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

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2016 Dec 1

PMID 27901631

Citations 101

Authors

Michael W OReilly

Punith Kempegowda

Carl Jenkinson

Angela E Taylor

Jonathan L Quanson

Karl-Heinz Storbeck

Wiebke Arlt

Affiliations

Soon will be listed here.

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.

Citing Articles

Exploring the Predictive Role of 11-Oxyandrogens in Diagnosing Polycystic Ovary Syndrome.

Mody A, Lodish M, Auchus R, Turcu A, Jiang F, Huddleston H Endocrinol Diabetes Metab. 2025; 8(1):e70022.

PMID: 39815717 PMC: 11735743. DOI: 10.1002/edm2.70022.

The Subcutaneous Adipose Microenvironment as a Determinant of Body Fat Development in Polycystic Ovary Syndrome.

Dumesic D, Rasouli M, Katz J, Lu G, Dharanipragada D, Turcu A J Endocr Soc. 2024; 8(11):bvae162.

PMID: 39345868 PMC: 11424691. DOI: 10.1210/jendso/bvae162.

Effects of interleukin-1 receptor antagonism in women with polycystic ovary syndrome-the FertIL trial.

Walchli-Popovic M, Monnerat S, Taylor A, Gilligan L, Schiffer L, Arlt W Front Endocrinol (Lausanne). 2024; 15:1435698.

PMID: 39324125 PMC: 11423739. DOI: 10.3389/fendo.2024.1435698.

The Role of 11-Oxygenated Androgens and Endocrine Disruptors in Androgen Excess Disorders in Women.

Vitku J, Varausova A, Skodova T, Kolatorova L, Vosatkova M, Vcelak J Int J Mol Sci. 2024; 25(17).

PMID: 39273637 PMC: 11395667. DOI: 10.3390/ijms25179691.

SHBG, Free Testosterone, and Type 2 Diabetes Risk in Middle-aged African Men: A Longitudinal Study.

Seipone I, Mendham A, Storbeck K, Oestlund I, Kufe C, Chikowore T J Endocr Soc. 2024; 8(8):bvae129.

PMID: 39055720 PMC: 11272087. DOI: 10.1210/jendso/bvae129.

References

Campana C, Rege J, Turcu A, Pezzi V, Gomez-Sanchez C, Robins D . Development of a novel cell based androgen screening model. J Steroid Biochem Mol Biol. 2015; 156:17-22. PMC: 4748855. DOI: 10.1016/j.jsbmb.2015.11.005. View

Mongraw-Chaffin M, Anderson C, Allison M, Ouyang P, Szklo M, Vaidya D . Association between sex hormones and adiposity: qualitative differences in women and men in the multi-ethnic study of atherosclerosis. J Clin Endocrinol Metab. 2015; 100(4):E596-600. PMC: 4399289. DOI: 10.1210/jc.2014-2934. View

Keevil B . LC-MS/MS analysis of steroids in the clinical laboratory. Clin Biochem. 2016; 49(13-14):989-97. DOI: 10.1016/j.clinbiochem.2016.04.009. View

Pretorius E, Arlt W, Storbeck K . A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids. Mol Cell Endocrinol. 2016; 441:76-85. DOI: 10.1016/j.mce.2016.08.014. View

OReilly M, Taylor A, Crabtree N, Hughes B, Capper F, Crowley R . Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione. J Clin Endocrinol Metab. 2014; 99(3):1027-36. PMC: 3955250. DOI: 10.1210/jc.2013-3399. View

Pretorius E, Africander D, Vlok M, Perkins M, Quanson J, Storbeck K . 11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored. PLoS One. 2016; 11(7):e0159867. PMC: 4956299. DOI: 10.1371/journal.pone.0159867. View

Turcu A, Nanba A, Chomic R, Upadhyay S, Giordano T, Shields J . Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur J Endocrinol. 2016; 174(5):601-9. PMC: 4874183. DOI: 10.1530/EJE-15-1181. View

Stewart P, Shackleton C, Beastall G, Edwards C . 5 alpha-reductase activity in polycystic ovary syndrome. Lancet. 1990; 335(8687):431-3. DOI: 10.1016/0140-6736(90)90664-q. View

Imamichi Y, Yuhki K, Orisaka M, Kitano T, Mukai K, Ushikubi F . 11-Ketotestosterone Is a Major Androgen Produced in Human Gonads. J Clin Endocrinol Metab. 2016; 101(10):3582-3591. DOI: 10.1210/jc.2016-2311. View

10.

Quinkler M, Sinha B, Tomlinson J, Bujalska I, Stewart P, Arlt W . Androgen generation in adipose tissue in women with simple obesity--a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5. J Endocrinol. 2004; 183(2):331-42. DOI: 10.1677/joe.1.05762. View

11.

Swart A, Schloms L, Storbeck K, Bloem L, du Toit T, Quanson J . 11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione. J Steroid Biochem Mol Biol. 2013; 138:132-42. DOI: 10.1016/j.jsbmb.2013.04.010. View

12.

Nada S, Thompson R, Padmanabhan V . Developmental programming: differential effects of prenatal testosterone excess on insulin target tissues. Endocrinology. 2010; 151(11):5165-73. PMC: 2954716. DOI: 10.1210/en.2010-0666. View

13.

Rege J, Nakamura Y, Satoh F, Morimoto R, Kennedy M, Layman L . Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. J Clin Endocrinol Metab. 2013; 98(3):1182-8. PMC: 3590473. DOI: 10.1210/jc.2012-2912. View

14.

Quanson J, Stander M, Pretorius E, Jenkinson C, Taylor A, Storbeck K . High-throughput analysis of 19 endogenous androgenic steroids by ultra-performance convergence chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2016; 1031:131-138. DOI: 10.1016/j.jchromb.2016.07.024. View

15.

Yazawa T, Uesaka M, Inaoka Y, Mizutani T, Sekiguchi T, Kajitani T . Cyp11b1 is induced in the murine gonad by luteinizing hormone/human chorionic gonadotropin and involved in the production of 11-ketotestosterone, a major fish androgen: conservation and evolution of the androgen metabolic pathway. Endocrinology. 2007; 149(4):1786-92. DOI: 10.1210/en.2007-1015. View

16.

Buttler R, Martens F, Fanelli F, Pham H, Kushnir M, Janssen M . Comparison of 7 Published LC-MS/MS Methods for the Simultaneous Measurement of Testosterone, Androstenedione, and Dehydroepiandrosterone in Serum. Clin Chem. 2015; 61(12):1475-83. DOI: 10.1373/clinchem.2015.242859. View

17.

Holownia P, Owen E, Conway G, Round J, Honour J . Studies to confirm the source of 11 beta-hydroxyandrostenedione. J Steroid Biochem Mol Biol. 1992; 41(3-8):875-80. DOI: 10.1016/0960-0760(92)90441-k. View

18.

Pasquali R, Zanotti L, Fanelli F, Mezzullo M, Fazzini A, Labate A . Defining Hyperandrogenism in Women With Polycystic Ovary Syndrome: A Challenging Perspective. J Clin Endocrinol Metab. 2016; 101(5):2013-22. DOI: 10.1210/jc.2015-4009. View

19.

Vassiliadi D, Barber T, Hughes B, McCarthy M, Wass J, Franks S . Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2009; 94(9):3558-66. DOI: 10.1210/jc.2009-0837. View

20.

Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale H, Franks S, Gambineri A . The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol. 2014; 171(4):P1-29. DOI: 10.1530/EJE-14-0253. View