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re not currently commercially available, thereby complicating the quantification of these steroids by LC-MS/MS. Nonetheless, comparisons between control groups and patient groups within these individual studies unequivocally demonstrate that the 11-oxygenated androgens are significantly elevated in both PCOS and 21OHD. Further studies with larger cohorts, as well as with the use of deuterated 11-oxygenated internal standards, are therefore required to establish reliable reference ranges in health and disease. Table 3. Serum Concentrations of Classical and 11-Oxygenated Androgens Steroid (nmol/L) Adrenal Vein Study—Rege et al. ( 9 ), Mean ± SEM CAH Study—Turcu et al. ( 22 ), Median (IQR) PCOS—This Study, Median (IQR)

Further studies with larger cohorts, as well as with the use of deuterated 11-oxygenated internal standards, are therefore required to establish reliable reference ranges in health and disease. Table 3. Serum Concentrations of Classical and 11-Oxygenated Androgens Steroid (nmol/L) Adrenal Vein Study—Rege et al. ( 9 ), Mean ± SEM CAH Study—Turcu et al. ( 22 ), Median (IQR) PCOS—This Study, Median (IQR) Adrenal Vein (n = 7; all women) Periphery (n = 7; all women) Controls (n = 38; 19 women) 21OHD (n = 38; 19 women) Controls (n = 49; all women) PCOS (n = 114; all women) DHEAS 3827 ± 1317 2210 ± 321 3793.4 (1585.1–5066.5) 508.7 (213.0–1745.2) 6038 (3402–9522) 8133 (5515–12,240) DHEA 125 ± 56.9 5.85 ± 1.01 6.0 (4.1–11.0) 1.0 (0.55–2.9) 7.1 (4.2–11.8) 14.1 (10.4–18.2) A4 79.0 ± 46.9 1.90 ± 0.47 1.5 (0.77–2.2) 5.4 (2.5–13.6) 5.9 (3.6–9.2) 26.8 (16.9–35.2) T 0.78 ± 0.26 0.44 ± 0.05 0.90 (0.42–10.7) 2.8 (1.3–5.6) 0.3 (0.2–0.5) 0.7 (0.5–1.0) 11OHA4 157 ± 96.2 1.90 ± 0.42 3.9 (2.3–5.1) 11.6 (6.2–26.2) 6.8 (4.9–12.3) 31.7 (16.8–47.8) 11KA4 0.99 ± 0.33 0.46 ± 0.07 1.0 (0.67–1.4) 3.2 (1.9–4.8) 2.7 (2.0–3.8) 13.4 (8.5–18.8) 11OHT 0.48 ± 0.17 0.22 ± 0.04 0.49 (0.30–0.69) 1.9 (0.69–3.4) 0.2 (0.1–0.3) 0.4 (0.3–0.5) 11KT 0.39 ± 0.09 0.44 ± 0.03 1.7 (0.96–2.6) 5.7 (3.5–12.1) 1.5 (1.2–1.8) 2.4 (1.8–3.9) Data are as measured in 3 separate studies: a comparison of adrenal vein and peripheral blood concentrations in women with primary aldosteronism (9); healthy control subjects vs patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency receiving routine steroid therapy (22); and this study comparing PCOS with healthy control subjects.

h 11OHT and 11KT levels are significantly elevated in PCOS, neither 11OHT nor 11KT correlated with BMI. This finding further supports the idea that androgen excess drives weight gain in PCOS. Our observations therefore provide further evidence for a causal link between androgen excess and metabolic dysfunction in PCOS. In summary, we have demonstrated that 11-oxygenated androgens are significantly elevated in obese and nonobese women with PCOS and cumulatively constitute a greater proportion of total circulating androgens than classic androgens. This observation has not been replicated in healthy control subjects, where classic androgens appear to constitute the majority of the circulating androgen pool. Intriguingly, 11KT circulates in significantly higher concentrations than T, both in women with PCOS and control subjects, opening up avenues for the exploring the origins of androgen excess in PCOS. Close correlation of a number of 11-oxygenated steroids with hyperinsulinemia further highlight a potential important role for these steroids as biomarkers not only of androgen excess but also of insulin resistance, metabolic dysfunction, and tissue-specific androgen activation in PCOS. Supplementary Material Supplemental_Table_1-2 Click here for additional data file.

In summary, we have demonstrated that 11-oxygenated androgens are significantly elevated in obese and nonobese women with PCOS and cumulatively constitute a greater proportion of total circulating androgens than classic androgens. This observation has not been replicated in healthy control subjects, where classic androgens appear to constitute the majority of the circulating androgen pool. Intriguingly, 11KT circulates in significantly higher concentrations than T, both in women with PCOS and control subjects, opening up avenues for the exploring the origins of androgen excess in PCOS. Close correlation of a number of 11-oxygenated steroids with hyperinsulinemia further highlight a potential important role for these steroids as biomarkers not only of androgen excess but also of insulin resistance, metabolic dysfunction, and tissue-specific androgen activation in PCOS. Supplementary Material Supplemental_Table_1-2 Click here for additional data file. Acknowledgments We thank the nurses of the National Institutes of Health Research/Wellcome Trust Clinical Research Facility, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK, for their help with patient recruitment and running of the study and all the patients and healthy volunteers who participated in this study.

s We thank the nurses of the National Institutes of Health Research/Wellcome Trust Clinical Research Facility, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK, for their help with patient recruitment and running of the study and all the patients and healthy volunteers who participated in this study. This work was supported by the Wellcome Trust (Clinical Research Training Fellowship 099909 to M.W.R. and Project Grant 092283 to W.A.) and the Newton Fund of the Royal Society (International Exchange Grant NI150069 to K.-H.S. and W.A.), by an Academy of Medical Sciences UK Newton Advanced Fellowship (to K.-H.S.), and by the National Institutes of Health Research UK (W.A). The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institutes of Health Research, or the UK Department of Health. Disclosure summary: The authors have nothing to disclose. Abbreviations: 11β-OH-An11β-hydroxyandrosterone 11KA411-ketoandrostenedione 11KT11-ketotestosterone 11OHA411β-hydroxyandrostenedione 11OHT11β-hydroxytestosterone 21OHD21-hydroxylase deficiency A4androstenedione AKR1C3aldo-keto reductase type 1C3 Anandrosterone BMIbody mass index DHEAdehydroepiandrosterone DHEASdehydroepiandrosterone sulfate FAIfree androgen index HOMA-IRhomeostasis model assessment of insulin resistance IQRinterquartile range LC-MS/MSliquid chromatography-tandem mass spectrometry PCOSpolycystic ovary syndrome Ttestosterone