Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty

Abstract

Context:Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including dehydroepiandrosterone (DHEA) sulfate (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 y; 13 prepubertal, 5 peripubertal, and 12 postpubertal) and 38 age-, sex-, and Tanner stage-matched healthy controls. Serum and 24-hour urine steroid metabolome analysis was performed by mass spectrometry and genetic analysis of the STS gene by multiplex ligation-dependent probe amplification and Sanger sequencing.Results:Genetic analysis showed STS mutations in all patients, comprising 27 complete gene deletions, 1 intragenic deletion and 2 missense mutations. STSD patients had apparently normal pubertal development. Serum and 24-hour urinary DHEAS were increased in STSD, whereas serum DHEA and testosterone were decreased. However, total 24-hour urinary androgen excretion was similar to controls, with evidence of increased 5α-reductase activity in STSD. Prepubertal healthy controls showed a marked increase in the serum DHEA to DHEAS ratio that was absent in postpubertal controls and in STSD patients of any pubertal stage.Conclusions:In STSD patients, an increased 5α-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 prepubertal surge in the serum DHEA to DHEAS ratio that was absent in STSD, indicative of physiologically up-regulated STS activity before puberty. This may represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty.

Polymorphisms of STS gene and SULT2A1 gene and neurosteroid levels in Han Chinese boys with attention-deficit/hyperactivity disorder: an exploratory investigation

“…The STS protein is a microsomal enzyme that converts DHEA-S into its unsulfated form of DHEA, which participates in a neurosteroid biosynthesis pathway of the brain5. Current evidence related to how STS genetic variants affect DHEA(S) concentrations is still scarce265253. Relative to previous investigations, the current study is advantaged in providing data about DHEA, DHEA-S and DHEA-S/DHEA ratios specific in ADHD population.…”

“…In humans, the STS gene is correlated with androgen synthesis and metabolism26, while STS deficiency has been proposed as a risk factor for ADHD1927. Chatterjee et al 28.…”

Sulfation pathways from red to green

“…Mutations in the X-localized gene for the steroid STS cause a skin condition known as X-linked ichthyosis (5), due to a build-up of cholesterol sulfate in the stratum corneum of the skin and visible scaling. Androgen metabolism and steroid secretion had been studied recently in a cohort of male X-linked ichthyosis patients before and after puberty (162). Circulating DHEAS was increased in these patients, whereas serum DHEA and testosterone were decreased.…”

Monogenic Disorders of Adrenal Steroidogenesis

“…This equilibrium was thought to be maintained by 2 counteracting enzymes, the DHEA sulfotransferase SULT2A1, responsible for sulfate conjugation of the DHEA molecule, and steroid sulfatase, STS, cleaving the sulfate group off the DHEAS molecule to make it accessible for downstream activation towards active androgens. However, in a number of in vivo studies, we have previously shown that the inactivating step catalyzed by SULT2A1 is the predominant direction in normal human physiology, whereas STS activity makes only minor contributions to androgen activation [131-133]. …”