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Reprint requests: Katherine E. Kostroun, M.D., Department of Obstetrics and Gynecology, University of Texas Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229.
To study whether application of the new 2018 guidelines for the diagnosis of polycystic ovary syndrome (PCOS) would decrease the diagnosis of PCOS. Second, to compare the metabolic profiles of women included and excluded in this new definition.
Design
Retrospective cross-sectional chart review.
Setting
University-affiliated hospital system.
Patient(s)
Women, ages 12–50, with the International Classification of Diseases code “Polycystic Ovary Syndrome” in 2017.
Intervention(s)
Application of the new 2018 guidelines for the diagnosis of PCOS.
Main Outcome Measure(s)
The primary outcome was the retention of PCOS diagnosis after applying the new 2018 guidelines. Secondary outcomes included the comparison of metabolic risk factors. Analysis was performed using chi-square tests for categorical variables and unpaired t tests for continuous variables, with a P value of <.05 determined to be significant.
Result(s)
Of 258 women with PCOS based on Rotterdam criteria, only 195 (76%) met the criteria based on the new 2018 guidelines. Those women who only met Rotterdam criteria (n = 63) had significantly lower body mass index (32.7 vs. 35.8), lower total cholesterol levels (151 vs. 176 mg/dL), lower triglyceride levels (96 vs. 124 mg/dL), lower total (33.2 vs. 52.3 ng/dL) and free testosterone levels (4.7 vs. 8.3), lower antimüllerian hormone levels (3.1 vs. 7.7 ng/mL), and were more likely to be multiparous (50% vs. 29%) than women who met 2018 criteria.
Conclusion(s)
Increasing the minimum antral follicle count to ≥20 antral follicles significantly decreases the number of women with the diagnosis of PCOS. Furthermore, the women that meet the new criteria have more health risks for metabolic syndrome than those who only meet the Rotterdam criteria.
The diagnostic criteria for polycystic ovary syndrome (PCOS) have evolved over time and are largely based on expert consensus. Although reports of enlarged ovaries in infertile women date back to the 1700s (
) who first described the triad of menstrual irregularities, hirsutism, and large ovaries with many follicles. In 1948, their technique of ovarian wedge resection proved successful in increasing fertility rates and returning normal cycles in their small cohort of women with Stein-Leventhal syndrome, later coined PCOS (
). After continued efforts to gain recognition for this condition, the first international conference was held in 1990 at the National Institutes of Health in Bethesda, Maryland. From this meeting came the first defined criteria for PCOS based largely on participant expert opinion, necessitating both chronic anovulation and hyperandrogenism (clinical or biochemical) (
). Ongoing research, however, suggested that ultrasound could be used to provide ovarian volume and follicle counts that were accurate and similar to histopathologic examination (
In 2003, the second international conference convened in Rotterdam, Netherlands. Acknowledgment of PCOS as a spectrum and recognition of the widespread use of ultrasound for ovarian evaluation led to the addition of ultrasound criteria (
Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).
) described the consensus definition of polycystic ovaries as at least 1 ovary with either ≥12 follicles measuring 2–9 mm or increased ovarian volume >10 cm3. This definition was largely based on research by Jonard et al. (
) that found using the previously mentioned criteria produced a 75% sensitivity and 99% specificity for identifying polycystic ovaries compared with the control. Thus, the Rotterdam criteria defined PCOS as 2 of 3 factors: oligo-anovulation, hyperandrogenism (clinical or biochemical), or ≥12 follicles in a single ovary or ovarian volume >10 cm3.
In 2018, Recommendations from the International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome was published in Fertility and Sterility, Human Reproduction and Clinical Endocrinology concurrently and redefined the minimum antral follicle count (
). The investigators argued that re-evaluation of these criteria was necessary given that the last ultrasound criteria were based on a single study and significant advancements had been made in ultrasound machinery. They concluded that a cutoff of ≥20 antral follicles in a single ovary using transvaginal ultrasound was a more appropriate definition of polycystic ovaries (
Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries.
). The 2018 Guideline also emphasized the well-studied health risks associated with women with PCOS, including obesity, metabolic syndrome, cardiovascular disease, diabetes, hyperlipidemia, endometrial cancer, anxiety, and depression (
). Specific screening and treatment guidelines are detailed in the updated recommendations and may serve as the foundation for comprehensive care of women with PCOS.
