition to measuring total testosterone, Dr. Legro recommended measuring sex hormone-binding globulin (SHBG) and DHEA sulfate. “If SHBG is low, total testosterone is high, and DHEA-S is high, then you know you've got system-wide hyperandrogenism,” he said.
The sensitive tools needed to measure elevated androgen levels in women are not readily available to everyone, noted Dr. Lujan, who said internists must trust the lab they use to analyze their specimens. “And if they don't trust those values, they need to get in contact with those of us that work in the area so we can direct them to the labs where we know you can get a concrete and sensitive assay,” she said.
After making a diagnosis, the next step is to formulate a management plan with patients to tackle the symptoms that are most important to them, Dr. Dokras said. Dr. Dunaif noted that while there are no FDA-approved medications for PCOS, clinicians often treat symptoms of androgen excess with combined oral contraceptive pills and widely use metformin, as well. “It is believed to act by improving insulin sensitivity,” she said. “It can restore regular menstrual cycles and improve glucose tolerance. In some women, it results in modest weight loss.”
A referral to an ob-gyn may be in order if the patient needs an alternative treatment, such as a hormonal intrauterine device, or is trying to get pregnant, Dr. Dokras said. However, she said a nutrition consult should be the most common referral for women with PCOS, especially for weight management and if blood glucose or cholesterol levels become slightly high. In one study of the genes involved in PCOS, published in September 2015 by Nature Communications, the researchers found that PCOS risk increased due to genetic variants associated with higher body mass index and insulin resistance. Thus, therapies to lower body weight and insulin resistance may help treat and prevent PCOS.
Since patients with PCOS are suffering, they tend to be motivated to change their lifestyles and understand their condition any way they can, said Dr. Dokras. “I do find that the vast majority of my patients are seeking options, not knowing what's the right thing. There's so much out there on social media, and they're looking for their physician to give them guidance,” she said. “The sooner we can recommend lifestyle changes, the better.”
Still, very few care guidelines for PCOS are evidence-based, and most are based instead on clinical consensus, Dr. Dunaif said. “I believe that this situation will only improve when physicians, particularly internists, and funders recognize that PCOS is a major metabolic disorder,” she said.