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Key Clinical Message: Cutaneous scaling and associated clinical syndrome displayed in X‐linked ichthyosis mandates multidisciplinary care. Patient with ichthyosis confronts a numerous challenge to an anesthesiologist and demands a rigorous management. As these patients are very vulnerable perioperatively, meticulous care and support are utmost. Ichthyosis is a group of genetic conditions distinguished by the appearance of hyperkeratotic scales on the skin's surface. X‐linked ichthyosis results from a mutation in the steroid sulfatase (STS) gene, which encodes the steroid sulfatase enzyme. Here we report a case of a 6‐year‐old child with X‐linked ichthyosis. He presented to our operation theater for correction of left‐sided undescended testis and underwent surgery uneventfully. To handle X‐linked ichthyosis perioperatively, meticulous planning and efficient anesthetic administration are critical. [ABSTRACT FROM AUTHOR]

Key Clinical Message Cutaneous scaling and associated clinical syndrome displayed in X‐linked ichthyosis mandates multidisciplinary care. Patient with ichthyosis confronts a numerous challenge to an anesthesiologist and demands a rigorous management. As these patients are very vulnerable perioperatively, meticulous care and support are utmost. Abstract Ichthyosis is a group of genetic conditions distinguished by the appearance of hyperkeratotic scales on the skin's surface. X‐linked ichthyosis results from a mutation in the steroid sulfatase (STS) gene, which encodes the steroid sulfatase enzyme. Here we report a case of a 6‐year‐old child with X‐linked ichthyosis. He presented to our operation theater for correction of left‐sided undescended testis and underwent surgery uneventfully. To handle X‐linked ichthyosis perioperatively, meticulous planning and efficient anesthetic administration are critical.

Objective: Ovarian fibromas are benign, sex cord-stromal tumors occurring in both peri- and post-menopausal women. Generally, these tumors are non-functional and do not produce hormones. However, this case report proves the first case of steroid hormone synthesis in an ovarian fibroma by immunohistochemistry. Case report: A 77-year-old post-menopausal woman presented with a left ovarian tumor, abnormal endometrial thickness, and high levels of estradiol (E2). The tumor was found to be a fibroma, which was positive for alpha-inhibin. We examined estrogen-producing enzymes using immunohistochemistry. The tumor was positive for estrogen receptor, progesterone receptor, 17β-hydroxysteroid dehydrogenase (HSD)-1, adrenal 4 binding protein/steroidogenic factor 1, 17β-HSD-5, steroid sulfatase, and P450c17. Conclusion: This case study shows that E2 can be locally produced from circulating inactive steroids, by estrogen-producing enzymes. This is the first report of steroid hormone synthesis in an ovarian fibroma.

Recessive X-linked ichthyosis (RXLI), a genetic disorder caused by deletion or point mutations of the steroid sulfatase (STS) gene, is the second most common form of ichthyosis. It is a disorder of keratinocyte cholesterol sulfate retention and the mechanism of extracutaneous phenotypes such as corneal opacities and attention deficit hyperactivity disorder are poorly understood. To understand the pathomechanisms of RXLI, the transcriptome of differentiated primary keratinocytes with STS knockdown was sequenced. The results were validated in a stable knockdown model of STS, to confirm STS specificity, and in RXLI skin. The results show that there was significantly reduced expression of genes related to epidermal differentiation and lipid metabolism, including ceramide and sphingolipid synthesis. In addition, there was significant downregulation of aldehyde dehydrogenase family members and the oxytocin receptor which have been linked to corneal transparency and behavioural disorders respectively, both of which are extracutaneous phenotypes of RXLI. These data provide a greater understanding of the causative mechanisms of RXLI’s cutaneous phenotype, and show that the keratinocyte transcriptome and lipidomics can give novel insights into the phenotype of patients with RXLI.

Steroid hormones play a crucial role in several aspects of human life, and steroidogenesis is the process by which hormones are produced from cholesterol using several enzymes that work in concert to obtain the appropriate levels of each hormone at the right time. Unfortunately, many diseases, such as cancer, endometriosis, and osteoporosis as examples, are caused by an increase in the production of certain hormones. For these diseases, the use of an inhibitor to block the activity of an enzyme and, in doing so, the production of a key hormone is a proven therapeutic strategy whose development continues. This account-type article focuses on seven inhibitors (compounds 1–7) and an activator (compound 8) of six enzymes involved in steroidogenesis, namely steroid sulfatase, aldo-keto reductase 1C3, types 1, 2, 3, and 12 of the 17β-hydroxysteroid dehydrogenases. For these steroid derivatives, three topics will be addressed: (1) Their chemical synthesis from the same starting material, estrone, (2) their structural characterization using nuclear magnetic resonance, and (3) their in vitro or in vivo biological activities. These bioactive molecules constitute potential therapeutic or mechanistic tools that could be used to better understand the role of certain hormones in steroidogenesis. [ABSTRACT FROM AUTHOR]

Background/aim: Breast cancer is mostly affected by estrogen, which promotes proliferation, tumorigenesis, and cancer progression. Estrogen sulfotransferase (SULT1E1) catalyzes sulfation to inactivate estrogens, whereas steroid sulfatase (STS) catalyzes estrogen sulfate hydrolysis to activate estrogens in breast cancer cells. Three major organosulfur compounds in garlic (Allium sativum L.), diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), are known to exert anticancer effects against breast cancer. This study aimed to investigate the effects of these compounds on proliferation and SULT1E1 and STS protein levels in breast cancer cells., Materials and Methods: Cell proliferation and SULT1E1 and STS protein levels in MCF-7 breast cancer cells treated with DAS, DADS, and DATS were analyzed via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide and western blotting assays, respectively., Results: DADS and DATS concentration-dependently inhibited MCF-7 cell proliferation. Specifically, DATS, followed by DADS and DAS (each 100 μmol/l), demonstrated the most significant inhibition of cell proliferation. DADS and DATS also decreased the STS protein levels. Notably, DAS, DADS, and DATS did not affect the SULT1E1 protein levels. In MCF-7 cells treated with DAS, DADS, and DATS, cell proliferation was positively correlated with STS protein expression., Conclusion: Overall, our findings highlight the potential of DADS and DATS as promising agents for preventing and treating breast cancer by decreasing STS protein expression and suppressing active estrogen levels in breast cancer cells., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The mammalian cytosolic sulfotransferases (SULTs) catalyze the sulfation of endocrine hormones as well as a broad array of drugs, environmental chemicals, and other xenobiotics. Many endocrine-disrupting chemicals (EDCs) interact with these SULTs as substrates and inhibitors, and thereby alter sulfation reactions responsible for metabolism and regulation of endocrine hormones such as estrogens and thyroid hormones. EDCs or their metabolites may also regulate expression of SULTs through direct interaction with nuclear receptors and other transcription factors. Moreover, some sulfate esters derived from EDCs (EDC-sulfates) may serve as ligands for endocrine hormone receptors. While the sulfation of an EDC can lead to its excretion in the urine or bile, it may also result in retention of the EDC-sulfate through its reversible binding to serum proteins and thereby enable transport to other tissues for intracellular hydrolysis and subsequent endocrine disruption. This mini-review outlines the potential roles of SULTs and sulfation in the effects of EDCs and our evolving understanding of these processes., (© 2024 The Author(s).)

The ovaries are key steroid hormone production sites in post-pubertal females. However, current research on steroidogenic enzymes, endogenous hormone concentrations and their effects on healthy ovarian function and malignant development is limited. Here, we discuss the importance of steroid enzymes in normal and malignant ovaries, alongside hormone concentrations, receptor expression and action. Key enzymes include STS, 3β-HSD2, HSD17B1, ARK1C3, and aromatase, which influence ovarian steroidal action. Both androgen and oestrogen action, via their facilitating enzyme, drives ovarian follicle activation, development and maturation in healthy ovarian tissue. In ovarian cancer, some data suggest STS and oestrogen receptor α may be linked to aggressive forms, while various oestrogen-responsive factors may be involved in ovarian cancer metastasis. In contrast, androgen receptor expression and action vary across ovarian cancer subtypes. For future studies investigating steroidogenesis and steroidal activity in ovarian cancer, it is necessary to differentiate between disease subtypes for a comprehensive understanding., (© 2024 The Author(s).)

Abstract Background Ovarian cancer is usually diagnosed at an advanced stage due to its early asymptomatic course and late-stage non-specific symptoms. This highlights the importance of researching the molecular mechanisms involved in ovarian carcinogenesis as well as the discovery of novel prognostic markers that could help improve the survival outcome of patients. The aim of this study was to evaluate the expression of the steroid sulfatase (STS) in 154 samples of primary ovarian tumors. This protein is crucial in the intracellular conversion of sulfated steroid hormones to active steroid hormones. The presence of STS, 3β-HSD, and 17β-HSD1 result in the production of testosterone which act through the androgen receptor (AR) in the tumor cell. The presence of STS and AR in epithelial ovarian tumors and their association to the overall survival of patients was evaluated using Kaplan–Meier and Cox regression analyses. Results Immunoreactivity for STS was detected in 65% of the tumors and no association was observed with histological subtypes and clinical stages of the tumor. The STS expression in the tumors exhibiting immunoreactive AR resulted in a reduced survival (log-rank test, p = 0.032) and a risk factor in univariate and multivariate analysis, HR = 3.46, CI95% 1.00–11.92, p = 0.049 and HR = 5.92, CI95% 1.34–26.09, p = 0.019, respectively. Conclusions These findings suggest that the intracellular synthesis of testosterone acting through its receptor can promote tumor growth and progression. Moreover, the simultaneous expression of STS and AR constitutes an independent predictor of poor prognosis in epithelial ovarian tumors.

• Steroid sulfatase (STS) was examined in male and female mouse tissues. • STS activity was high in livers of both sexes and was also high in testes. • Hepatic and testicular STS activities were lower in younger mice. • STS protein was visualized in hepatocytes, Leydig cells and seminiferous tubules. Steroid hormones often circulate in the plasma as inactive sulfated forms, such as estrone sulfate and dehydroepiandrosterone sulfate. The enzyme steroid sulfatase (STS) converts these steroids into active forms, mainly estrogens, in peripheral tissues. STS is present in most tissues, but it occurs at higher levels in certain organs, notably liver and placenta. In this study, we examined the tissue distribution of STS in a prominent laboratory model, the house mouse (Mus musculus). Tissues included were heart, liver, small intestine, skeletal muscle, and gonads of both sexes. An 3H-estrone-sulfate conversion assay was used to measure STS activity in tissue homogenates and extracts. STS activities were high for hepatic tissue homogenates of both genders. Testicular STS levels were similar to those of liver, while STS activities of ovary, small intestine, heart, and muscle were considerably lower. The specific STS inhibitors, EMATE and STX-64 virtually eliminated STS activity in hepatic microsomes and cytosols, verifying that the observed enzyme activity was due to STS. Enzyme kinetic assays showed Km values of 8.6 µM for liver and 9.1 µM for testis, using E 1 S as substrate. Hepatic and testicular STS activities, measured in CHAPS-extracted microsome, were low up to 5 weeks of age and were higher through 56 weeks. Western blotting, with a specific STS antibody, confirmed the presence of STS protein (65 Da) in both liver and testis. Immunofluorescence of tissue sections detected the presence of STS protein in hepatocytes, in testicular Leydig cells and in seminiferous tubules (Leydig cells and developing germ cells). These results suggest that STS may have a significant role in testicular function. [ABSTRACT FROM AUTHOR]

Steroid sulfation and desulfation participates in the regulation of steroid bioactivity, metabolism and transport. The authors focused on sulfation and desulfation balance in three neurodegenerative diseases: Alzheimer´s disease (AD), Parkinson´s disease (PD), and multiple sclerosis (MS). Circulating steroid conjugates dominate their unconjugated counterparts, but unconjugated steroids outweigh their conjugated counterparts in the brain. Apart from the neurosteroid synthesis in the central nervous system (CNS), most brain steroids cross the blood-brain barrier (BBB) from the periphery and then may be further metabolized. Therefore, steroid levels in the periphery partly reflect the situation in the brain. The CNS steroids subsequently influence the neuronal excitability and have neuroprotective, neuroexcitatory, antidepressant and memory enhancing effects. They also exert anti-inflammatory and immunoprotective actions. Like the unconjugated steroids, the sulfated ones modulate various ligand-gated ion channels. Conjugation by sulfotransferases increases steroid water solubility and facilitates steroid transport. Steroid sulfates, having greater half-lives than their unconjugated counterparts, also serve as a steroid stock pool. Sulfotransferases are ubiquitous enzymes providing massive steroid sulfation in adrenal zona reticularis and zona fasciculata.. Steroid sulfatase hydrolyzing the steroid conjugates is exceedingly expressed in placenta but is ubiquitous in low amounts including brain capillaries of BBB which can rapidly hydrolyze the steroid sulfates coming across the BBB from the periphery. Lower dehydroepiandrosterone sulfate (DHEAS) plasma levels and reduced sulfotransferase activity are considered as risk factors in AD patients. The shifted balance towards unconjugated steroids can participate in the pathophysiology of PD and anti-inflammatory effects of DHEAS may counteract the MS.

Considering the emergence of new anticancer drugs, in this review we emphasized and highlighted the recent reports and advances related to sulfamate-incorporating compounds with potential anticancer activity during the last 5 years (2020-2024). Additionally, we discussed their structure-activity relationship, clarifying their potent bioactivity as anticancer agents. Sulfamate derivatives hold promise as effective therapeutic candidates against cancer. By targeting biological targets associated with the development of cancer, such as steroid sulfatases (STS), carbonic anhydrases (CAs), microtubules, NEDD8-activating enzyme, small ubiquitin-like modifiers (SUMO)-activating enzyme (SAE), cyclin-dependent kinases (CDKs), breast cancer susceptibility gene 1 (BRCA1), and so on, this can furnish small molecules as anticancer lead candidates serving the drug discovery field. For example, compound 2, an STS inhibitor, demonstrated superior activity compared to its reference, irosustat, by fivefold. In addition, compound 21, an SAE, is under phase I clinical trials. Continued research into sulfamate derivatives holds potential for the development of novel therapeutic agents targeting various diseases., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Steroid sulfate esters are important metabolites for anti-doping efforts in sports, pathology and research. Analysis of these metabolites is facilitated by hydrolysis using either acid or enzymatic catalysis. Although enzymatic hydrolysis is preferred for operating at neutral pH, no known enzyme is capable of hydrolyzing all steroid sulfate metabolites. Pseudomonas aeruginosa arylsulfatase (PaS) is ideal for the hydrolysis of β-configured steroid sulfates but like other known class I sulfatases it is inefficient at hydrolyzing α-configured steroid sulfates. We have used directed evolution with liquid chromatography mass spectrometry screening to find variants capable of hydrolyzing a α-configured steroid sulfate: etiocholanolone sulfate (ECS). After targeting two regions of PaS, four residues were identified and optimized to yield a final variant with a total of seven mutations (DRN-PaS) capable of hydrolyzing ECS ~80 times faster than the best PaS variant previously available. This DRN-PaS also shows improved activity for other α-configured steroid sulfates. Simultaneous mutagenesis was essential to obtain DRN-PaS due to complementarity between targeted residues. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is the most common gynecological malignancy in resource-abundant countries. The majority of EC cases are estrogen dependent but the mechanisms of estrogen biosynthesis and oxidative metabolism and estrogen action are not completely understood. Here, we evaluated formation of estrogens in models of moderately and poorly differentiated EC: RL95-2 and KLE cells, respectively. Results revealed high expression of estrone-sulfate (E1-S) transporters (SLCO1A2, SLCO1B3, SLCO1C1, SLCO3A1, SLC10A6, SLC22A9), and increased E1-S uptake in KLE vs RL95-2 cells. In RL95-2 cells, higher levels of sulfatase and better metabolism of E1-S to E1 were confirmed compared to KLE cells. In KLE cells, disturbed balance in expression of HSD17B genes led to enhanced activation of E1 to E2, compared to RL95-2 cells. Additionally, increased CYP1B1 expression and down-regulation of genes encoding phase II metabolic enzymes: COMT, NQO1, NQO2, and GSTP1 suggested decreased detoxification of carcinogenic metabolites in KLE cells. Results indicate that in model cell lines of moderately and poorly differentiated EC, estrogens can be formed via the sulfatase pathway.

In recent years, focusing on new potent anticancer agents with selective activity is one of the greatest challenges in cancer therapy. Breast cancer is the most common cancer and the main cause of cancer deaths in women. The sulfatase enzyme plays an important role in converting the sulfated steroids into non-sulfate steroid hormones, which increases the growth and development of many hormone-dependent cancers, such as breast cancer. In this regard, structure-based optimization was conducted to design novel flavone-sulfonates pharmacophore as a new steroid sulfatase inhibitor. In the present work, the conventional methods for the synthesis of 4-oxo-2-phenyl-4H-chromen-7-yl methanesulfonate derivatives were reported. Their cytotoxicity was evaluated with MTT assay against a breast cancer cell line (MCF-7). The apoptosis inducing activity of the most cytotoxic compound 3c with an IC50 value of 0.615 µM was evaluated in comparison to docetaxel in the presence of estradiol which is a crucial growth factor to survive the cancerous cells. The results of double staining Annexin V-FITC/PI analysis suggested that the cytotoxic activity of this compound 3c in MCF-7 cells occurs via apoptosis. Molecular docking studies were conducted to clarify the inhibition mode of the most promising compound (3c) over the sulfatase (1P49) binding site. The analysis revealed the role of hydrogen bond interaction with Gly181 and hydrophobic interactions through the 1P49 active site in the ligand-receptor complex as significant descriptors to rationalize the potential inhibition activity. [ABSTRACT FROM AUTHOR]

Abstract Background X-linked ichthyosis (XLI; OMIM# 308100) is a recessive keratinization disorder characterized by the presence of dark brown, polygonal, adherent scales on different parts of the body surface. It almost exclusively affects males and the estimated prevalence ranges from 1:2000–6000 in males worldwide. Extracutaneous manifestations are frequent including corneal opacities, cryptorchidism, neuropsychiatric symptoms or others. Up to 90% of XLI cases are caused by recurrent hemizygous microdeletion encompassing entire STS gene on chromosome Xp22.3, while only a minority of patients shows partial deletions or loss of function point mutations in STS. Larger deletions also involving contiguous genes are identified in syndromic patients. Methods Here, we report clinical and genetic findings of a large Pakistani family having 16 affected individuals including 2 females with XLI. Molecular karyotyping and direct DNA sequencing of coding region of the STS gene was performed. Results The clinical manifestations in affected individuals involved generalized dryness and scaling of the skin with polygonal, dark scales of the skin on scalp, trunk, limbs, and neck while sparing face, palms and soles. There were no associated extra-cutaneous features such as short stature, cryptorchidism, photophobia, corneal opacities, male baldness, and behavioral, cognitive, or neurological phenotypes including intellectual disability, autism or attention deficit hyperactivity disorder. Molecular karyotyping was normal and no copy number variation was found. Sanger sequencing identified a novel hemizygous nonsense mutation (c.287G > A; p.W96*), in exon 4 of STS gene in all affected male individuals. In addition, two XLI affected females in the family were found to be homozygous for the identified variant. Conclusions This study is useful for understanding the genetic basis of XLI in the patients studied, for extending the known mutational spectrum of STS, diagnosis of female carriers and for further application of mutation screening in the genetic counseling of this family.

Steroid sulfatase (STS) cleaves sulfate groups from steroid hormones; its expression/activity increases in late pregnancy and into the postpartum period. STS-deficient human and mouse mothers display elevated psychopathology and abnormal behaviour respectively; in mice, these effects can be partially normalised by antipsychotic (ziprasidone) administration.

Background: Ovarian cancer is usually diagnosed at an advanced stage due to its early asymptomatic course and late-stage non-specific symptoms. This highlights the importance of researching the molecular mechanisms involved in ovarian carcinogenesis as well as the discovery of novel prognostic markers that could help improve the survival outcome of patients. The aim of this study was to evaluate the expression of the steroid sulfatase (STS) in 154 samples of primary ovarian tumors. This protein is crucial in the intracellular conversion of sulfated steroid hormones to active steroid hormones. The presence of STS, 3β-HSD, and 17β-HSD1 result in the production of testosterone which act through the androgen receptor (AR) in the tumor cell. The presence of STS and AR in epithelial ovarian tumors and their association to the overall survival of patients was evaluated using Kaplan–Meier and Cox regression analyses. Results: Immunoreactivity for STS was detected in 65% of the tumors and no association was observed with histological subtypes and clinical stages of the tumor. The STS expression in the tumors exhibiting immunoreactive AR resulted in a reduced survival (log-rank test, p = 0.032) and a risk factor in univariate and multivariate analysis, HR = 3.46, CI95% 1.00–11.92, p = 0.049 and HR = 5.92, CI95% 1.34–26.09, p = 0.019, respectively. Conclusions: These findings suggest that the intracellular synthesis of testosterone acting through its receptor can promote tumor growth and progression. Moreover, the simultaneous expression of STS and AR constitutes an independent predictor of poor prognosis in epithelial ovarian tumors. [ABSTRACT FROM AUTHOR]

In post-menopausal women, intra-mammary estrogen, which is converted from extra-ovarian estrone (E1), promotes the growth of breast cancer. Since the aromatase inhibitor letrozole does not suppress 17ß-estradiol (E2) production from E1, high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy. Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with breast cancer progression. In the present study, we introduced a Pgrmc1 heterozygous knockout (hetero KO) murine model exhibiting low Pgrmc1 expression, and observed estrogen levels and steroidogenic gene expression. Naïve Pgrmc1 hetero KO mice exhibited low estrogen (E2 and E1) levels and low progesterone receptor (PR) expression, compared to wild-type mice. In contrast, Pgrmc1 hetero KO mice that have been ovariectomized (OVX), including letrozole-treated OVX mice (OVX-letrozole), exhibited high estrogen levels and PR expression. Increased extra-ovarian estrogen production in Pgrmc1 hetero KO mice was observed with the induction of steroid sulfatase (STS). In MCF-7 cell, letrozole suppressed PR expression, but PGRMC1 knockdown increased PR and STS expression. Our presented results highlight the important role of Pgrmc1 in modulating estrogen production when ovary-derived estrogen is limited, thereby suggesting a potential therapeutic approach for letrozole resistance. [ABSTRACT FROM AUTHOR]

Background: Decreased testosterone (T) to LH ratio and increased 17β‐estradiol (E2) serum concentrations represent a common finding among patients with severe spermatogenic failure, suggesting a concurrent Leydig cell steroidogenic dysfunction. Aromatase overexpression has been associated with increased serum and intratesticular E2 in these patients. However, it is unknown whether the sulfatase pathway contributes to the increased availability of active estrogens in patients with primary spermatogenic failure. Objectives: To assess estrogen sulfotransferase (SULT1E1) and steroid sulfatase (STS) mRNA abundance in testicular tissue of patients with Sertoli cell‐only syndrome (SCOS) and normal tissues, its association with serum and intratesticular hormone levels, and to explore the mRNA and protein testicular localization of both enzymes. Materials and Methods: Testicular tissues of 23 subjects with SCOS (cases) and 22 patients with obstructive azoospermia and normal spermatogenesis (controls) were obtained after biopsy. SULT1E1 and STS transcripts accumulation was quantified by RT‐qPCR. For mRNA and protein localization, we performed RT‐qPCR in Leydig cell clusters and seminiferous tubules isolated by laser‐capture microdissection and immunofluorescence in testicular tissues. Serum and intratesticular hormones were measured by immunoradiometric assays. Results: SULT1E1 mRNA accumulation was similar in both groups. The amount of STS mRNA was higher in cases (p = 0.007) and inversely correlated with T/LH ratio (r = −0.402; p = 0.02). Also, a near significant correlation was observed with intratesticular E2 (r = 0.329, p = 0.057), in agreement with higher intratesticular E2 in cases (p < 0.001). Strong STS immunoreaction was localized in the wall of small blood vessels but not in Leydig cells. Both SULT1E1 and STS mRNA abundance was similar in Leydig cell clusters and the tubular compartment, except for lower SUTL1E1 mRNA in the seminiferous tubules of SCOS patients (p = 0.001). Conclusions: Our results suggest that an unbalance of the STS/SULT1E1 pathway contributes to the testicular hyperestrogenic microenvironment in patients with primary spermatogenic failure and Leydig cell dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. Approximately 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). The reverse reaction is DHEA sulfation. Besides these two enzyme reactions, the DHEAS transported through the cell membrane is important for its distribution and excretion.Case Presentation: We present a female adolescent with overweight and a very high DHEAS. The presence of a DHEAS-producing tumor was rejected using ultrasonography, Magnetic Resonance Tomography (MRT), and dexamethasone suppression. STS deficiency was suspected. Sequence analysis revealed a heterozygous nonsense mutation which predicts a truncation of the carboxyl region of the STS that is implicated in substrate binding. No partial gene deletion outside exon 5 was detected by multiplex ligation-dependent probe amplification. The bioassay revealed normal enzyme activity in the patient's leukocytes. A defect of transporter proteins was suggested. Both efflux [multidrug-resistance protein (MRP)2 and breast cancer-resistance protein (BCRP)] and uptake [organic anion-transporting polypeptide (OATP) and organic anion transporter (OAT) carriers] transporters were studied. Sequence analysis of exons revealed a heterozygous Q141K variant for BCRP.Conclusions: A novel heterozygous nonsense mutation in the STS gene and a known heterozygous missense variant in the BCRP gene were found. The heterozygous nonsense mutation in the STS gene is not supposed to be responsible for STS deficiency. The BCRP variant is associated with reduced efflux transport activity only in its homozygous state. The combination of the two heterozygous mutations could possibly explain the observed high levels of DHEAS and other sulfated steroids.

A series of fluorinated analogs based on the frameworks of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates have been synthesized as steroid sulfatase (STS) inhibitors. The design of chemical structures of new potential STS inhibitors was supported by molecular docking techniques to identify potential interactions between inhibitors and amino acid residues located in the STS active site. The STS inhibitory potency was evaluated on STS isolated from human placenta. We found that compounds substituted with fluorine atom at the meta position demonstrated the highest inhibitory effects in enzymatic STS assay. The most active analog 12e – inhibited STS enzyme with the IC50 value of 36 nM. [ABSTRACT FROM AUTHOR]

Introduction: An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. Approximately 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). The reverse reaction is DHEA sulfation. Besides these two enzyme reactions, the DHEAS transported through the cell membrane is important for its distribution and excretion. Case Presentation: We present a female adolescent with overweight and a very high DHEAS. The presence of a DHEAS-producing tumor was rejected using ultrasonography, Magnetic Resonance Tomography (MRT), and dexamethasone suppression. STS deficiency was suspected. Sequence analysis revealed a heterozygous nonsense mutation which predicts a truncation of the carboxyl region of the STS that is implicated in substrate binding. No partial gene deletion outside exon 5 was detected by multiplex ligation-dependent probe amplification. The bioassay revealed normal enzyme activity in the patient's leukocytes. A defect of transporter proteins was suggested. Both efflux [multidrug-resistance protein (MRP)2 and breast cancer-resistance protein (BCRP)] and uptake [organic anion-transporting polypeptide (OATP) and organic anion transporter (OAT) carriers] transporters were studied. Sequence analysis of exons revealed a heterozygous Q141K variant for BCRP. Conclusions: A novel heterozygous nonsense mutation in the STS gene and a known heterozygous missense variant in the BCRP gene were found. The heterozygous nonsense mutation in the STS gene is not supposed to be responsible for STS deficiency. The BCRP variant is associated with reduced efflux transport activity only in its homozygous state. The combination of the two heterozygous mutations could possibly explain the observed high levels of DHEAS and other sulfated steroids. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis of two Raloxifene monosulfamates and Raloxifene bissulfamate is reported. • The three target compounds were tested against steroid sulfatase (STS) enzyme. • Their binding affinity to estrogen receptor α (Erα) receptor was investigated in comparison to Raloxifene. • The bissulfamate R-bis 7 showed the strongest potency against STS enzyme & T-47D cells. • A stability study of the three target compounds was conducted. All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8 – 9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC 50 of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker. The estrogen receptor-modulating activities of 7 – 9 showed generally lower affinities compared to Raloxifene HCl, diethylstilbestrol and other known ligands, with mono-sulfamate 8 being the best ligand (Ki of 1.5 nM) for ERα binding, although 7 had a Ki of 13 nM and both showed desirable antagonist activity. The antiproliferative activities of the sulfamate derivatives against the T-47D breast cancer cell line showed 7 as most potent (GI 50 = 7.12 µM), comparable to that of Raloxifene. Compound 7 also showed good antiproliferative potency in the NCI-60 cell line panel with a GI 50 of 1.34 µM against MDA-MB-231 breast cancer cells. Stability testing of 7 – 9 showed that bis-sulfamate 7 hydrolyzed by desulfamoylation at a surprisingly rapid rate, initially leading selectively to 8 and finally to Raloxifene 3 without formation of 9. The mechanisms of these hydrolysis reactions could be extensively rationalized. Conversion of Raloxifene (3) into its bis-sulfamate (7) thus produced a promising drug lead with nanomolar dual activity as an STS inhibitor and ERα antagonist, as a potential candidate for treatment of estrogen-dependent breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background X-linked ichthyosis is a dermatological condition caused by deficiency for the enzyme steroid sulfatase. Previously, X-linked ichthyosis/steroid sulfatase deficiency has been associated with developmental and neurological phenotypes. Here, we show for the first time, that X-linked ichthyosis may be comorbid with an additional psychiatric phenotype (psychosis). Case presentation We report the case of an 11-year-old Saudi Arabian boy with X-linked ichthyosis associated with psychosis, mental retardation, autism spectrum disorder, inattentive attention deficit hyperactivity disorder, and epilepsy. Genetic analysis revealed a 1.68 Mb deletion encompassing STS in 95% of cells while biochemical analysis revealed correspondingly low steroid sulfatase activity consistent with a diagnosis of X-linked ichthyosis. The psychotic symptoms could be reasonably well controlled by administration of an atypical antipsychotic. Conclusions This report describes a case of comorbid X-linked ichthyosis and psychosis (most closely corresponding to early-onset schizophrenia) for the first time, and suggests that deficiency for steroid sulfatase and contiguous genes may increase vulnerability to psychosis as well as other psychological disorders.

Background: X-linked ichthyosis (XLI; OMIM# 308100) is a recessive keratinization disorder characterized by the presence of dark brown, polygonal, adherent scales on different parts of the body surface. It almost exclusively affects males and the estimated prevalence ranges from 1:2000–6000 in males worldwide. Extracutaneous manifestations are frequent including corneal opacities, cryptorchidism, neuropsychiatric symptoms or others. Up to 90% of XLI cases are caused by recurrent hemizygous microdeletion encompassing entire STS gene on chromosome Xp22.3, while only a minority of patients shows partial deletions or loss of function point mutations in STS. Larger deletions also involving contiguous genes are identified in syndromic patients. Methods: Here, we report clinical and genetic findings of a large Pakistani family having 16 affected individuals including 2 females with XLI. Molecular karyotyping and direct DNA sequencing of coding region of the STS gene was performed. Results: The clinical manifestations in affected individuals involved generalized dryness and scaling of the skin with polygonal, dark scales of the skin on scalp, trunk, limbs, and neck while sparing face, palms and soles. There were no associated extra-cutaneous features such as short stature, cryptorchidism, photophobia, corneal opacities, male baldness, and behavioral, cognitive, or neurological phenotypes including intellectual disability, autism or attention deficit hyperactivity disorder. Molecular karyotyping was normal and no copy number variation was found. Sanger sequencing identified a novel hemizygous nonsense mutation (c.287G > A; p.W96*), in exon 4 of STS gene in all affected male individuals. In addition, two XLI affected females in the family were found to be homozygous for the identified variant. Conclusions: This study is useful for understanding the genetic basis of XLI in the patients studied, for extending the known mutational spectrum of STS, diagnosis of female carriers and for further application of mutation screening in the genetic counseling of this family. [ABSTRACT FROM AUTHOR]

In the present article, we reviewed the sulfamate-containing compounds reported as bioactive molecules. The possible molecular targets of sulfamate derivatives include steroid sulfatase enzyme, carbonic anhydrases, acyl transferase, and others. Sulfamate derivatives can help treat hormone-dependent tumors including breast, prostate, and endometrial cancers, Binge eating disorder, migraine, glaucoma, weight loss, and epilepsy. Sulfamate derivatives can act also as calcium sensing receptor agonists and can aid in osteoporosis. Furthermore, acyl sulfamate derivatives can act as antibacterial agents against Gram-positive bacteria. A recent study revealed a new side effect of topiramate, a sulfamate-containing compound, which is sialolithiasis. The structural and biological characteristics of the reviewed compounds are presented in detail. Image 1 • The recently reported biologically active sulfamate derivatives have been reviewed. • Sulfamates have been reported as inhibitors of STS, aromatase, carbonic anhydrases (CAs), and 17β-HSD. • Irosustat (7) is an STS inhibitor with no estrogenic side effects and currently in clinical trials. • Compound 33 is DASI, it inhibits both STS and aromatase enzymes. • Topiramate (46) inhibits CA and when combined with phentermine can treat epilepsy and cause weight loss. [ABSTRACT FROM AUTHOR]

Human steroid sulfatase (STS) has been linked with poor prognosis in steroid-associated tumors and represents an important clinical target in cancers, yet the mechanism of STS-induced carcinogenesis remains unclear. To correlate STS with cancer metabolism, we determined the effects of STS on aerobic glycolysis. STS overexpression increased cellular levels of lactic acid, the final product of aerobic glycolysis. Moreover, STS suppressed the oxygen consumption rate (OCR), which represents mitochondrial respiration. Inhibition of STS by the specific inhibitor STX064 recovered STS-induced OCR repression and lactic acid over-production. DHEA, but not DHEA-S, suppressed the OCR level and enhanced lactic acid production. To understand the molecular mechanism of STS-induced cancer metabolism, we measured the expression of glycolytic enzymes hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), which was highly upregulated by STS and DHEA at both protein and mRNA levels. HIF1α is a key mediator of aerobic glycolysis, and STS enhanced HIF1α promoter activity, mRNA expression, and protein expression. Down-regulation of HIF1α by siRNA suppressed the HK2 and PKM2 expression induced by both STS and DHEA. HIF1α siRNA also recovered the OCR repression and lactic acid over-production induced by both STS and DHEA. To explore the mechanism in vivo , we produced transgenic mice overexpressing STS and found that STS expression was particularly enhanced in the lung. Consistent with our in vitro results, the expression of HIF1α, HK2, and PKM2 was also increased in mouse lung tissues. In conclusion, we suggest that STS may induce aerobic glycolysis through enhancing HIF1α expression. • STS and its metabolite DHEA increase lactic acid production and suppress oxygen consumption in HeLa cells. • STS induces expression of glycolytic enzymes both in vivo and in vitro. • STS and DHEA triggers HIF1α induction. • HIF1α is a crucial mediator of STS-induced aerobic glycolysis. [ABSTRACT FROM AUTHOR]

In the present work, we described convenient methods for the synthesis of N‐thiophosphorylated 3‐(4‐aminophenyl)‐coumarin‐7‐O‐sulfamates as steroid sulfatase (STS) inhibitors. To design the structures of the potential STS inhibitors, molecular modeling techniques were used. A computational docking method was used to determine the binding modes of the synthesized inhibitors as well as to identify potential interactions between specified functional groups on the inhibitors and the amino acid residues present in the active site of the enzyme. The inhibitory activities of the synthesized compounds were tested in an enzymatic assay with STS isolated from a human placenta. Within the set of newly synthesized compounds, 9e demonstrated the highest inhibitory activity in the enzymatic assay with an IC50 value of 0.201 μM (the IC50 value of 667‐COUMATE in the same test was 0.062 μM). Furthermore, we tried to verify if the obtained STS inhibitors are able to pass through the cellular membrane effectively in cell line experiments. In the course of our study, we determined the STS activity in the MCF‐7 cell line after incubation in the presence of the inhibitors (at 100 nM concentration). For this evaluation, we included newly synthesized compounds 9a‐g and their N‐phosphorylated analogs 6a‐h, whose synthesis has been previously described. We found that the lowest STS activities were measured in the presence of N‐phosphorylated derivatives 6e (0.1% of STS activity) and 6f (0.2% of STS activity). The measured STS activity in the presence of 667‐COUMATE (used as a reference) was 0.1%. Moreover, at concentrations up to 1 μM, the most active compounds (6e, 6f, 9b, and 9e) did not exert any toxic effects on zebrafish embryos. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is the most common malignancy of the female gynaecological tract and increased exposure to estrogens is a risk factor. EC cells are able to produce estrogens locally using precursors like, among others, adrenal steroids present in the serum. This is referred to as local estrogen metabolism (or intracrinology) and consists of a complex network of multiple enzymes. Particular relevant to the final generation of active estrogens in endometrial cells are: steroid sulfatase (STS), estrogen sulfotransferase (SULT1E1), aromatase (CYP19A1), 17β-hydroxysteroid dehydrogenase (HSD17B) type 1 and type 2. During the last decades, a plethora of studies explored the level of these enzymes in EC but contrasting data were reported, which generated vigorous debate and controversies. Several reviews attempted at clarifying some of the debated issues, but published reviews are based on investigator-defined bibliography selection and not on systematic analysis. Therefore, we performed a systematic review of the literature reporting about the level of STS, SULT1E1, CYP19A1, HSD17B1 and HSD17B2 in EC. Additional intracrine enzymes and networks (e.g., HSD17Bs other than types 1 and 2, aldo-keto reductases, progesterone and androgen metabolism) were non-systematically reviewed as well. • This is a systematic review on: sulfatase, aromatase pathways, HSD17B1 & 2 in endometrial cancer. • Sulfatase pathway is a major route of estrogen supply and removal in endometrial cells. • The balance of the sulfatase pathway is shifted towards the formation of free estrone. • HSD17B1/2 balance is relevant to endometrial pathophysiology. • The intracrine metabolism shows important inter-subject variability. [ABSTRACT FROM AUTHOR]

Abstract Adrenal androgens dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) are potential substrates for intracrine production of testosterone (T) and dihydrotestosterone (DHT), or directly to DHT, by prostate cancer (PCa) cells. Production of DHT from DHEAS and DHEA, and the role of steroid sulfatase (STS), were evaluated ex vivo using fresh human prostate tissue and in vitro using human PCa cell lines. STS was expressed in benign prostate tissue and PCa tissue. DHEAS at a physiological concentration was converted to DHT in prostate tissue and PCa cell lines, which was STS-dependent. DHEAS activation of androgen receptor (AR) and stimulation of PCa cell growth were STS-dependent. DHEA at a physiological concentration was not converted to DHT ex vivo and in vitro , but stimulated in vivo tumor growth of the human PCa cell line, VCaP, in castrated mice. The findings suggest that targeting metabolism of DHEAS and DHEA may enhance androgen deprivation therapy. Highlights • Prostate tissue and prostate cancer cell lines converted DHEAS and DHEA to DHT. • Conversion of DHEAS to DHT depended on steroid sulfatase. • DHEAS and DHEA activated AR and stimulated growth of prostate cancer cell lines. • DHEAS-stimulated growth i n vitro was STS- and AR-dependent. • DHEA sustained growth of prostate cancer cell line VCaP in castrated mice. [ABSTRACT FROM AUTHOR]

Sulfation and desulfation of steroids are opposing processes that regulate the activation, metabolism, excretion, and storage of steroids, which account for steroid homeostasis. Steroid sulfation and desulfation are catalyzed by cytosolic sulfotransferase and steroid sulfatase, respectively. By modifying and regulating steroids, cytosolic sulfotransferase (SULT) and steroid sulfatase (STS) are also involved in the pathophysiology of steroid-related diseases, such as hormonal dysregulation, metabolic disease, and cancer. The estrogen sulfotransferase (EST, or SULT1E1) is a typical member of the steroid SULTs. This review is aimed to summarize the roles of SULT1E1 and STS in steroid homeostasis and steroid-related diseases. [ABSTRACT FROM AUTHOR]

Boron has become a crucial weapon in anticancer research due to its significant intervention in cell proliferation. Being an excellent bio-isosteric replacement of carbon, it has modulated the anticancer efficacy of various molecules in the development pipeline. It has elicited promising results through interactions with various therapeutic targets such as HIF-1α, steroid sulfatase, arginase, proteasome, etc. Since boron liberates alpha particles, it has a wide-scale application in Boron Neutron Capture therapy (BNCT), a radiotherapy that demonstrates selectivity towards cancer cells due to high boron uptake capacity. Significant advances in the medicinal chemistry of boronated compounds, such as boronated sugars, natural/unnatural amino acids, boronated DNA binders, etc. , have been reported over the past few years as BNCT agents. In addition, boronated nanoparticles have assisted the field of bio-nano medicines by their usage in radiotherapy. This review exclusively focuses on the medicinal chemistry aspects, radiotherapeutic, and chemotherapeutic aspects of boron in cancer therapeutics. Emphasis is also given on the mechanism of action along with advantages over conventional therapies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Zebrafish steroid sulfatase (zfSts) was identified in this study. • zfSts was capable of hydrolyzing steroid sulfate including estrone-sulfate. • Catalytic properties of zfSts were comparable to those of human STS. Abstract Steroid sulfatase (STS) plays an important role in the regulation of steroid hormones. Metabolism of steroid hormones in zebrafish has been investigated, but the action of steroid sulfatase remains unknown. In this study, a zebrafish sts was cloned, expressed, purified, and characterized in comparison with the orthologous human enzyme. Enzymatic assays demonstrated that similar to human STS, zebrafish Sts was most active in catalyzing the hydrolysis of estrone-sulfate and estradiol-sulfate, among five steroid sulfates tested as substrates. Kinetic analyses revealed that the K m values of zebrafish Sts and human STS differed with respective substrates, but the catalytic efficiency as reflected by the V max / K m appeared comparable, except for DHEA-sulfate with which zebrafish Sts appeared less efficient. While zebrafish Sts was catalytically active at 28 °C, the enzyme appeared more active at 37 °C and with similar K m values to those determined at 28 °C. Assays performed in the presence of different divalent cations showed that the activities of both zebrafish and human STSs were stimulated by Ca2+, Mg2+, and Mn2+, and inhibited by Zn+2 and Fe2+. EMATE and STX64, two known mammalian steroid sulafatase inhibitors, were shown to be capable of inhibiting the activity of zebrafish Sts. Collectively, the results obtained indicated that zebrafish Sts exhibited enzymatic characteristics comparable to the human STS, suggesting that the physiological function of STS may be conserved between zebrafish and humans. [ABSTRACT FROM AUTHOR]

Highlights • Heavier women had lower serum DHEA, DHT and SHBG compared to their leaner co-twins. • Serum DHEA concentration was best predicted by percent body fat within twin pairs. • Insulin resistance did not explain serum androgen or SHBG levels within twin pairs. • STS and AKR1C genes were more expressed in adipose tissue from the heavier women. • Intra-abdominal fat and leptin were important regarding adipocyte expression of STS. Abstract Objective Obesity may alter serum steroid concentrations and metabolism. We investigated this in healthy young women with increased body fat and their leaner co-twin sisters. Design Age and genetic background both strongly influence serum steroid levels and body composition. This is a cross-sectional study of 13 female monozygotic twin pairs (age, 23–36 years), ten of which were discordant for body mass index (median difference in body weight between the co-twins, 19 kg). Methods We determined body composition by dual energy X-ray absorptiometry and magnetic resonance imaging, serum androgens by liquid chromatography-tandem mass spectrometry, and mRNA expression of genes in subcutaneous adipose tissue and adipocytes. Results The heavier women had lower serum dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) (P < 0.05 for all) compared to their leaner co-twins with no differences in serum testosterone or androstenedione levels. Serum DHEA correlated inversely with %body fat (r = −0.905, P = 0.002), and DHT positively with SHBG (r = 0.842, P = 0.002). In adipose tissue or adipocytes, expressions of STS (steroid sulfatase) and androgen-related genes were significantly higher in the heavier compared to the leaner co-twin, and within pairs, correlated positively with adiposity but were not related to serum androgen levels. None of the serum androgen or SHBG levels correlated with indices of insulin resistance. Conclusions Serum DHEA levels were best predicted by %body fat, and serum DHT by SHBG. These or other serum androgen concentrations did not reflect differences in androgen-related genes in adipose tissue. General or intra-abdominal adiposity were not associated with increased androgenicity in young women. [ABSTRACT FROM AUTHOR]

Androgen signal has been recently suggested to be associated with the progression of bladder cancer. Steroid sulfatase (STS) is a steroid sulfate activation enzyme, considered to be one of the key enzymes in the androgen signaling pathway. However, the role of STS in bladder cancer has not been elucidated. The purpose of the present study was to determine the clinical and functional significance of STS in bladder cancer. Immunohistochemical analysis of surgical specimens obtained by radical cystectomy (n=114) demonstrated that overexpression of STS was associated with the invasion of bladder cancer, as evidenced by the incidence of STS-positive cancers (11.5 and 37.1% in non-muscle invasive and muscle invasive bladder cancers, respectively; P=0.003). STS-positive cancer demonstrated shorter recurrence-free survival and cancer-specific survival (P=0.0027 and 0.0030, respectively). Furthermore, knockdown of STS significantly reduced cell migration and invasion capacities of bladder cancer cells (P<0.001 and P=0.005, respectively), accompanied by the upregulation of E-cadherin and downregulation of vimentin. In summary, the present study demonstrated that STS promotes the invasion capability of bladder cancer via regulation of the epithelial-mesenchymal transition, and may be a useful marker for predicting the progression of bladder cancers. [ABSTRACT FROM AUTHOR]

Highlights • A novel method for a highly sensitive and accurate measurement of SULT1E1 activity is presented. • The sulfatase pathway is actively present in the endometrium and in EC. • STS seems the major route of intracellular estrogen supply in endometrial cells. Abstract Objective Contradictory results are reported about the level of steroid sulfatase (STS), estrogen sulfotransferase (SULT1E1; together, the sulfatase pathway) and aromatase (CYP19A1) in endometrial cancer (EC). The aim of this study was to explore the levels of these enzymes in a well-characterized cohort of EC patients and postmenopausal controls. Materials and Methods Endometrial tissues from 31 EC patients (21 grade 1 and 10 grade 2–3) and 19 postmenopausal controls were collected. Levels of mRNA (RT-qPCR) and protein (immunohistochemistry) were determined. STS enzyme activity was measured by HPLC, whereas SULT1E1 enzyme activity was determined using a novel method based on liquid chromatography-mass spectrometry (LC-MS/MS). Results No significant differences in STS, SULT1E1 mRNA or protein levels and STS:SULT1E1 ratio were found. STS enzyme activity and STS:SULT1E1 activity ratio were significantly decreased in ECs compared with controls. CYP19A1 mRNA levels were lower in ECs than in controls. Conclusion A novel highly sensitive and accurate protocol to assess SULT1E1 activity is presented. STS enzyme activity and the STS:SULT1E1 activity ratio seem to be lower in ECs than in controls. STS is an important route for estrogen supply in endometrial cells. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Reasons for limited effects of sulfatase inhibition in breast cancer was analyzed. • DHT Restoration improves anti-proliferative effects of sulfatase inhibition. • The promising combined treatment for ER + breast cancer has been proposed. Abstract Steroid sulfatase is detectable in most hormone-dependent breast cancers. STX64, an STS inhibitor, induced tumor reduction in animal assay. Despite success in phase І clinical trial, the results of phase II trial were not that significant. Breast Cancer epithelial cells (MCF-7 and T47D) were treated with two STS inhibitors (STX64 and EM1913). Cell proliferation, cell cycle, and the concentrations of estradiol and 5α-dihydrotestosterone were measured to determine the endocrinological mechanism of sulfatase inhibition. Comparisons were made with inhibitions of reductive 17β-hydroxysteroid dehydrogenases (17β-HSDs). Proliferation studies showed that DNA synthesis in cancer cells was modestly decreased (approximately 20%), accompanied by an up to 6.5% in cells in the G0/G1 phase and cyclin D1 expression reduction. The concentrations of estradiol and 5α-dihydrotestosterone were decreased by 26% and 3% respectively. However, supplementation of 5α-dihydrotestosterone produced a significant increase (approximately 35.6%) in the anti-proliferative effect of sulfatase inhibition. This study has clarified sex-hormone control by sulfatase in BC, suggesting that the different roles of estradiol and 5α-dihydrotestosterone can lead to a reduction in the effect of sulfatase inhibition when compared with 17β-HSD7 inhibition. This suggests that combined treatment of sulfatase inhibitors with 17β-HSD inhibitors such as the type7 inhibitor could hold promise for hormone-dependent breast cancer. [ABSTRACT FROM AUTHOR]

Steroid hormones can exist in functionally dissociable sulfated and non-sulfated (free) forms and can exert profound effects on numerous aspects of mammalian physiology; the ratio of free-to-sulfated steroids is governed by the antagonistic actions of steroid sulfatase (STS) and sulfotransferase (SULT) enzymes. Here, I examine evidence from human and animal model studies, which suggests that STS and its major substrate (dehydroepiandrosterone sulfate, DHEAS) and product (DHEA) can influence brain function, behaviour and mental health, before summarising how the activity of this axis varies throughout mammalian pregnancy and the postpartum period. I then consider how the steroid sulfate axis might impact upon normal maternal behaviour and how its dysfunction might contribute towards risk of postpartum psychiatric illness. Understanding the biological substrates underlying normal and abnormal maternal behaviour will be important for maximising the wellbeing of new mothers and their offspring. [ABSTRACT FROM AUTHOR]

Boars exhibit high concentrations of sulfonated estrogens (SE) mainly originating from the testicular-epididymal compartment. Intriguingly, in porcine Leydig cells, sulfonation of estrogens is colocalized with aromatase and steroid sulfatase (STS), indicating that de novo synthesis of unconjugated estrogens (UE), their sulfonation and hydrolysis of SE occur within the same cell type. So far in boars no plausible concept concerning the role of SE has been put forward. To obtain new information on SE formation and hydrolysis, the porcine testicular-epididymal compartment was screened for the expression of the estrogen-specific sulfotransferase SULT1E1 and STS applying real-time RT-qPCR, Western blot and immunohistochemistry. The epididymal head was identified as the major site of SULT1E1 expression, whereas in the testis, it was virtually undetectable. However, SE tissue concentrations are clearly consistent with the testis as the predominant site of estrogen sulfonation. Results from measurements of estrogen sulfotransferase activity indicate that in the epididymis, SULT1E1 is the relevant enzyme, whereas in the testis, estrogens are sulfonated by a different sulfotransferase with a considerably lower affinity. STS expression and activity was high in the testis (Leydig cells, rete testis epithelium) but also present throughout the epididymis. In the epididymis, SULT1E1 and STS were colocalized in the ductal epithelium, and there was evidence for their apocrine secretion into the ductal lumen. The results suggest that in porcine Leydig cells, SE may be produced as a reservoir to support the levels of bioactive UE via the sulfatase pathway during periods of low activity of the pulsatile testicular steroidogenesis. [ABSTRACT FROM AUTHOR]