When major diagnostic criteria for a disorder change, it is imperative to assess the implications for patients and practitioners. The purpose of this study was to evaluate whether the change in the minimum antral follicle count criteria makes a significant difference in the diagnosis of PCOS. Importantly, we sought to compare the metabolic health risks present in women who continue to meet diagnostic criteria versus those who are excluded by these new guidelines. This study asks an important question: does creating more strict ultrasound criteria identify women at risk for health complications associated with PCOS?
Materials and methods
This is a retrospective cross-sectional chart review of women with PCOS at a large academic center. This project was determined to be an exempt study and approved by a university hospital institutional review board. Charts were queried with the International Classification of Diseases 10th Revision code of “Polycystic Ovary Syndrome” E28.2 and using the inclusion criteria of female sex, age 12–50, and diagnosis coded in 2017. Subjects were identified within a single institution from 15 clinical sites, including private and public clinics, as well as a large academic hospital. A total of 515 subjects resulted from the query, but 257 charts were excluded from the study because of a lack of documentation in the women’s chart of PCOS diagnosis. In general, these women were being seen for other reasons than PCOS. The resulting 258 women were evaluated and included in this study.
Study data were collected and managed using Research Electronic Data Capture electronic data capture tools (
). Data collection was performed by a single researcher and was subsequently systematically reviewed and validated by the primary investigator.
The initial visit for PCOS evaluation and diagnosis was identified in the chart. The clinic or hospital setting was noted, and the provider specialty. Demographic information was collected, including age, ethnicity, and parity. Ethnicity was self-identified and collected from the demographic field in the electronic health record. The systolic and diastolic blood pressure and body mass index (BMI) were noted. Menstrual data with reported cycle irregularity, length of cycles, number of cycles per year, and days of bleeding were obtained as available. The PCOS symptoms, including clinical hyperandrogenism with acne, hirsutism, and alopecia, were recorded along with any previous diagnosis of PCOS.
Laboratory evaluation of biochemical hyperandrogenism was included as available if it resulted within 1 year of the identified initial visit. Laboratory findings collected included total and free testosterone, bioavailable testosterone, and dehydroepiandrosterone sulfate (DHEA-S). Individual laboratory cutoffs were used to classify each laboratory value as normal or elevated. Transvaginal gynecologic ultrasound data was recorded as available, including bilateral ovarian measurements, ovarian volumes, and antral follicle count per ovary. Additional laboratory evaluations of metabolic status, including hemoglobin A1c, liver function, and cholesterol panel, were noted. The anti-müllerian hormone was also documented as available.
All available diagnostic information was used to classify women as meeting the criteria for PCOS based on Rotterdam criteria vs. new 2018 diagnostic criteria. Women met the diagnosis for PCOS based on Rotterdam criteria if they had 2 of 3 factors: irregular menses, evidence of hyperandrogenism, and ≥12 ovarian follicles in an ovary or ovarian volume of ≥10 mL. Irregular menses was defined as reported irregularity in the menstrual cycle with a reported cycle length of <21 or >35 days or <8 cycles in 1 year. Hyperandrogenism was defined as having any single elevated laboratory value of total, free or bioavailable testosterone, or DHEA-S, if testosterone levels were normal or any patient-reported clinical symptom, including acne, hirsutism, or alopecia. Ultrasound criteria were met if a woman had ≥12 ovarian follicles in a single ovary or a single ovary with a volume ≥10 mL. Women were then excluded from the new 2018 diagnostic criteria if they required ultrasound criteria for diagnosis but did not have ≥20 ovarian follicles in a single ovary or a single ovary with a volume ≥10 mL.
The interquartile outlier rule was used to detect and remove outliers from the dataset. Chi-square and Fisher’s exact tests were used for categorical variables as appropriate. Continuous data were evaluated for Gaussian distribution using a D’Agostino-Pearson test and Normal Q-Q plot. Unpaired t tests were used to determine statistical differences for continuous, normally distributed variables. A Mann-Whitney test was used to analyze non-Gaussian data sets. A P value of <.05 was used to determine significance. Data analysis was performed using GraphPad Prism.
Results
A total of 258 women were evaluated in this study. Most women were Hispanic (39%) or White (35%), with the remaining being Black (5%) and Asian (4%). Out of the 258 women, only 195 (76%) retained the diagnosis of PCOS based on the new 2018 guidelines (P<.001). Ultimately, 63 (24%) women were excluded from PCOS diagnosis on the basis of the new 2018 criteria. (Fig. 1)
Figure 1Derivation of the study cohort. ICD = International Classification of Diseases; PCOS = polycystic ovary syndrome.
