Q&A: Clinical, research goals for PCOS Awareness Month

September is designated Polycystic Ovary Syndrome Awareness Month to raise awareness of the reproductive condition.

According to the HHS Office on Women’s Health, about 10% of women of childbearing age are affected by PCOS. However, the precise cause of PCOS is unknown, but both elevated androgen levels and insulin resistance may play a role in its development. It also has a multitude of symptoms, some of which include irregular menses and hair growth, making it difficult to define.

Despite this, PCOS treatment costs nearly $8 billion annually in the United States, with the direct mental health costs of the syndrome exceeding $6 billion annually.

We spoke with Andrea Dunaif, MD, co-editor of Healio | Endocrine Today, the Lillian and Henry M. Stratton Professor of Molecular Medicine at the Icahn School of Medicine at Mount Sinai and chief of the Hilda and J. Lester Gabrilove Division of Endocrinology, Diabetes and Bone Disease for the Mount Sinai Health System in New York City, to learn more about PCOS, its impact on practice and action for the future.

Healio: Why is it important to raise awareness about PCOS?

Dunaif: Awareness of PCOS is high in the OB/GYN community because its typical presentation is as a reproductive disorder. Long and irregular periods are a common reason for women to seek care. PCOS is the most common cause of irregular menses. Gynecologists will see women with PCOS in their teens and 20s. It is also the most common cause of infertility related to ovulatory dysfunction. I think what is underappreciated is the fact that PCOS also has metabolic and psychological health implications. Women with PCOS — particularly with what we call the NIH phenotype of irregular menstrual cycles, which is a marker for ovulatory dysfunction, and evidence of high male hormone levels, hyperandrogenism — are at increased risk for insulin resistance and its clinical consequences, metabolic syndrome and type 2 diabetes. In addition, although it has not been definitively proven, the risk for cardiovascular events, such as strokes and heart attacks, appears to be increased in women with PCOS. Consequently, it is very important for women with PCOS to have preventive care aimed at reducing risk for adverse metabolic outcomes, either from gynecologists and women's health physicians, who provide this care themselves, or who work in partnership with primary care physicians. Anxiety and depression are also more common in women with PCOS.

The real knowledge deficit about PCOS is among specialties other than OB/GYN. We recently presented a study at the annual meeting of the Endocrine Society in June 2022 using a commercial insurance database to determine which providers care for women of reproductive age with PCOS diagnosis codes. We found that these women are seeing primary care providers more frequently than OB/GYNs. They are also seeing cardiologists and psychiatrists more frequently than women without PCOS. These specialties need to be educated about PCOS and its associated morbidities.

Healio: What challenges are there in diagnosing and treating PCOS?

Dunaif: There is a lot of confusion about the PCOS diagnostic criteria because the experts argue over them. The first set of diagnostic criteria were a byproduct of the 1990 NIH- [National Institute of Child Health and Human Development] scientific meeting on PCOS. Experts attending the meeting completed a survey on potential diagnostic criteria. The criteria receiving the most votes — hyperandrogenism and chronic anovulation, with the exclusion of known disorders of the ovary, adrenals or pituitary — became the so-called NIH diagnostic criteria. Polycystic ovarian morphology was not included as a diagnostic criterion because it was already established that this morphology was a nonspecific finding that was also present in 20% to 30% of women without reproductive symptoms. However, at a conference sponsored by the European Society of Human Reproduction and Embryology in Rotterdam in 2003, polycystic ovarian morphology was added as a diagnostic criterion. What became known as the Rotterdam criteria require the presence of two of the three diagnostic features of PCOS: hyperandrogenism, chronic anovulation and polycystic ovarian morphology, with the exclusion of known reproductive disorders. The Rotterdam criteria encompass the NIH criteria but include two additional phenotypes: hyperandrogenism and polycystic ovaries without chronic anovulation, and chronic anovulation and polycystic ovaries without hyperandrogenism. Both the NIH and the Rotterdam criteria are frequently referred to as consensus criteria. However, they are based on expert opinion and were not developed through a formal consensus process.

