11-oxygenated C19 steroids are the predominant androgens in polycystic ovary syndrome

CONTEXT: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS) but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to the androgen excess phenotype in women with PCOS.

METHODS: 114 women with PCOS and 49 healthy controls underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. 24-h urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for calculation of homeostatic model assessment of insulin resistance (HOMA-IR). Baseline demographic data including body mass index were recorded.

RESULTS: As expected, serum concentrations of the classic androgens testosterone (p<0.001), androstenedione (p<0.001), and DHEA (p<0.01) were significantly increased in PCOS. Mirroring this, serum concentrations of the 11-oxygenated androgens 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone and 11-ketotestosterone were all significantly higher in PCOS women than controls, as was the urinary excretion of the 11-oxygenated androgen metabolite 11β-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in PCOS compared to controls [53.0% (IQR 48.7-60.3) vs. 44.0% (IQR 32.9-54.9), p<0.0001]. Both obese (n=51) and non-obese (n=63) PCOS patients had significantly increased 11-oxygenated androgens. Serum 11β-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance.

CONCLUSIONS: For the first time, we show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk.