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

Tara McDonnell; Leanne Cussen; Clare Miller; Benson Jacob; Angela Taylor; Wiebke Arlt; Marie McIlroy; Karl Heinz-Storbech; Leanne Hodson; Jeremy Tomlinson; Mark Sherlock; Michael W. O

doi:10.1530/endoabs.99.P6

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Endocrine Abstracts (2024) 99 P6 | DOI: 10.1530/endoabs.99.P6

ECE2024 Poster Presentations Adrenal and Cardiovascular Endocrinology (95 abstracts)

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

Tara McDonnell ^1,2 , Leanne Cussen ^1,2 , Clare Miller ^2,3 , Benson Jacob ³ , Angela Taylor ⁴ , Wiebke Arlt ^4,5,6 , Marie McIlroy ¹ , Karl Heinz-Storbech ⁷ , Leanne Hodson ⁸ , Jeremy Tomlinson ⁸ , Mark Sherlock ^1,2 & Michael W. O’Reilly ^1,2

Err

Author affiliations

¹Royal College of Surgeons in Ireland, Academic Division of Endocrinology, Department of Medicine, Dublin, Ireland; ²Beaumont Hospital, Department of Endocrinology, Dublin, Ireland; ³Royal College of Surgeons in Ireland, Academic Division of Endocrinology, Dublin, Ireland; ⁴University of Birmingham, Institute of Metabolism and Systems Research, Birmingham, UK; ⁵MRC Laboratory of Medical Sciences, UK; ⁶Imperial College London, Institute of Clinical Sciences, UK; ⁷Stellenbosch University, Department of Biochemistry, Stellenbosch, South Africa; ⁸OCDEM, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Headington, UK

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. Androgen excess is a cardinal biochemical feature of PCOS and correlates closely with markers of insulin resistance. 11-oxygenated androgens are the predominant androgens in 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 clamp (HEC) testing was carried out at baseline and after 7 days of androgen precursor administration. Participants were randomized 1:1 to receive 150 mg of either 11-ketoandrostenedione (11KA4) or dehydroandrostenedione (DHEA) for 7 days Serum and urinary multi-steroid profiling was performed by liquid chromatography–tandem mass spectrometry. Twenty women with PCOS were enrolled (n=10 in each intervention arm); 7 women crossed over to complete both study arms. Median age and BMI were 30.9 years (IQR 26–33) and 34.9 kg/m² (IQR 28.4–36.2), respectively. The intervention arms were matched for age and BMI. Following 7 days of 11KA4 150 mg daily, we observed priming of the 11-oxygenated pathway, with statistically significant elevations in serum 11KA4, 11β-hydroxyandrostenedione, 11β-hydroxytestosterone and 11-ketotestosterone (P<0.05 for each). Urinary 11-oxygenated androgen metabolites including 11β-hydroxyandrosterone and 11β-hydroxyetiocholanolone also increased significantly (P<0.01 for each). Serum classic androgens including testosterone did not change significantly after 11KA4. Oral DHEA 150 mg daily resulted in upregulation of classic androgens in both serum and urine, without any significant associated changes in levels of serum or urinary 11-oxygenated androgens. On HEC testing, glucose infusion rates, unadjusted for insulin, did not change significantly after either DHEA or 11KA4 administration (Table 1). Oral administration of the androgen precursors DHEA and 11KA4 is a powerful in vivo tool to study downstream classic and 11-oxygenated androgen metabolism, respectively. Further data and studies are required to delineate whether classic and 11-oxygenated androgens have differential effects on insulin sensitivity and metabolic risk in women with PCOS.

Table 1 The effect of androgen precursor administration on glucose metabolised (M-value) during a Two-Step Hyperinsulinaemic Euglycaemic Clamp.
Metabolic Variable	DHEA			11KA4
	Before	After	P-value	Before	After	P-Value
M value, (mg/kg · min)
Low insulin	1.71 [0.63–2.40]	1.51 [1.14–2.0]	0.41	1.88 [1.53–2.08	1.63 [1.11–2.03]	0.44
High insulin	7.21 [4.38–8.99]	6.99 [4.80–7.97]	0.79	7.16 [5.59–9.16]	8.42 [5.76–9.16]	0.53