Demographic comparison of women meeting criteria by new 2018 guidelines vs. those only meeting Rotterdam criteria is detailed in Table 1. Women were similar in median age (26 vs. 27), and there were no differences in ethnic background. The women meeting new criteria were more likely to be nulliparous (P = .01) and have a higher BMI (35.8 vs. 32.7) (P = .01) than those meeting Rotterdam criteria. In regards to metabolic parameters, women meeting the 2018 criteria had statistically higher cholesterol levels (176 vs. 151 mg/dL) (P = .003) and triglyceride levels (124 vs. 96 mg/dL) (P = .04) (Table 2). There were no statistical differences found in hemoglobin A1c, liver function tests, low-density lipoprotein, or high-density lipoprotein concentrations. There were no statistical differences in blood pressure between the 2 groups.
Table 1Demographic differences in patients included and excluded in the 2018 criteria.
Note: Data are n (%) or n (range) with outliers excluded. Bold lettering emphasizes variables meeting significance with P value of <0.05. Am Indian = American Indian; Pac Island = Pacific Island.
a Data available for 195/195 and 63/63 subjects. Data nonparametric and presented as median (range).
Note: Data are mean (range) with outliers excluded. Bold lettering is used to emphasize variables meeting significance with P value of <0.05. A1c = hemoglobin A1c; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; HDL = high-density lipoprotein; LDL = low-density lipoproteins.
a Data available for 114/195 and 24/63 subjects.
b Data available for 114/195 and 26/63 subjects. Data nonparametric and presented as median (range).
Total testosterone (52.3 vs. 33.2, P<.001) and free testosterone (8.3 vs. 4.7, P<.001) were significantly higher in women meeting the 2018 criteria. There was no significant difference in bioavailable testosterone or DHEA-S in the 2 groups (Table 3). The antimüllerian hormone was significantly higher in the 2018 criteria group than in the Rotterdam-only group (7.7 vs. 3.1 ng/mL) (P = .01).
Table 3Androgen laboratory parameters in patients included and excluded in the 2018 criteria.
Data are mean (range) with outliers excluded. Bold lettering used to emphasize variables meeting significance with P value of <0.05. DHEA-S, dehydroepiandrosterone sulfate.
Women were evaluated by a variety of specialties, including obstetrician gynecologist (n = 173), family medicine (n = 71), pediatrics (n = 8), and endocrinology (n = 6). Women were more likely to have an ultrasound evaluation if they were seen by an obstetrician gynecologist at the time of diagnosis (P<.001), with an odds ratio of 4.61 (95% CI, 2.64–7.97).
Discussion
The diagnosis of PCOS has been through several consensus guidelines and was most recently updated in 2018. Using a retrospective chart review, we determined how the new diagnostic guidelines may affect the diagnosis of women with PCOS. Significantly fewer women met the strict definition for PCOS based on the new 2018 criteria; specifically, increasing antral follicle count (AFC) excluded 24% of women previously diagnosed with PCOS. The women meeting the 2018 criteria for diagnosis of PCOS had higher BMIs, higher cholesterol levels, higher triglyceride levels, and higher total and free testosterone levels than those who only met Rotterdam criteria.
Clinically, the precise diagnosis of PCOS aids in the counseling of women about their metabolic and cardiovascular risks (
). The link between PCOS and diabetes is well established, with PCOS women being twofold to fourfold more likely to develop impaired glucose tolerance or type 2 diabetes mellitus (
). However, cardiovascular disease, which is the leading cause of death in women in the United States, can be difficult to study in PCOS women, given most study cohorts are relatively young (
This is the first study to support that the new 2018 AFC criteria of ≥20 follicles in a single ovary excludes women from PCOS diagnoses that have significantly lower metabolic risk factors. Few similar studies have been published that found differing results (
) published a cross-sectional cohort analysis in 2016 that compared PCOS exclusion on the basis of ≥25 antral follicle threshold. In their study, excluded women still had evidence of metabolic risk (insulin resistance, total cholesterol) that was significantly higher than their control group. In 2020, Kim et al. (
) published a case-control study that evaluated women meeting PCOS criteria in a category that required polycystic ovaries and compared a cut off of ≥12 vs ≥20 antral follicles. They noted that 48% of women that required polycystic ovaries for PCOS diagnosis were excluded with the increased cutoff, and that these excluded women still had elevated metabolic markers (BMI, metabolic syndrome, insulin resistance) compared with control subjects (
). However, it is noted in their discussion that there are significant ethnic differences in PCOS, with this study being in South Korea where the major phenotype is irregular menses plus polycystic ovaries. Indeed, Huang et al. (
) found that 93% of Asian women with Rotterdam criteria PCOS demonstrated polycystic ovaries, whereas only 69.9% of Caucasian women with PCOS have polycystic ovaries. In our study, the majority phenotype was irregular menses plus hirsutism (69%). Therefore, it is reasonable to suggest that different ethnic groups may require different AFC cutoffs.
The diagnosis of PCOS is often a drawn out and difficult process for many women involving multiple provider appointments, laboratory work and invasive imaging. In one study of 210 women, it took a median of 5 years to be diagnosed with PCOS (
). Whereas to some women the diagnosis comes as a relief and a final answer to years of symptomatology, to others it is a burden. It is known that PCOS is associated with increased anxiety and depression (
). The goal of precisely defining PCOS is to identify the women at risk for adverse health consequences while balancing the emotional burden of the diagnosis of this complex disease.
There are multiple additional results in our study that support that the new stricter AFC more precisely identifies PCOS. All of the collected biochemical markers for hyperandrogenism were higher in the cohort who met the 2018 consensus definition, and those for total and free testosterone met statistical significance (Table 3). Interestingly, several studies have noted that biochemical hyperandrogenism could be independently associated with increased metabolic parameters (
Biochemical hyperandrogenism is associated with metabolic syndrome independently of adiposity and insulin resistance in Romanian polycystic ovary syndrome patients.
Relationships between biochemical markers of hyperandrogenism and metabolic parameters in women with polycystic ovary syndrome: a systematic review and meta-analysis.
). Additionally, antimüllerian hormone was significantly higher in the 2018 criteria group, (7.7 vs. 3.1 ng/mL). Many have proposed the use of antimüllerian hormone as a screening for PCOS, and Dietz de Loos et al. (
) recently published in Fertility and Sterility a validated cutoff of 3.2 ng/mL for identifying polycystic ovarian morphology with a sensitivity of 88.6% and specificity of 84.6%.
As a retrospective chart review, our data was limited to information provided within the electronic medical record. Our study identified women with the International Classification of Diseases code of PCOS in their record, but many of these women simply had a coded history of PCOS. Ultimately those women were excluded from the analysis, and decision was made to continue with the study given the significant number of women meeting Rotterdam criteria that remained (Fig. 1). Additional limitations include the self-reported nature of many clinical data such as hirsutism and acne, as opposed to a standardized scale like the Ferriman-Gallwey. In addition, ultrasounds were performed by a variety of ultrasonographers with differing equipment. Although this could lead to variability, it also supports the generalizability of our results. A total of 123/258 women had ultrasound data in our cohort. We chose to include patients who did not have ultrasound data but did meet criteria based on irregular menses and hyperandrogenism in our analysis because we felt this made our data more generalizable to the PCOS population. Finally, our demographic data should be considered when discussing the generalizability of our results given that nearly half of our population was Hispanic.
A future study might include additional relevant parameters to assess metabolic syndrome including abdominal circumference and fasting glucose levels, which were not available for this study. It should be noted that many variables had low availability as noted in Tables 2 and 3, and further studies are needed to confirm these results. Additionally, treatment outcomes were not addressed in this manuscript but will be the subject of future research at this institution.
Conclusion
Increasing the minimum AFC requirement to ≥20 antral follicles significantly decreases the diagnosis of PCOS. Women who only meet Rotterdam criteria have less metabolic risk factors than those who continue to meet strict 2018 criteria. Finally, continued assessment should be considered for the long-term metabolic outcomes for those women excluded by the 2018 guidelines.
Acknowledgment
The authors thank the UT Health San Antonio Department of Population Health Science for help with the statistical analysis.
Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries.
Biochemical hyperandrogenism is associated with metabolic syndrome independently of adiposity and insulin resistance in Romanian polycystic ovary syndrome patients.
Relationships between biochemical markers of hyperandrogenism and metabolic parameters in women with polycystic ovary syndrome: a systematic review and meta-analysis.
K.E.K. has nothing to disclose. K.G. has nothing to disclose. J.N.M. has nothing to disclose. R.D.R. has nothing to disclose. E.M. has nothing to disclose. S.R. has nothing to disclose. Z.W. has nothing to disclose. X.S. has nothing to disclose. J.F.K. has nothing to disclose.
This project was supported by grant no. K23 HD097307 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health (to J.F.K.)
An abstract of this project was presented at the American Society for Reproductive Medicine Scientific Congress and Expo 2020, held virtually, October 19–21, 2020, and published in Fertility and Sterility in September 2020.
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