Polycystic ovary syndrome (PCOS) is a common disorder that affects approximately 5-20% of women, though this varies by the criteria used to ascribe the diagnosis1-4. Women with PCOS experience a number of symptoms, ranging from insulin resistance to infertility. Despite the high prevalence of symptoms that characterize PCOS, experts worldwide struggle to agree on the proper criteria to be used in both PCOS diagnosis and study5. The authors developed a study to further elucidate the influence of diets that impact PCOS symptoms through improving insulin sensitivity; specifically, a paleolithic-type diet and the American Diabetes Association (ADA) recommended diet. Due to the stringency of our study requirements for PCOS diagnosis, our group has struggled to recruit candidates in the Bay Area, despite being a tertiary referral center and recruiting from local PCOS clinics. We also attempted to recruit from the general population in the San Francisco Bay Area through flyers at both the UCSF and UC Berkeley health centers, through Facebook groups, the PCOS clinic study trial page, the UCSF clinical trial recruiting website, local endocrinologist offices, and our listing at clinicaltrials.gov. We therefore decided to investigate the use of varying PCOS criteria in clinical study design, and subsequent subject recruitment. Here, we first discuss PCOS symptoms, to evaluate which subjects would undergo testing for PCOS, the various criteria for PCOS, current treatment options, and finally, we discuss our study outcomes and why we applied the criteria that we did. We hypothesize that depending on what study outcomes are desired, varying definitions of PCOS could be applied. The objective of this study is to measure patient recruitment under our group’s selected PCOS diagnosis criteria. In this study, we reflect on PCOS diagnostic criteria and influence on patient recruitment to clinical trial.
1.1 PCOS Signs and Symptoms
Women with PCOS may experience the following signs and symptoms: 1) elevated androgen levels, 2) insulin resistance, 3) potential to produce ovarian cysts, 4) infertility, 5) irregular menstrual cycles, 6) hirsutism and/or 7) changes in mental health status6.
Abnormal release of gonadotropin-releasing hormone (GnRH) disrupts normal luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, in turn produce increased androgen levels. These disruptions in hormone levels can lead to both oligo- or a-menorrhea (the loss of a regular menstrual cycle) and hirsutism (abnormal hair growth). Without regular menstrual cycles, women can experience difficulties when trying to get pregnant. Both the stress of coping with these symptoms and disruptions in normal hormone levels can lead to changes in mental health status, which can increase risk for depression and/or anxiety7.
Aside from the hormone changes experienced, women with PCOS are often insulin resistant and approximately 50% of women are overweight or obese. These metabolic health factors increase risk for high blood sugar, diabetes, stroke, heart disease, high blood pressure, high cholesterol, and sleep apnea8. The increased presence of insulin resistance, trouble regulating blood glucose levels, and prevalence of obesity/overweightness in women with PCOS diagnoses led our team to inquire about the influence of diet, specifically diets low in refined carbohydrates (e.g., refined sugars, processed grain cereals, “junk” food), which tends to lower insulin levels, as a method to potentially improve PCOS symptoms9-12.
1.2 PCOS Criteria
Since the first documented PCOS patients in 1935, the criteria used for diagnosis has shifted over time. The first PCOS cases were reported by Stein and Leventhal based on seven cases of women with: 1) polycystic ovaries, 2) oligo/amenorrhea with subfertility 3) hirsutism, or 4) lower abdominal pain13. In 1990 at a National Institute of Health (NIH) meeting, the following updated criteria was suggested by Zawadski and Dunaif: 1) hyperandrogenism and/or hyperandrogenemia 2) oligo-ovulation 3) exclusion of other known disorders14. In 2003, the Rotterdam criteria for PCOS were suggested. These criteria are used today by a wide range of medical professionals and researchers and are based on expert meetings, not evidence-based treatment guidance15. Following these criteria, a PCOS diagnosis is given if two of these three criteria are met: 1) oligo-anovulation, 2) hyperandrogenism or hyperandrogenemia, 3) polycystic ovaries. Although these criteria are the most widely adopted among medical professionals, they remain controversial.
In 2006, the Androgen Excess Society (AES) Task Force members, including Azziz and his team, outlined updated criteria for PCOS diagnosis16. Considering the four features of 1) ovulatory dysfunction, 2) hirsutism, 3) hyperandrogenemia, and 4) polycystic ovaries, the task force identified nine different phenotypes that could be considered as being PCOS with currently available evidence. These 9 phenotypes are as follows: A) hyperandrogenemia, hirsutism, oligo-anovulation, and polycystic ovaries B) hyperandrogenemia, hirsutism, and oligo-anovulation C) hyperandrogenemia, oligo-anovulation, and polycystic ovaries D) hyperandrogenemia and oligo-anovulation E) hirsutism, oligo-anovulation, and polycystic ovaries F) hirsutism and polycystic ovaries G) hyperandrogenemia, hirsutism, and polycystic ovaries H) hirsutism and polycystic ovaries I) hyperandrogenemia and polycystic ovaries. Figure 1 outlines the differences between the above discussed criteria.
1.3 Recent Criteria Used in Clinical Study
In recent studies, groups have differed in which set of criteria they use in defining PCOS in their recruitment of candidates. However, it is common to use criteria which address the androgen excess many PCOS patients experience. These criteria recommended by the AES task force may place too much excess on hyperandrogenemia. There are many other syndromes and diseases in which patients suffer from hyperandrogenemia, and it is important to first eliminate these diagnoses before diagnosing a patient with PCOS17. Elevated levels of another hormone, anti-müllerian hormone, has also been suggested as a potential marker for PCOS, however, further study is needed18-19. Our group believes the absence of a regular menstrual cycle is a key symptom in PCOS and should not be overlooked, even with the presence of hyperandrogenemia.
Although the above discussed criteria may be sufficient in clinical diagnosis with the goal of patient symptom improvement, more stringent criteria prove useful in specific clinical studies. Clinical studies differ in their goals, which can include treatment reform, providing updated clinical information to patients, and are typically broader scoped than a patient in a doctor’s office20-21. With this in mind, PCOS studies in particular have to proceed with caution when choosing which patients to recruit and which criteria to follow when defining “PCOS”22. Although our team recruits from PCOS clinics in the Bay Area, we have found that many women who have been referred by their doctor to the UCSF clinic do not meet our criteria for PCOS. We know that at least some of the subjects do not have a PCOS diagnosis, and are referred to the clinic by their doctor to find out if they have PCOS.