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In order to evaluate the role of substituents at 3-C and 17-C in the cytotoxic and cytoprotective actions of DHEA and 5-AED molecules, their derivatives were synthesized by esterification using the corresponding acid anhydrides or acid chlorides. As a result, seven compounds were obtained: four DHEA derivatives (DHEA 3-propionate, DHEA 3-butanoate, DHEA 3-acetate, DHEA 3-methylsulfonate) and three 5-AED derivatives (5-AED 3-butanoate, 5-AED 3,17-dipropionate, 5-AED 3,17-dibutanoate). All of these compounds showed micromolar cytotoxic activity toward HeLa and K562 human cancer cells. The maximum cytostatic effect during long-term incubation for five days with HeLa and K562 cells was demonstrated by the propionic esters of the steroids: DHEA 3-propionate and 5-AED 3,17-dipropionate. These compounds stimulated the growth of normal Wi-38 cells by 30–50%, which indicates their cytoprotective properties toward noncancerous cells. The synthesized steroid derivatives exhibited antioxidant activity by reducing the production of reactive oxygen species (ROS) by peripheral blood mononuclear cells from healthy volunteers, as demonstrated in a luminol-stimulated chemiluminescence assay. The highest antioxidant effects were shown for the propionate ester of the steroid DHEA. DHEA 3-propionate inhibited luminol-stimulated chemiluminescence by 73% compared to the control, DHEA, which inhibited it only by 15%. These data show the promise of propionic substituents at 3-C and 17-C in steroid molecules for the creation of immunostimulatory and cytoprotective substances with antioxidant properties. [ABSTRACT FROM AUTHOR]

In order to evaluate the role of substituents at 3-C and 17-C in the cytotoxic and cytoprotective actions of DHEA and 5-AED molecules, their derivatives were synthesized by esterification using the corresponding acid anhydrides or acid chlorides. As a result, seven compounds were obtained: four DHEA derivatives (DHEA 3-propionate, DHEA 3-butanoate, DHEA 3-acetate, DHEA 3-methylsulfonate) and three 5-AED derivatives (5-AED 3-butanoate, 5-AED 3,17-dipropionate, 5-AED 3,17-dibutanoate). All of these compounds showed micromolar cytotoxic activity toward HeLa and K562 human cancer cells. The maximum cytostatic effect during long-term incubation for five days with HeLa and K562 cells was demonstrated by the propionic esters of the steroids: DHEA 3-propionate and 5-AED 3,17-dipropionate. These compounds stimulated the growth of normal Wi-38 cells by 30–50%, which indicates their cytoprotective properties toward noncancerous cells. The synthesized steroid derivatives exhibited antioxidant activity by reducing the production of reactive oxygen species (ROS) by peripheral blood mononuclear cells from healthy volunteers, as demonstrated in a luminol-stimulated chemiluminescence assay. The highest antioxidant effects were shown for the propionate ester of the steroid DHEA. DHEA 3-propionate inhibited luminol-stimulated chemiluminescence by 73% compared to the control, DHEA, which inhibited it only by 15%. These data show the promise of propionic substituents at 3-C and 17-C in steroid molecules for the creation of immunostimulatory and cytoprotective substances with antioxidant properties.

The emotion of disgust protects individuals against pathogens, and it has been found to be elevated during pregnancy. Physiological mechanisms discussed in relation to these changes include immune markers and progesterone levels. This study aimed to assess the association between steroids and disgust sensitivity in pregnancy. Using a prospective longitudinal design, we analyzed blood serum steroid concentrations and measured disgust sensitivity via text-based questionnaires in a sample of 179 pregnant women during their first and third trimesters. We found positive correlations between disgust sensitivity and the levels of C19 steroids (including testosterone) and its precursors in the Δ 5 pathway (androstenediol, DHEA, and their sulfates) and the Δ 4 pathway (androstenedione). Additionally, positive correlations were observed with 5α/β-reduced C19 steroid metabolites in both trimesters. In the first trimester, disgust sensitivity was positively associated with 17-hydroxypregnanolone and with some estrogens. In the third trimester, positive associations were observed with cortisol and immunoprotective Δ 5 C19 7α/β-hydroxy-steroids. Our findings show that disgust sensitivity is positively correlated with immunomodulatory steroids, and in the third trimester, with steroids which may be related to potential maternal-anxiety-related symptoms. This study highlights the complex relationship between hormonal changes and disgust sensitivity during pregnancy.

Genetic research of elite athletic performance has been hindered by the complex phenotype and the relatively small effect size of the identified genetic variants. The aims of this study were to identify genetic predisposition to elite athletic performance by investigating genetically-influenced metabolites that discriminate elite athletes from non-elite athletes and to identify those associated with endurance sports. By conducting a genome wide association study with high-resolution metabolomics profiling in 490 elite athletes, common variant metabolic quantitative trait loci (mQTLs) were identified and compared with previously identified mQTLs in non-elite athletes. Among the identified mQTLs, those associated with endurance metabolites were determined. Two novel genetic loci in FOLH1 and VNN1 are reported in association with N-acetyl-aspartyl-glutamate and Linoleoyl ethanolamide, respectively. When focusing on endurance metabolites, one novel mQTL linking androstenediol (3alpha, 17alpha) monosulfate and SULT2A1 was identified. Potential interactions between the novel identified mQTLs and exercise are highlighted. This is the first report of common variant mQTLs linked to elite athletic performance and endurance sports with potential applications in biomarker discovery in elite athletic candidates, non-conventional anti-doping analytical approaches and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Potential mechanistic signal pathways involved in protective role of ADIOL against AA induced colitis. [Display omitted] • The ER-β is highly expressed in the colon and has been shown to play a therapeutic role in IBD. • 5-androstenediol (ADIOL) functions as selective estrogen receptor β (ERβ) ligand. • ADIOL ameliorated AA-induced colitis mostly through increasing expression and activation of ER-β leading to increased NLRP6 expression with subsequent blockade of TLR4-Mediated PI3K/Akt and NF- κ B Pathways. 5-androstenediol (ADIOL) functions as a selective estrogen receptor β (ERβ) ligand with a protective effect against many diseases. So, we conducted a novel insight into its role in acetic acid (AA)-induced colitis and investigated its effect on TLR4-Mediated PI3K/Akt and NF- κ B Pathways and the potential role of ERβ as contributing mechanisms. Methods: Rats were randomized into 5 Groups; Control, Colitis, Colitis + mesalazine (MLZ), Colitis + ADIOL, and Colitis + ADIOL + PHTPP (ER-β antagonist). The colitis was induced through a rectal enema of acetic acid (AA) on the 8th day. At the end of treatment, colons were collected for macroscopic assessment. Tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor kappa b (NF- κ B), toll-like receptor (TLR4), and phosphorylated Protein kinase B (pAKT) were measured. Besides, Gene expression of interleukin-1beta (IL-1β), metalloproteases 9 (Mmp9), inositol 3 phosphate kinase (PI3K), Neutrophil gelatinase-associated lipocalin (NGAL), ERβ and NLRP6 were assessed. Histopathological and immunohistochemical studies were also investigated. Results: Compared to the untreated AA group, the disease activity index (DAI) and macroscopic assessment indicators significantly decreased with ADIOL injections. Indeed, ADIOL significantly decreased colonic tissue levels of MDA, TLR4, pAKT, and NF- κ B immunostainig while increased SOD activity and β catenin immunostainig. ADIOL mitigated the high genetic expressions of IL1β, NGAL, MMP9, and PI3K while increased ERβ and NLRP6 gene expression. Also, the pathological changes detected in AA groups were markedly ameliorated with ADIOL. The specific ERβ antagonist, PHTPP, largely diminished these protective effects of ADIOL. Conclusion: ADIOL could be beneficial against AA-induced colitis mostly through activating ERβ. [ABSTRACT FROM AUTHOR]

The human enzyme 17β-hydroxysteroid dehydrogenase 14 (17β-HSD14) oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD + as cofactor. However, the physiological role of the enzyme remains unclear. We recently described the first class of nonsteroidal inhibitors for this enzyme with compound 1 showing a high 17β-HSD14 inhibitory activity. Its crystal structure was used as starting point for a structure-based optimization in this study. The goal was to develop a promising chemical probe to further investigate the enzyme. The newly designed compounds revealed mostly very high inhibition of the enzyme and for seven of them the crystal structures of the corresponding inhibitor-enzyme complexes were resolved. The crystal structures disclosed that a small change in the substitution pattern of the compounds resulted in an alternative binding mode for one inhibitor. The profiling of a set of the most potent inhibitors identified 13 ( K i  = 9 nM) with a good selectivity profile toward three 17β-HSDs and the estrogen receptor alpha. This inhibitor displayed no cytotoxicity, good solubility, and auspicious predicted bioavailability. Overall, 13 is a highly interesting 17β-HSD14 inhibitor, which might be used as chemical probe for further investigation of the target enzyme. [ABSTRACT FROM AUTHOR]

Introduction: Sepsis is a disease process characterized by an extreme inflammatory response followed by a period of severe immunosuppression. In recent years, there has been improved survival in the initial immune response during systemic inflammatory response syndrome, and compensatory anti-inflammatory response, yet is mostly unchanged with 18–30% mortality during the later stage of sepsis despite numerous Phase 3 clinical trials. Areas covered: This review article presents a critical evaluation of the most promising newer studies aimed at improving the immunosuppressive stage of sepsis. Administration of DHEA/AED/AET show promise in improving survival. Blockade of signaling pathways for PD-1/PD-L1/CTLA-4, and partial blockade of TREM-1 signaling, and modification to sTREM-1 and the JAK/STAT pathway are promising methods of restoring host immune response and improving survival. While there has been significant progress, currently no findings have been translated into effective clinical interventions. Expert commentary: Clinical success by immunomodulation with individual immune mediator is encouraging and should progress to evaluating combined methods of immunoregulation. Since most of the animal studies do not reproduce human sepsis, development of better animal models and moving toward human studies for intervention will lead to the most beneficial findings in translational science. [ABSTRACT FROM PUBLISHER]

Proliferation in endometria of women with polycystic ovarian syndrome (PCOS) is increased, similar to the biosynthesis of androstenediol (estrogenic metabolite). As previously shown, in human endometrial cells, androstenediol increases CYCLIN D1 levels and KI67 and decreases P27 content. The objective of the present investigation was to determine the mechanisms by which androstenediol promotes endometrial cell-cycle progression. Estrogen receptor α (ERα) activation and changes in CYCLIN D1 and P27 levels were evaluated by Western blot in T-HESC and St-T1b endometrial cell lines, using receptor antagonists; activation of PI3K-protein kinase B (AKT) and mitogen-activated protein kinases-extracellular signal–regulated kinases (MAPK-ERK)1/2 pathways was evaluated using PI3K, MAPK/ERK kinase (MEK)1/2, and RNA-polymerase II inhibitors. The data showed that androstenediol treatment significantly increases CYCLIN D1 and decreases P27 levels through ERα activation (P < .05). In addition, an increase in AKT/ERK1/2 phosphorylations was determined (P < .05). In the presence of RNA-polymerase II inhibitor, phosphorylation of AKT/ERK1/2 decreased (P < .05), meaning that endometrial cells need transcriptional activity to activate the kinases involved. It was also observed that PI3K action is required for P27 and CYCLIN D1 changes. Therefore, the action of androstenediol in endometria depends on PI3K-AKT and MAPK-ERK1/2 pathways activation, together with cell transcriptional machinery. This could be of clinical significance, as in pathologies such as PCOS, increased endometrial levels of androstenediol together with a high prevalence of endometrial hyperplasia and adenocarcinoma have been reported. [ABSTRACT FROM AUTHOR]

Aims: We have previously shown that the neurosteroid androstenediol (ADIOL) promotes remyelination following gliotoxin-induced demyelination. However, the impact of this ADIOL on axonal recovery is not yet known. In the present study, we investigated the impact of ADIOL on axonal integrity following a focal demyelination in the corpus callosum. Methods: A 2 µl solution of either ethidium bromide (EB; 0.04%) or pyrogen-free saline were stereotaxically injected into the corpus callosum of Sprague Dawley rats. Each of these two rat groups was divided into two subgroups and received daily subcutaneous injections of either ADIOL (5 mg/kg) or vehicle. The brains were collected at 2, 7 and 14 days post-stereotaxic injection. Immunofluorescent staining was used to explore the impact of ADIOL on axonal integrity (neurofilament (NF)-M) and microglial activation (ionized calcium binding adapter molecule 1, Iba1). The inducible nitric oxide synthase (iNOS) and arginase-1 (arg-1), two major markers of microglial polarization towards the proinflammatory M1 and the regulatory M2 phenotypes respectively, were monitored using western blot. Results: ADIOL increased the density of NF fibers and decreased the extent of axonal damage in the vicinity of the demyelination lesion. ADIOL-induced decrease in axonal damage was manifested by decreased number of axonal spheroids at both 2 and 7 days post-demyelination insult. This reduced axonopathy was associated with decreased expression of iNOS and enhanced expression of arg-1 during the acute phase. Conclusion: These data strongly suggest that ADIOL reduces demyelination-induced axonal damage, likely by dampening the local inflammatory response in the white matter and shifting microglial polarization towards a reparative mode. [ABSTRACT FROM AUTHOR]

17β-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD+ as cofactor. The goal of this study was to identify and optimize 17β-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17β-HSD1 and 17β-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17β-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17β-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a Ki equal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17β-HSD1 and 17β-HSD2 is also addressed. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a progressive neurodegenerative disorder with a wide spectrum of cognitive, behavioral and motor abnormalities. The mitochondrial toxin 3-nitropropionic acid (3-NP) effectively induces specific behavioral changes and selective striatal lesions similar to that observed in HD. Some neurosteroids, synthesized in neurons and glial cells, previously showed neuroprotective abilities. 5-Androstene-3β-17β-diol (ADIOL) is a major metabolite of dehydroepiandrosterone (DHEA) with previously reported anti-inflammatory, anti-apoptotic and neuroprotective activities. The neuroprotective potential of ADIOL in HD was not previously investigated. Therefore, the present study investigated the neuroprotective effects of ADIOL against 3-NP-induced behavioral changes, oxidative stress, inflammation and apoptosis. Intraperitoneal administration of 3-NP (20 mg/kg) for 4 consecutive days in rats caused significant loss in body weight, reduced prepulse inhibition (PPI) of acoustic startle response, locomotor hypoactivity with altered cortical/striatal histological structure, increased cortical/striatal oxidative stress, inflammation and apoptosis. Administration of ADIOL (25 mg/kg, s.c.) for two days before 3-NP significantly attenuated the reduction in body weights and PPI, increased locomotor activity and restored cortical/striatal histological structure nearly to normal. Moreover, it displayed anti-oxidant, anti-inflammatory and anti-apoptotic activities as evidenced by the elevation of cortical and striatal reduced glutathione levels, reductions of cortical and striatal malondialdehyde, striatal tumor necrosis factor alpha and interleukin-6 levels. Only a small number of iNOS and caspase-3 positive cells were detected in sections from rats pretreated with ADIOL. This study suggests a potential neuroprotective role of ADIOL against 3-NP-induced Huntington's disease-like manifestations. Such neuroprotection can be attributed to its anti-oxidant, anti-inflammatory and anti-apoptotic activities. [ABSTRACT FROM AUTHOR]

Women with polycystic ovary syndrome (PCOS) show high prevalence of endometrial hyperplasia and adenocarcinoma. Endometrial proliferation is increased, evaluated by high levels of Ki67 (cell cycle marker) and low levels of p27 (negative regulator of cell cycle). Nevertheless, endometrial changes in cyclin D1 (positive regulator of cell cycle) in PCOS-women are not described. Androst-5-ene-3β,17β-diol (androstenediol), steroid with estrogenic activity present in endometria, could be related to increased endometrial cell proliferation. The objective of this study was to determine protein content of cyclin D1 and androstenediol levels in endometria from PCOS and control-women and to evaluate the possible mechanism favoring cell proliferation associated with hormonal characteristics of patients. Therefore, cyclin D1 protein content in PCOS-women and control-endometrial tissue were assessed by western blot and immunohistochemistry. The androstenediol levels were evaluated by ELISA. To further analyze the effect of steroids (androstenediol, 17β-estradiol, testosterone) in cell proliferation, levels of proteins cyclin D1, p27 and Ki67 were evaluated in an in vitro model of stromal endometrial cells T-HESC and St-T1b. An increase in cyclin D1 and androstenediol was observed in tissues from PCOS-women relative to control group ( p < 0.05). In the in vitro model, androstenediol exerted increase in cyclin D1 ( p < 0.05) and a decrease in p27 protein level ( p < 0.05), while Ki67 in St-T1b cells increased under this stimulus ( p < 0.05). Testosterone produces opposite effects in the levels of the above markers ( p < 0.05). Therefore, the hormonal imbalance associated with this syndrome could alter endometrial tissue homeostasis, promoting cell proliferation. Androstenediol is a molecule that could be involved by stimulating proliferation, whereas testosterone elicits a role of cell cycle repressor. [ABSTRACT FROM AUTHOR]

β Androstene steroids up-regulate immunity to increase host resistance against lethal infection by viruses, bacteria, and parasites. They also repair injury after lethal radiation exposure by mediating a rapid recovery of hematopoietic precursor cells. β Androstenes increase the levels of the TH1 cytokines, IL-2, IL-3, IFNγ and counteract hydrocortisone mediated immune suppression. Increased host resistance results in protection from lethal infection by DNA or RNA viruses such as herpes virus, coxsackievirus B4, influenza, and arthropod borne viruses. They provide similar protection against lethal Gram positive and negative bacteria as well as parasitic infections. During shock response, the hypothalamic-pituitary-adrenal axis (HPA) causes unchecked inflammation and sepsis. Androstenetriol treatment reduces Th2 and increases in Th1 cytokines, and significantly increases survival after severe trauma hemorrhage and shock by modulating the HPA response. In contrast to its epimer, 17α androstenediol inhibits proliferation and mediates apoptosis in tumor cells of murine and human origin and autophagy in human glioblastoma. The anti-proliferative functions or the immune up regulation by these neurosteroids are independent of either the estrogen or androgen receptors for activity. Results demonstrate that endoplasmic reticulum (ER) stress is linked to 17α androstenediol induced autophagy by PERK/eIF2 signaling in human malignant glioma cells and transformed fibroblast. The β androstene hormones increase host resistance to infections by enhancing cell mediated immunity while α androstene exerts an anti- tumor effect by apoptosis, autophagy and increase ER stress. [ABSTRACT FROM AUTHOR]

Many synthetic chemicals with structural similarity to estradiol bind to the estrogen receptor and disrupt the normal estrogen physiology in humans and other vertebrates. Most of these xenoestrogens contain a structure that mimics the phenolic A ring on E2. This phenolic A ring is a defining property of E2 that distinguishes it from aldosterone, cortisol, progesterone and testosterone. However, Δ5-androstenediol, 5α-androstanediol and 27-hydroxycholesterol also have estrogenic activity, despite having important structural differences in their A rings compared to E2. Unlike E2, these steroids have a saturated A ring with a 3β-hydroxyl and a C19 methyl group. An implication of their estrogenic activity is that synthetic chemicals containing a saturated A ring with a 3β-hydroxyl and a C19 methyl group are potential xenoestrogens. [ABSTRACT FROM AUTHOR]

