SFEIES24 Oral Communications Oral Communications (10 abstracts)
Investigation of the differential impact of oral classic and 11-oxygenated androgen precursor administration on downstream androgen metabolism and insulin sensitivity in women with polycystic ovary syndrome (PCOS)
Tara McDonnell 1,2 , Leanne Cussen 1,2 , Clare Miller 1,2 , Benson Jacob 1 , Angela E. Taylor 3 , Lorna Gilligan 3 , Wiebke Arlt 3,4,5 , Karl-Heinz Storbeck 6,4 , Leanne Hodson 7 , Jeremy Tomlinson 7 , Mark Sherlock 1,2 & Michael W. O’Reilly 1,2
1Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; 2Department of Endocrinology, Beaumont Hospital, Dublin, Ireland; 3Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom; 4Medical Research Council Laboratory of Medical Sciences, London, United Kingdom; 5Institute of Clinical Sciences, Imperial College London, London, United Kingdom; 6Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa; 7Oxford Centre for Diabetes, Endocrinology, and Metabolism, NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom
Androgen excess is a cardinal biochemical feature of PCOS and correlates closely with markers of insulin resistance. 11-oxygenated androgens are elevated in women with PCOS, however, their relationship with metabolic dysfunction is unclear. The aims of this study were (i) to evaluate the downstream impact on androgen metabolism of oral classic and 11-oxygenated precursor administration and (ii) to delineate the differential impact of androgen excess on insulin sensitivity in women with PCOS. An interventional, open-label study was conducted in 20 women with PCOS. Metabolic phenotyping including hyperinsulinaemic-euglycaemic (HI-EG) clamp testing was carried out at baseline and after 7days of androgen precursor administration. Participants were randomized 1:1 to receive 150 mg of either 11-ketoandrostenedione (11KA4) or dehydroepiandrosterone (DHEA) once daily for 7 days. Serum and urinary multi-steroid profiling was performed by liquid chromatography-tandem mass spectrometry. Enrichment of C13-labelled glucose in exhaled breath samples was determined by gas chromatography-mass spectrometry. Twenty women with PCOS were enrolled (n = 10 in each arm); Median age was 30.9 years (IQR 26-33), median BMI 34.9 kg/m2 (IQR 28.4 – 36.2). Following 7days of 11KA4 150 mg daily, we observed significant increases in serum 11KA4, 11β-hydroxyandrostenedione, 11-ketotestosterone and 11β-hydroxytestosterone(all P < 0.05). Urinary 11-oxygenated androgen metabolites also increased significantly (P < 0.01). Oral DHEA daily resulted in upregulation of classic androgens in both serum and urine, without any significant change in the 11-oxygenated androgen profile. On HI-EG clamp testing, glucose infusion rates, unadjusted for insulin, did not change significantly after either DHEA or 11KA4 administration. Oral administration of the androgen precursors are a powerful in vivo tool to study downstream classic and 11-oxygenated androgen metabolism. Our results demonstrate that orally administered DHEA is converted to androstenedione and further to testosterone, but that conversion of androstenedione to enter the 11-oxygenated pathway is only possible in the adrenal and not following oral ingestion and hepatic first pass.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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