Steroid sulfatase contributes to systemic androgen activation in pre-pubertal boys: lessons from steroid sulfatase deficiency

Jan Idkowiak; Angela E Taylor; Donna M O; Sandra Subtil; Raymon Vijzelaar; Renuka P Dias; Rakesh Amin; Timothy G Barrett; Jeremy W Kirk; Cedric H L Shackleton; Celia Moss; Wiebke Arlt

doi:10.1530/endoabs.34.P357

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Endocrine Abstracts (2014) 34 P357 | DOI: 10.1530/endoabs.34.P357

SFEBES2014 Poster Presentations Steroids (39 abstracts)

Steroid sulfatase contributes to systemic androgen activation in pre-pubertal boys: lessons from steroid sulfatase deficiency

Jan Idkowiak ^1, , Angela E Taylor ¹ , Donna M O’Neil ¹ , Sandra Subtil ¹ , Raymon Vijzelaar ² , Renuka P Dias ^3, , Rakesh Amin ⁵ , Timothy G Barrett ^1, , Jeremy W Kirk ⁴ , Cedric H L Shackleton ¹ , Celia Moss ⁶ & Wiebke Arlt ¹

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¹Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK; ²MRC Holland, Amsterdam, The Netherlands; ³Centre for Rare Diseases and Personalized Medicine, University of Birmingham, Birmingham, UK; ⁴Department of Paediatric Endocrinology, Children’s Hospital Birmingham NHS Foundation Trust, Birmingham, UK; ⁵Department of Paediatric Endocrinology, Great Ormond Hospital for Children NHS Trust, London, UK; ⁶Department of Paediatric Dermatology, Children’s Hospital NHS Foundation Trust, Birmingham, UK.

Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including DHEAS, the inactive sulfate ester of the adrenal androgen precursor DHEA. Deficient DHEA sulfation, the opposite enzymatic reaction to that catalysed by STS, results in androgen excess by increased conversion of DHEA to active androgens. STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen homeostasis in STSD has not been studied in detail yet.

Here, we have investigated 30 male patients with genetically confirmed STSD (age 6–30 years) and 45 age- and sex-matched healthy controls including detailed clinical and genetic assessment and serum and 24 h urine steroid analysis by mass spectrometry (GC/MS and LC/MSMS).

Multiplex-ligand probe-amplification (MLPA) revealed that 27/30 (90%) of the STSD patients had complete, isolated deletions of the STS gene; one patient had a partial deletion of exon 7 and two patients had a known, disease-causing missense mutation confirmed by Sanger sequencing. There were no apparent abnormalities in physical development and pubertal progression in STSD patients. Urinary excretion of active androgen metabolites did not differ in STSD and controls. However, serum testosterone levels in the post-pubertal subgroup were lower than in controls (P=0.03), albeit in the normal range. DHEAS and sulfated androgen precursor metabolites were higher in STSD but DHEA was lower. The ratios of serum DHEA:DHEAS, reflecting STS activity, in pre-/peri-pubertal controls were significantly higher than in post-pubertal controls whereas all STSD patients had low DHEA:DHEAS ratios. In addition, STSD patients had a higher ratio of the 5α-reduced glucocorticoid precursor 5α-tetrahydrocortisol over tetrahydrocortisol, indicating enhanced global 5α-reductase activity, possibly compensating for slightly lower testosterone levels via enhanced androgen activation. The finding of a higher DHEA:DHEAS ratio in healthy subjects before puberty suggests a physiological role of STS in androgen regulation prior to but not after puberty.