Steroid sulfatase sulfatase deficiency and androgen activation before and after puberty

Jan Idkowiak, Angela E Taylor, Sandra Subtil, Donna M. O'neil, Raymon Vijzelaar, Renuka P. Dias, Rakesh Amin, Timothy G. Barrett, Cedric H.l. Shackleton, Jeremy M.w. Kirk, Celia Moss, Wiebke Arlt

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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 catalyzed 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 synthesis and metabolism in STSD have not been studied in detail yet.
Patients and Methods:
We carried out a cross-sectional study in 30 males with STSD (age 6–27 years; 13 pre-pubertal, 5 peri-pubertal, 12 post-pubertal) and 38 age-, sex- and Tanner stage-matched healthy controls. Serum and 24-h urine steroid metabolome analysis was performed by mass spectrometry and genetic analysis of the STS gene by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing.
Genetic analysis showed STS mutations in all patients, comprising 27 complete gene deletions, one intragenic deletion and two missense mutations. STSD patients had apparently normal pubertal development. Serum and 24-h urinary DHEAS were increased in STSD while serum DHEA and testosterone were decreased. However, total 24-h urinary androgen excretion was similar to controls, with evidence of increased 5|ga-reductase activity in STSD. Pre-pubertal healthy controls showed a marked increase in the serum DHEA/DHEAS ratio that was absent in post-pubertal controls and in STSD patients of any pubertal stage.
In STSD patients, an increased 5|ga-reductase activity appears to compensate for a reduced rate of androgen generation by enhancing peripheral androgen activation in affected patients. In healthy controls, we discovered a pre-pubertal surge in the serum DHEA/DHEAS ratio that was absent in STSD, indicative of physiologically upregulated STS activity prior to puberty. This may represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty.
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Original languageEnglish
Pages (from-to)2545-53
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Issue number6
Early online date22 Mar 2016
Publication statusPublished - 2 Jun 2016


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