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.

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence

“…It is becoming apparent that the steroidogenic repertoire of the adrenal and, perhaps, the theca cell include 11-hydroxyandrostenedione, which is ultimately converted to the potent androgen 11-ketotestosterone [14]. Women with PCOS showed higher serum concentrations of the 11-oxygenated androgens 11β-hy droxyandrostenedione, 11-ketoandrostenedione, 11β-hy droxytestosterone, and 11-ketotestosterone concentrations than control women [15]. …”

Monogenic Disorders of Adrenal Steroidogenesis

“…Importantly, the in vitro androgen receptor-transactivating activity of 11-keto-T and 11-keto-DHT is similar to that of testosterone and DHT [32, 39-41]. The implications of this additional androgen class are wide-ranging: recent studies have shown that they play a key role in androgen excess states, representing the majority of circulating androgens in polycystic ovary syndrome [42]. In addition, 11-oxygenated androgens are found to be increased in CAH due to CYP21A2 deficiency [43-46].…”

Human Adrenal Cortex: Epigenetics and Postnatal Functional Zonation

“…Recent evidence has shown that the human adrenal cortex would express the enzymes to complete all the steps in the backdoor pathway to DHT [25-27] and that this pathway would contribute to the androgen production in pathological states in which 17OHP accumulates [21, 22, 24]. Moreover, recent studies have demonstrated that the human adrenal cortex also produces a unique set of 11-oxygenated C19 steroids [19, 20, 23]. The first step of the 11-oxygenated androgen pathway is dependent on the adrenal CYP11B1 -catalyzed 11β-hydroxylation of A4 to 11β-hydroxyandrostenedione, which is a major product of adrenal steroidogenesis [19, 20].…”