FP11-2 Compensated Mild Androgen Deficiency in Boys With Steroid Sulfatase Deficiency: Evidence From Steroid Metabolomics

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP11-Pediatric Endocrinology
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:05 AM
Room 104 (Moscone Center)

Poster Board SAT-598
Jan Idkowiak*1, Angela E Taylor1, Donna M O'Neil1, Sandra Subtil1, Raymon Vijzelaar2, Renuka Dias1, Zaki K Hassan-Smith1, Rakesh Amin3, Timothy Barrett1, Paul M Stewart1, Jeremy Kirk4, Celia Moss4, Cedric H Shackleton1 and Wiebke Arlt1
1University of Birmingham, Birmingham, United Kingdom, 2MRC Holland, Amsterdam, Netherlands, 3Great Ormond Street Hospital for Children, London, United Kingdom, 4Birmingham Children's Hospital, Birmingham, United Kingdom
The enzyme Steroid Sulfatase (STS) cleaves sulfate groups from steroid hormones, including the adrenal androgen metabolite DHEAS (1). STS deficiency (STSD) due to inactivating deletions or mutations in the STS gene causes X-linked ichthyosis (OMIM 308100), a skin condition characterized by dry scales due to the epidermal accumulation of cholesterol sulfate. A defect in DHEA sulfation - the opposite enzymatic reaction of STS - results in androgen excess due to increased conversion of DHEA to active androgens (2). The aim of this study was to investigate androgen metabolism in patients with STSD in order to explore whether this defect would have the opposite effect on circulating androgens.

We recruited 30 male patients with STSD (age 6-30 years) and 45 age-matched healthy controls. We genetically confirmed the diagnosis of STSD in all subjects identifying either complete (n=27) or partial deletions (n=1) of the STS gene; two patients harbored a hemizygous missense mutation (p.R454C). The KAL1 locus was intact in all patients. There were no apparent abnormalities in the physical development of the STSD patients. Urinary steroid metabolomics (gas-chromatography/mass-spectrometry) revealed decreased excretion of active androgen precursor metabolites (Androsterone, An and Etiocholoanolone, Et) over androgen precursor metabolites (DHEA, 16hydroxy-DHEA, pregnenediol and 5-pregnenetriol) as compared to controls (p<0.001). 5α-reductase activity assessed as the ratio of 5α-reduced tetrahydrocortisol (THF) over THF (5αTHF/THF) was significantly increased in STSD (p<0.001). Serum steroid measurements (liquid chromatography/ tandem mass spectrometry) revealed decreased DHEA levels in all STSD age-groups (p<0.001) but testosterone was only lower in the adult subgroup (p=0.009). Cholesterol-sulfate was grossly elevated in all STSD subjects but DHEAS levels did not differ significantly. However, the ratio of DHEA/DHEAS was lower in STSD patients (p<0.001).

Our study demonstrates that though physical/pubertal development does not seem to be impaired in STSD, the steroid metabolome of these patients indicate a mild androgen deficiency with elevation of androgen precursors. We hypothesize that this reflects a mechanism of compensation, with further evidence of up regulation of peripheral androgen activation due to increased 5α-reductase activity. This illustrates for the first time in vivo that STS contributes to androgen metabolism in the context of DHEA sulfation.

1.        Reed MJ, Purohit A, Woo LWL, Newman SP, Potter BVL 2005 Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev 26:171–202 2.        Noordam C, Dhir V, McNelis JC, Schlereth F, Hanley NA, Krone N, et al. 2009 Inactivating PAPSS2Mutations in a Patient with Premature Pubarche. N Engl J Med 360:2310–2318

Nothing to Disclose: JI, AET, DMO, SS, RV, RD, ZKH, RA, TB, PMS, JK, CM, CHS, WA

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm