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

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Abstract

We analyzed the androgen metabolome in women with polycystic ovary syndrome by mass spectrometry, revealing that 11-oxygenated androgens represent the majority of circulating androgen excess.

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 11 β-hydroxyandrostenedione, 11-ketoandrostenedione, 11 β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11 β-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 11 β-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.

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Most cited references 28

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The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.

Gerard Conway, Didier Dewailly, Evanthia Diamanti-Kandarakis … (2014)

Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.

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Hyperandrogenemia Predicts Metabolic Phenotype in Polycystic Ovary Syndrome: The Utility of Serum Androstenedione

Michael W. O'Reilly, Angela Taylor, Nicola Crabtree … (2014)

Context: Polycystic ovary syndrome (PCOS) is a triad of anovulation, insulin resistance, and hyperandrogenism. Androgen excess may correlate with metabolic risk and PCOS consensus criteria define androgen excess on the basis of serum T. Here we studied the utility of the androgen precursor serum androstenedione (A) in conjunction with serum T for predicting metabolic dysfunction in PCOS. Patients and Methods: Eighty-six PCOS patients fulfilling Rotterdam diagnostic consensus criteria and 43 age- and body mass index-matched controls underwent measurement of serum androgens by tandem mass spectrometry and an oral glucose tolerance test with homeostatic model assessment of insulin resistance and insulin sensitivity index calculation. We analyzed 24-hour urine androgen excretion by gas chromatography/mass spectrometry. Results: PCOS patients had higher levels of serum androgens and urinary androgen metabolites than controls (all P < .001). Within the PCOS cohort, both serum A and T were positively correlated with the free androgen index (T × 100/SHBG) and total androgen metabolite excretion (all P < .001). All subjects with T above the normal reference range [high T (HT)] also had high A (HA/HT group, n = 56). However, the remaining 30 patients had normal T levels, either in the presence of HA (HA/NT; n = 20) or normal A (NA/NT; n = 10). The groups did not differ in age or BMI. The HA/HT and HA/NT groups had higher total androgen excretion than NA/NT (P < .01 and P < .05, respectively). Multiple linear regression showed a strong negative association between serum androstenedione and insulin sensitivity. The incidence of dysglycemia according to an oral glucose tolerance test increased with the severity of androgen phenotype (NA/NT, 0%; HA/NT, 14%; HA/HT, 25%, P = .03). Conclusion: Simultaneous measurement of serum T and A represents a useful tool for predicting metabolic risk in PCOS women. HA levels are a sensitive indicator of PCOS-related androgen excess.

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Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.

Wiebke Arlt, Elizabeth Walker, Nicole Draper … (2004)

Congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency is associated with accumulation of steroid metabolites, indicating impaired activity of 17alpha-hydroxylase and 21-hydroxylase. However, no mutations have been reported in the CYP17 and CYP21 genes, which encode these P450 enzymes. Affected girls are born with ambiguous genitalia, but their circulating androgens are low, and virilisation does not progress. We aimed to investigate the underlying molecular basis of congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency in affected children. We did sequence analysis of the human gene encoding P450 oxidoreductase, an enzyme that is important in electron transfer from NADPH to P450C17 and P450C21. We studied two unrelated families with a total of three affected children and 100 healthy controls. Wild-type and mutant P450 oxidoreductase proteins were bacterially expressed, purified, and assayed for cytochrome c reductase activity. We identified four mutations encoding single aminoacid changes in P450 oxidoreductase. All patients were compound heterozygotes, whereas their parents and an unaffected sibling harboured a mutation in only one allele. By contrast, no mutations were noted in the controls. Bacterial expression of recombinant mutant proteins revealed deficient or reduced enzyme activity. Molecular pathogenesis of this form of congenital adrenal hyperplasia is caused by mutations in the gene encoding P450 oxidoreductase. Deficiency of this enzyme could suggest an alternative pathway in human androgen synthesis, present only in fetal life, which explains the combination of antenatal androgen excess and postnatal androgen deficiency.

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Author and article information

Contributors

Wiebke Arlt

Journal

Journal ID (nlm-ta): J Clin Endocrinol Metab

Journal ID (iso-abbrev): J. Clin. Endocrinol. Metab

Journal ID (publisher-id): jcem

Title: The Journal of Clinical Endocrinology and Metabolism

Publisher: Endocrine Society (Washington, DC )

ISSN (Print): 0021-972X

ISSN (Electronic): 1945-7197

Publication date Collection: 01 March 2017

Publication date (Electronic): 30 November 2016

Volume: 102

Issue: 3

Pages: 840-848

Affiliations

[1 ]Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;

[2 ]Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Edgbaston, Birmingham B15 2TH, United Kingdom;

[3 ]Department of Biochemistry, Stellenbosch University, Stellenbosch 7600, South Africa; and

[4 ]National Institute of Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University Hospital Birmingham, NHS Foundation Trust, Birmingham B15 2GW, United Kingdom

Author notes

[*]

These authors contributed equally to this work.

[†]

These authors are joint senior authors.

Address all correspondence and requests for reprints to: Professor Wiebke Arlt, DSc, Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. E-Mail: w.arlt@ 123456bham.ac.uk .

Article

Publisher ID: jcem_163285

DOI: 10.1210/jc.2016-3285

PMC ID: 5477805

SO-VID: 75cd9487-df4b-4762-8ac7-29a9368be856

License:

This article has been published under the terms of the Creative Commons Attribution License (CC-BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).

History

Date received : 22 September 2016

Date accepted : 29 November 2016

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Pages: 9

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

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 28

The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.

Hyperandrogenemia Predicts Metabolic Phenotype in Polycystic Ovary Syndrome: The Utility of Serum Androstenedione

Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.

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Cited by 30

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