I think that the varying criteria and the inclusion of polycystic ovarian morphology in the diagnosis has created considerable confusion about the diagnosis of PCOS, particularly outside OB/GYN. Indeed, there was an NIH-sponsored state-of-the-science meeting in 2012, the Evidence-based Methodology Workshop on Polycystic Ovary Syndrome. This workshop followed a consensus-like process where the data were presented to a panel of experts in the field who were not engaged in research on PCOS. The panel stated that the name PCOS was a distraction and an impediment to progress. The name “polycystic ovary syndrome” is a misnomer since there are no cysts in the ovaries. The structures being labeled as cysts are normal ovarian follicles that are arrested in development. Further, polycystic ovaries are neither necessary nor sufficient for the diagnosis of PCOS. You can certainly meet all the other criteria and not have polycystic ovaries, and you can have polycystic ovaries and not have the rest of the syndrome.

Because we do not know the causes of PCOS, our treatment is focused on ameliorating the clinical features of the syndrome. Accordingly, treatment is targeted at symptoms of androgen excess, most commonly hirsutism, but also acne and female pattern hair loss, irregular or infrequent menses, and infertility. Weight management is a major concern for patients, particularly in the U.S., where about 80% to 90% of women with PCOS are obese. Reduction of metabolic risk is an important consideration, particularly in obese women with PCOS. Management should include screening for prediabetes, type 2 diabetes, and other cardiovascular disease risk factors, such as metabolic syndrome. Mental health should also be considered given the association of PCOS with anxiety and depression.

There are no FDA-approved drugs for the treatment of PCOS in the U.S. Commonly used drugs include 1) oral contraceptives for symptoms of androgen excess and regulation of menses; 2) spironolactone, which is widely used off-label in high doses as an anti-androgen; and 3) metformin, an oral diabetes drug that is used off-label to regulate menses, restore ovulation and reduce risk for type 2 diabetes. First-line drugs for ovulation induction are clomiphene citrate or letrozole (off-label) before proceeding to assisted reproductive technologies. As little as a 10% loss in body weight improves reproductive features and reduces metabolic risk in PCOS. Metformin has been widely use in PCOS for weight management. However, there is emerging evidence that GLP-1 receptor agonists are more effective for weight management in PCOS.

Healio: How does a patient's PCOS diagnosis affect the overall care their provider gives them?

Dunaif: Providers need to be aware that PCOS is a metabolic as well as a reproductive disorder. Women with PCOS, particularly women with obesity who have irregular menses and hyperandrogenism (NIH phenotype PCOS), should be screened for metabolic abnormalities such as metabolic syndrome, prediabetes and type 2 diabetes.

Healio: What work still needs to be done to properly address the burden of PCOS?

Dunaif: There is a dearth of information on the long-term health consequences of PCOS. There are very limited studies that have followed women beyond reproductive age. There have been no gold standard prospective, longitudinal studies of women with PCOS through their 60s and 70s, ages at which cardiovascular events, such as myocardial infarction and stroke, become common. Prospective cohort studies have found that women with long or irregular menstrual cycles during their reproductive years have increased risk for cardiovascular events, type 2 diabetes cancers, including non-gynecologic cancers and premature mortality. Since PCOS is the leading cause of irregular menstrual cycles, these studies highlight the urgent need to determine the syndrome’s long-term health risks. There are numerous large cohort studies, such as the Physicians’ Health Study, the Nurses’ Health Study and the Women's Health Study. We need a PCOS Health Study.

Healio: Is there anything else you would like to highlight about PCOS?

Dunaif: In the last decade, tremendous progress has been made identifying pathways causing PCOS with modern genetic analyses. Using these approaches, it has been possible to show that the current PCOS diagnostic criteria, which are based on expert opinion, do not identify genetically distinct subgroups of PCOS. However, using machine learning approaches, discrete subtypes of PCOS have been identified based on its reproductive and metabolic traits. These subtypes appear to be associated with unique genetic loci suggesting the subtypes better capture the underlying biology. I believe that we will see the field move toward these data-driven approaches to classification of the disorders that are currently lumped together as Rotterdam criteria PCOS. Future diagnostic criteria will be based on objective biologic differences rather than subjective opinions.

References:

Polycystic ovary syndrome. https://www.womenshealth.gov/a-z-topics/polycystic-ovary-syndrome. Published Feb. 22, 2021. Accessed Aug. 19, 2022.