Role of steroid sulfatase in steroid homeostasis

[liftsiron]

Mol Cell Endocrinol

. 2016 Dec 5;437:142-153.
doi: 10.1016/j.mce.2016.08.019. Epub 2016 Aug 13.
Role of steroid sulfatase in steroid homeostasis and characterization of the sulfated steroid pathway: Evidence from steroid sulfatase deficiency
Alberto Sánchez-Guijo 1 , Jens Neunzig 2 , Adrian Gerber 2 , Vinzenz Oji 3 , Michaela F Hartmann 4 , Hans-Christian Schuppe 5 , Heiko Traupe 3 , Rita Bernhardt 2 , Stefan A Wudy 4
Affiliations

PMID: 27531568 DOI: 10.1016/j.mce.2016.08.019

Abstract

The impact of steroid sulfatase (STS) activity in the circulating levels of both sulfated and unconjugated steroids is only partially known. In addition, the sulfated steroid pathway, a parallel pathway to the one for unconjugated steroids, which uses the same enzymes, has never been characterized in detail before. Patients with steroid sulfatase deficiency (STSD) are unable to enzymatically convert sulfated steroids into their unconjugated forms, and are a good model to elucidate how STS affects steroid biosynthesis and to study the metabolism of sulfated steroids. We quantified unconjugated and sulfated steroids in STSD serum, and compared these results with data obtained from serum of healthy controls. Most sulfated steroids were increased in STSD. However, androstenediol-3-sulfate and epiandrosterone sulfate showed similar levels in both groups, and the concentrations of androsterone sulfate were notably lower. Hydroxylated forms of DHEAS and of pregnenolone sulfate were found to be increased in STSD, suggesting a mechanism to improve the excretion of sulfated steroids. STSD testosterone concentrations were normal, but cholesterol and DHEA were significantly decreased. Additionally, serum bile acids were three-fold higher in STSD. Correlations between concentrations of steroids in each group indicate that 17α-hydroxy-pregnenolone-3-sulfate in men is mainly biosynthesized from the precursor pregnenolone sulfate and androstenediol-3-sulfate from DHEAS. These findings confirm the coexistence of two steroidogenic pathways: one for unconjugated steroids and another one for sulfated steroids. Each pathway is responsible for the synthesis of specific steroids. The equal levels of testosterone, and the reduced level of unconjugated precursors in STSD, support that testosterone is primarily synthesized from sulfated steroids. In consequence, testosterone synthesis in STSD relies on an enzyme with sulfatase activity other than STS. This study reveals that STS is a key player of steroid biosynthesis regulating the availability of circulating cholesterol.

Keywords: Cholesterol; Recessive X-linked ichthyosis; Steroid biosynthesis; Steroid sulfatase; Sulfated steroids.

[Kluso]

Interesting

[reps]

Ok lifts explain this to me in lament terms lol

[liftsiron]

Ok lifts explain this to me in lament terms lol

Guys with low (STSD) are unable to enzymatically convert sulfated steroids into their unconjugated forms, and are a good model to elucidate how STS affects steroid biosynthesis of testosterone. STS is a key player of steroid biosynthesis regulating the availability of circulating cholesterol which is converted to other steroids.. While the abstract says The impact of steroid sulfatase (STS) activity in the circulating levels of both sulfated and unconjugated steroids is only partially known. In addition, the sulfated steroid pathway, a parallel pathway to the one for unconjugated steroids, which uses the same enzymes, has never been characterized in detail before. Patients with steroid sulfatase deficiency (STSD) are unable to enzymatically convert sulfated steroids into their unconjugated forms.
I figure that we will start seeing some type of STS replacement drugs in the near future once science has a better understanding of STSD.

[reps]

Guys with low (STSD) are unable to enzymatically convert sulfated steroids into their unconjugated forms, and are a good model to elucidate how STS affects steroid biosynthesis of testosterone. STS is a key player of steroid biosynthesis regulating the availability of circulating cholesterol which is converted to other steroids.. While the abstract says The impact of steroid sulfatase (STS) activity in the circulating levels of both sulfated and unconjugated steroids is only partially known. In addition, the sulfated steroid pathway, a parallel pathway to the one for unconjugated steroids, which uses the same enzymes, has never been characterized in detail before. Patients with steroid sulfatase deficiency (STSD) are unable to enzymatically convert sulfated steroids into their unconjugated forms.
I figure that we will start seeing some type of STSD replacement drugs in the near future once science has a better understanding of STSD.

Ty brother and you even answered my next question.

My bad I was supposed to say STS replacement drugs, STSD is a deficiency STS.

[liftsiron]

Clin Endocrinol Metab. 2016 Jun; 101(6): 2545–2553.
Published online 2016 Mar 22. doi: 10.1210/jc.2015-4101
PMCID: PMC4891801
PMID: 27003302
Steroid 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,* and Wiebke Arltcorresponding

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.

Sulfation has been identified as a critical step in regulating the balance between conversion of the principal androgen precursor dehydroepiandrosterone (DHEA) to active androgens and its inactivation through sulfation to DHEA sulfate (DHEAS) (Figure 1). The latter reaction is mainly catalyzed by DHEA sulfotransferase, SULT2A1, and recent reports have revealed this enzyme as a crucial switch controlling androgen activation. Disruption of DHEA sulfation due to inactivating mutations in the human gene encoding PAPSS2, a crucial cofactor of SULT2A1, has been shown to result in increased androgen activation and a polycystic ovary syndrome (PCOS) phenotype in both homozygous and heterozygous individuals (1, 2).