Clustering Identifies Subtypes With Different Phenotypic Characteristics in Women With Polycystic Ovary Syndrome

Abstract

Context: Hierarchical clustering (HC) identifies subtypes of polycystic ovary syndrome (PCOS).

Objective: This work aimed to identify clinically significant subtypes in a PCOS cohort diagnosed with the Rotterdam criteria and to further characterize the distinct subtypes.

Methods: Clustering was performed using the variables body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), testosterone, insulin, and glucose. Subtype characterization was performed by analyzing the variables estradiol, androstenedione, dehydroepiandrosterone, cortisol, anti-Müllerian hormone (AMH), total follicle count (TFC), lipid profile, and blood pressure. Study participants were girls and women who attended our university hospital for reproductive endocrinology screening between February 1993 and February 2021. In total, 2502 female participants of European ancestry, aged 13 to 45 years with PCOS (according to the Rotterdam criteria), were included. A subset of these (n = 1067) fulfilled the National Institutes of Health criteria (ovulatory dysfunction and hyperandrogenism). Main outcome measures included the identification of distinct PCOS subtypes using cluster analysis. Additional clinical variables associated with these subtypes were assessed.

Results: Metabolic, reproductive, and background PCOS subtypes were identified. In addition to high LH and SHBG levels, the reproductive subtype had the highest TFC and levels of AMH (all P < .001). In addition to high BMI and insulin levels, the metabolic subtype had higher low-density lipoprotein levels and higher systolic and diastolic blood pressure (all P < .001). The background subtype had lower androstenedione levels and features of the other 2 subtypes.

Conclusion: Reproductive and metabolic traits not used for subtyping differed significantly in the subtypes. These findings suggest that the subtypes capture distinct PCOS causal pathways.

Keywords: PCOS; cluster analysis; metabolic; reproductive; subtypes.

Figure 1.

Principal component analysis (PCA) plot, box plot, and heat map of normalized variables of the 3 subtypes—total cohort. A, PCA based on 8 predefined variables. The metabolic subtype is highlighted in red triangles, the reproductive subtype is indicated with blue squares, and the background subtype is indicated with gray circles. The direction and length of the arrows indicate the contribution of that specific variable to define the clusters. B, Box plot indicating the median and interquartile ranges (IQR) for each normalized variable. The corresponding Z scores are shown on the y-axis. The metabolic, reproductive, and background subtypes are shown in red, blue, and gray. C, Heat map colors reflect the variable Z-scores. Red indicates high values and blue indicates low values. The 3 subtypes are indicated in the color bar on top of the graph. The metabolic subtype appears in red, the reproductive subtype in red, and the background subtype in gray. The row-based dendrogram indicates the relation and relative distances between variable distributions. BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; Glu0, glucose; Ins0, insulin; LH, luteinizing hormone; SHBG, sex hormone–binding globulin; T, testosterone.

Figure 2.

Principal component analysis (PCA) plot, box plot, and heat map of normalized variables of the 3 subtypes—subset NIH criteria. A, PCA based on 8 predefined variables. The metabolic subtype is highlighted in red triangles, the reproductive subtype is indicated with blue squares, and the background subtype is indicated with gray circles. The black arrows indicate the magnitude and direction of that specific variable to define the clusters. B, Box plot indicating the median and interquartile ranges (IQR) for each normalized variable. The corresponding Z scores are shown on the y-axis. The metabolic, reproductive, and background subtypes are shown in red, blue, and gray. C, Heat map colors reflect the variable Z scores. Red indicates high values and blue indicates low values. The 3 clusters are indicated in the color bar on top of the graph. The metabolic subtype appears in red, the reproductive subtype in red, and the background subtype in gray. The row-based dendrogram indicates the relation and relative distances between variable distributions. BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; Glu0, glucose; Ins0, insulin; LH, luteinizing hormone; SHBG, sex hormone–binding globulin; T, testosterone.