Abstract: The ups and downs of a multi-year medicinal chemistry optimisation effort in the quest of identifying inhibitors of human steroid sulfatase as potential topical therapeutics are summarised. The focus lies on dead ends, redirection and mastering of the hurdles rather than detailed structure-activity relationship results of a series. In addition to the usual multi-parameter optimisation towards drug-like properties, unexpected barriers prohibitive for the planned clinical application had to be overcome. While a substrate- and mechanism-based design approach rapidly yielded aryl sulfamates as potent, irreversible enzyme inhibitors, this inhibitor class had to be abandoned due to inherent chemical instability in solution. The rescue of the project was a hit class from a random screening approach, but from there it still took quite some efforts to invent potent reversible inhibitors appropriate for development towards a clinical candidate.Graphical abstract: [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis of 21 tricyclic and tetracyclic sulfamates as STS inhibitors. • Design novel nonsteroidal tetracyclic coumarin skeleton for STS inhibition. • Para substitutions at the phenyl ring of tricyclic analogs gave the best STS inhibition. • 9e and 10c had k inact / K I of 28.6 and 19.1 nM−1min−1 on human STS, respectively. • Cytotoxicity of 9e (IC 50 of 0.65 µM) and 10c (IC 50 of 4.7 µM) on T-47D cells. Inhibition of steroid sulfatase (STS) decreases estrogen production and thus, suppresses tumor proliferation. Inspired by irosustat, the first STS inhibitor in clinical trials, we explored twenty-one tricyclic and tetra-heterocyclic coumarin–based derivatives. Their STS enzyme kinetic parameters, docking models, and cytotoxicity toward breast cancer and normal cells were evaluated. Tricyclic derivative 9e and tetracyclic derivative 10c were the most promising irreversible inhibitors developed in this study, with K I of 0.05 and 0.4 nM, and k inact / K I ratios of 28.6 and 19.1 nM−1min−1 on human placenta STS, respectively. [ABSTRACT FROM AUTHOR]

A central part of human sulfation pathways is the spatially and temporally controlled desulfation of biologically highly potent steroid hormones. The responsible enzyme - steroid sulfatase (STS) - is highly expressed in placenta and peripheral tissues, such as fat, colon, and the brain. The shape of this enzyme and its mechanism are probably unique in biochemistry. STS was believed to be a transmembrane protein, spanning the Golgi double-membrane by stem region formed by two extended internal alpha-helices. New crystallographic data however challenge this view. STS now is portraited as a trimeric membrane-associated complex. We discuss the impact of these results on STS function and sulfation pathways in general and we hypothesis that this new STS structural understanding suggests product inhibition to be a regulator of STS enzymatic activity. [Display omitted] • Steroid sulfatase (STS) is a central enzyme, regulating steroid hormone trafficking and action. • New structural data show this STS enzyme to form a trimeric complex, associated with membranes. • These findings may have implications for the mode-of-action of STS and its regulation by product inhibition. [ABSTRACT FROM AUTHOR]

Biscoumarin derivatives, a dimeric form of coumarin, are well known derivatives of coumarin, occurred in the bioactive metabolites of marine and terrestrial organisms. On account of pharmacological and biological applications, biscoumarins have long been the subject of innumerable enzyme inhibition studies. In this review the pros and cons of enzyme inhibition studies of biscoumarins as urease inhibitors, aromatase inhibitors, NPPs, α -glucosidase inhibitors, α -amylase inhibitors, HIV-1 integrase inhibition, steroid sulfatase inhibitors and c-Met inhibitors are discussed in a systematic way. Moreover, the review discusses the structure activity relationship of biscoumarin scaffold with enzyme inhibitory potency which would unleash new avenues for further development. The purpose of the current review is to disclose the value of biscoumarins as potent and efficient enzyme inhibitor. This review provides a guideline to elaborate the diversity of biscoumarin inhibitors by exploring the effects of electronic groups linked with biscoumarin nucleus. [ABSTRACT FROM AUTHOR]

Background: X-linked ichthyosis is a dermatological condition caused by deficiency for the enzyme steroid sulfatase. Previously, X-linked ichthyosis/steroid sulfatase deficiency has been associated with developmental and neurological phenotypes. Here, we show for the first time, that X-linked ichthyosis may be comorbid with an additional psychiatric phenotype (psychosis).Case Presentation: We report the case of an 11-year-old Saudi Arabian boy with X-linked ichthyosis associated with psychosis, mental retardation, autism spectrum disorder, inattentive attention deficit hyperactivity disorder, and epilepsy. Genetic analysis revealed a 1.68 Mb deletion encompassing STS in 95% of cells while biochemical analysis revealed correspondingly low steroid sulfatase activity consistent with a diagnosis of X-linked ichthyosis. The psychotic symptoms could be reasonably well controlled by administration of an atypical antipsychotic.Conclusions: This report describes a case of comorbid X-linked ichthyosis and psychosis (most closely corresponding to early-onset schizophrenia) for the first time, and suggests that deficiency for steroid sulfatase and contiguous genes may increase vulnerability to psychosis as well as other psychological disorders. [ABSTRACT FROM AUTHOR]

X-linked ichthyosis (XLI) is a relatively common, recessive condition caused by mutations in the steroid sulfatase ( STS ) gene. Common loss-of-function mutations in the filaggrin gene ( FLG ) cause ichthyosis vulgaris and predispose individuals to atopic eczema. We report a case of a 6-year-old boy who presented with unusually severe XLI, an increased serum immunoglobulin E level (2120 IU/ml) and moyamoya angiopathy. Whole-exome sequencing identified a gross deletion encompassing the STS in Xp22.31 and the p.K4022X FLG mutation. The deletion is at least 1.6 Mb in size in the proband, based on real-time quantitative polymerase chain reaction results. No other genetic mutations related to ichthyosis, moyamoya or hyper-immunoglobulin E syndrome were detected. Furthermore, his mother's brothers suffered from mild XLI and only had a deletion encompassing the STS . Additionally, his father and older sister suffered from mild ichthyosis vulgaris and had the p.K4022X FLG mutation. We report the first case of XLI with concurrent moyamoya syndrome. Moreover, an IgE-mediated immune response may have triggered the moyamoya signaling cascade in this patient with ichthyosis. Furthermore, our study strengthens the hypothesis that filaggrin defects can synergize with an STS deficiency to exacerbate the ichthyosis phenotype in an ethnically diverse population. [ABSTRACT FROM AUTHOR]

Sulfated steroid hormones, such as dehydroepiandrosterone sulfate or estrone-3-sulfate, have long been regarded as inactive metabolites as they cannot activate classical steroid receptors. Some of them are present in the blood circulation at quite high concentrations, but generally sulfated steroids exhibit low membrane permeation due to their hydrophilic properties. However, sulfated steroid hormones can actively be imported into specific target cells via uptake carriers, such as the sodium-dependent organic anion transporter SOAT, and, after hydrolysis by the steroid sulfatase (so-called sulfatase pathway), contribute to the overall regulation of steroid responsive organs. To investigate the biological significance of sulfated steroid hormones for reproductive processes in humans and animals, the research group “Sulfated Steroids in Reproduction” was established by the German Research Foundation DFG (FOR1369). Projects of this group deal with transport of sulfated steroids, sulfation of free steroids, desulfation by the steroid sulfatase, effects of sulfated steroids on steroid biosynthesis and membrane receptors as well as MS-based profiling of sulfated steroids in biological samples. This review and concept paper presents key findings from all these projects and provides a broad overview over the current research on sulfated steroid hormones in the field of reproduction. [ABSTRACT FROM AUTHOR]