The role of sulfated steroid hormones in reproductive processes

Geyer, Joachim; Bakhaus, Katharina; Bernhardt, Rita; Blaschka, C.; Dezhkam, Y; Fietz, Daniela; Grosser, Gary; Hartmann, Katja; Hartmann, Michaela F.; Neunzig, Jens; Papadopoulos, Dimitrios; Sánchez‐Guijo, Alberto; Scheiner‐Bobis, Georgios; Schuler, Gerhard; Shihan, Mazen; Wrenzycki, C.; Wudy, Stefan A.; Bergmann, Martin

doi:10.1016/j.jsbmb.2016.07.002

Cited by 75 publications

(51 citation statements)

References 154 publications

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“…Another four glucuronide carbons were observed as a multiplet (δ 71.9-79.0). As expected, these labelled glucuronide 13 C NMR signals had significantly greater signal intensity than the non-enriched carbons of the steroidal backbone. In summary, the 13…”

Section: Methodssupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

“…The stepwise approach was not investigated for these examples, but could be pursued in by both short (one bond) and long-range (two or three bond) 13 C-1 H coupling, making the 1 H NMR spectrum complex. However, characterisation was more straightforward in the broadband decoupled 13 C NMR spectrum, due to the characteristic splitting caused by 13 C-13 C couplings. For example, testosterone { 13 C 6 }-glucuronide { 13 C 6 }-19 had an apparent doublet of triplets (δ 176.6, J 58.8, 4.9 Hz) observed for the carbonyl carbon, while a second doublet of triplets (δ 104.5, J 47.1, 4.9 Hz) was observed for the anomeric carbon.…”

Section: Methodsmentioning

confidence: 99%

“…Surprisingly, glucuronylation to afford androst-5-ene-3β,17β-diol 3-sulfate 17glucuronide 24 consistently gave low conversion (15%). Purification was achieved by SPE (WAX and C18) in a manner similar to that described for the bisglucuronides above (Section 3.1) to afford the products with > 95% purity and these were characterised by 1 H NMR, 13 C NMR, LRMS, and HRMS. In total, ten pure steroid sulfate glucuronides 23-32…”

Section: Methodsmentioning

confidence: 99%

“…At least 97% of steroids excreted in urine are present as some form of phase II conjugate [11]. However, phase II conjugates also serve other important roles in steroid transport and regulation, with steroids such as dehydroepiandrosterone (DHEA) sulfate and estrone sulfate serving as an endogenous depot in steroid hormone metabolism [12], [13].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of steroid bisglucuronide and sulfate glucuronide reference materials: Unearthing neglected treasures of steroid metabolism

et al. 2019

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Doubly or bisconjugated steroid metabolites have long been known as minor components of the steroid profile that have traditionally been studied by laborious and indirect fractionation, hydrolysis and gas chromatography-mass spectrometry (GC-MS) analysis.Recently, the synthesis and characterisation of steroid bis(sulfate) (aka disulfate or bissulfate) reference materials enabled the liquid chromatography-tandem mass spectrometry (LC-MS/MS) study of this metabolite class and the development of a constant ion loss (CIL) scan method for the direct and untargeted detection of steroid bis(sulfate) metabolites. Methods for direct LC-MS/MS detection of other bisconjugated steroids, such as steroid bisglucuronide and mixed steroid sulfate glucuronide metabolites, have great potential to reveal a more complete picture of the steroid profile. However, access to steroid bisglucuronide or sulfate glucuronide reference materials necessary for LC-MS/MS method development, metabolite identification or quantification is severely limited. In this work, ten steroid bisglucuronide and ten steroid sulfate glucuronide reference materials were synthesised through an ordered combination of chemical sulfation and/or enzymatic glucuronylation reactions. All compounds were purified and characterised using NMR and MS methods. Chemistry for the preparation of stable isotope labelled steroid { 13 C 6 }glucuronide internal standards has also been developed and applied to the preparation of two selectively mono-labelled steroid bisglucuronide reference materials used to characterise more completely MS fragmentation pathways. The electrospray ionisation and fragmentation of the bisconjugated steroid reference materials has been studied.Preliminary targeted ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis of the reference materials prepared revealed the presence of three steroid sulfate glucuronides as endogenous human urinary metabolites.Highlights  Ten steroid bisglucuronide reference materials synthesised and characterised  Ten steroid sulfate glucuronide reference materials synthesised and characterised  Stable isotope labelled internal standards using 18 O and 13 C prepared  Electrospray ionisation and fragmentation of reference materials studied  Three steroid sulfate glucuronide metabolites confirmed in human urine Keywords:Steroid bisglucuronide; steroid sulfate glucuronide; steroid conjugate; phase II metabolism; stable isotope labelled internal standard; mass spectrometry. AbbreviationsCID = collision induced dissociation, CIL = constant ion loss, DHEA = dehydroepiandrosterone, EA = epiandrosterone, E. coli = Escherichia coli, GC-MS = gas chromatography-mass spectrometry, LC-MS = liquid chromatography-mass spectrometry, LC-MS/MS = liquid chromatography-tandem mass spectrometry, NL = neutral loss, PORD = cytochrome P450 Oxido-Reductase Deficiency, SIM = single ion monitoring, SLOS = Smith-Lemli-Opitz Syndrome, SPE = solid phase extraction, SRM = selected reaction monitoring, STSD = Steroi...

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Section: Methodssupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis of steroid bisglucuronide and sulfate glucuronide reference materials: Unearthing neglected treasures of steroid metabolism

et al. 2019

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Sex-Dependent Role of Estrogen Sulfotransferase and Steroid Sulfatase in Metabolic Homeostasis

Garbacz

Jiang

Xie

2017

Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity

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Sulfonation and desulfation are two opposing processes that represent an important layer of regulation of estrogenic activity via ligand supplies. Enzymatic activities of families of enzymes, known as sulfotransferases and sulfatases, lead to structural and functional changes of the steroids, thyroids, xenobiotics, and neurotransmitters. Estrogen sulfotransferase (EST) and steroid sulfatase (STS) represent negative and positive regulation of the estrogen activity, respectively. This is because EST-mediated sulfation deactivates estrogens, whereas STS-mediated desulfation converts the inactive estrogen sulfates to active estrogens. In addition to the known functions of estrogens, EST and STS in reproductive processes, regulation of estrogens and other signal molecules especially at the local tissue levels has gained increased attention in the context of metabolic disease in recent years. EST expression is detectable in the subcutaneous adipose tissue in both obese women and men, and the expression of EST is markedly induced in the livers of rodent models of obesity and type 2 diabetes. STS was found to be upregulated in patients with chronic inflammatory liver diseases. Interestingly, the tissue distribution and the transcriptional regulation of EST and STS exhibit obvious sex and species specificity. EST ablation produces completely opposite metabolic phenotype in female and male obese mice. Adipogenesis is also differentially regulated by EST in murine and human adipocytes. This chapter focuses on the recent progress in our understanding of the expression and regulation EST and STS in the context of metabolic homeostasis.

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Steroid Sulphotransferase and Sulphatase Deficiency

Rumsby

2018

Disorders of Steroidogenesis

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The role of sulfated steroid hormones in reproductive processes

Cited by 75 publications

References 154 publications

Synthesis of steroid bisglucuronide and sulfate glucuronide reference materials: Unearthing neglected treasures of steroid metabolism

Synthesis of steroid bisglucuronide and sulfate glucuronide reference materials: Unearthing neglected treasures of steroid metabolism

Sex-Dependent Role of Estrogen Sulfotransferase and Steroid Sulfatase in Metabolic Homeostasis

Steroid Sulphotransferase and Sulphatase Deficiency

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