11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome

Abstract

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 androgen excess in women with PCOS.

Methods: One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four-hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. 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 dehydroepiandrosterone (P < 0.01) were significantly increased in PCOS. Mirroring this, serum 11-oxygenated androgens 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11β-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in patients with PCOS compared with control subjects [53.0% (interquartile range, 48.7 to 60.3) vs 44.0% (interquartile range, 32.9 to 54.9); P < 0.0001]. Obese (n = 51) and nonobese (n = 63) patients with PCOS had significantly increased 11-oxygenated androgens. Serum 11β-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance.

Conclusions: We show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk.

Figure 1.

Schematic of androgen synthesis illustrating the classic androgen pathway (gray boxes) and the steroids of the 11-oxygenated androgen pathway (black boxes). Dotted lines relate distinct steroids to their corresponding urinary steroid metabolite. Abbreviations: 11KDHT, 11-ketodihydrotestosterone; 17OH-PREG, 17α-hydroxypregnenolone; CYB5A, cytochrome b₅; CYP11B1, cytochrome P450 11β-hydroxylase; CYP17A1, cytochrome P450 17α-hydroxylase/17,-20-lyase; DHT, 5α-dihydrotestosterone; HSD11B2, 11β-hydroxysteroid dehydrogenase type 2; HSD3B, 3β-hydroxysteroid dehydrogenase; PREG, pregnenolone; SRD5A, steroid 5α-reductase; SULT2A1, sulfotransferase family 2A member 1.

Figure 2.

Serum concentrations of (A, B) classic and (C–F) 11-oxygenated steroids in women with PCOS (n = 114) and healthy sex- and age-matched control subjects (n = 49). (G–I) Major urinary androgen metabolite deriving from the classic androgen pathway, An and etiocholanolone (Et), and the 11β-hydroxyandrostenedione metabolite 11β-OH-An.

Figure 3.

Relative contribution (median; %) of the classic androgen pathway (DHEA, A4, T; shades of blue) and the 11-oxygenated C19 steroid pathway (11OHA4, 11KA4, 11OHT, 11KT; shades of red) to the total circulating androgenic steroid pool, comparing patients with PCOS (n = 114) with sex- and age-matched healthy control subjects (n = 49).