Abstract: Novel 17-exo-oxadiazoles in the androst-5-ene series were efficiently synthesized in a two-step sequence via the corresponding O-acylamidoxime intermediates (obtained from steroidal 17-carboxylic acids and amidoximes in the presence of coupling reagent), which then underwent tetrabutylammonium fluoride-induced cyclocondensation under mild reaction conditions. The synthesized compounds were subjected to in vitro pharmacological studies to investigate their inhibitory effect on rat testicular C17,20-lyase and their antiproliferative action on four malignant human adherent cell lines (HeLa, MCF7, A2780 and A431). One of the oxadiazolyl derivatives proved to exert significant enzyme-inhibitory action (IC50 = 0.60 μM), while some of the isolated O-acylated amidoxime intermediates displayed high cytotoxic activities on all examined cell lines, with IC50 values in the range 0.22–3.94 μM. [Copyright &y& Elsevier]

DHEA, 17α-AED, 17β-AED, and 17β-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED, and 17β-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERα may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR, only in the presence of high dexamethasone concentrations. These results underscore themajor difference between androstene hormone interactions with these nuclear receptors and their biological effects. [ABSTRACT FROM AUTHOR]

Δ5-androstene-3β,17α-diol (17α-AED) mediates oncophagy of human myeloid, glioma, and breast tumor cells by apoptotic- and autophagic-programmed cell death pathways, whereas the 17β-epimer does not. In hematologically derived myeloid tumor cells, 17α-AED induced apoptosis, as determined by TUNEL staining, caspase, PARP activation, and electron microscopy. In contrast, 17α-AED treatment of glioma cells of neuroectodermal lineaged induced autophagy, evident by the presence of acidic vesicular organelles, LC3 processing, and upregulation of beclin-1. Proliferation inhibition studies on primary and established glioma cells demonstrated that the IC-50 of the steroid is ∼15 μM. In the case of breast cancer cells, the bioactivity of 17α-AED is independent of the expression of estrogen or androgen receptors. Collectively, oncophagy is induced by 17α-AED treatment in human tumor cells and proceeds by the induction of either autophagy or apoptosis. The neoplastic cell determines which oncophagic pathway is utilized. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To compare the bleeding patterns and cycle control of an oral contraceptive (OC) containing ethinylestradiol (EE) 30μg/drospirenone (drsp) 3mg administered in a 21/7 regimen versus a lower-dose OC containing EE 20μg/drsp 3mg administered in a 24/4 regimen, using data from two identically designed studies. Materials and methods: In the first study, 326 healthy women (18–35years) received EE 30μg/drsp 3mg in a 21/7 regimen. In the second study, 1027 healthy women (17–36years) received EE 20μg/drsp 3mg in a 24/4 regimen. Participants recorded bleeding using daily completed diaries over 13 treatment cycles. Results: During cycles 1–12, the prevalence of scheduled withdrawal bleeding was lower with EE 20μg/drsp 3mg 24/4 than with EE 30μg/drsp 3mg 21/7 (82.0–91.7% versus 94.8–100.0% of women, respectively); moreover, a higher proportion of women reported a maximum intensity of light scheduled withdrawal bleeding with EE 20μg/drsp 3mg 24/4 than with EE 30μg/drsp 3mg 21/7 (30.9–39.0% versus 13.8–20.5% of women, respectively). In cycles 2–13, unscheduled intracyclic bleeding was reported by 7.7–13.8% of EE 20μg/drsp 3mg 24/4 recipients and 3.8–7.9% of EE 30μg/drsp 3mg 21/7 recipients; these were mainly single bleeding days. During reference periods 1–4, the mean number of bleeding episodes was similar between groups (3.1–3.3 episodes with EE 20μg/drsp 3mg 24/4 versus 3.2 episodes with EE 30μg/drsp 3mg 21/7). Conclusions: A low-dose 24/4 regimen OC containing EE 20μg/drsp 3mg is generally comparable in terms of bleeding to a higher-dose 21/7 regimen OC containing EE30μg/drsp 3mg. Between-treatment differences in bleeding intensity and unscheduled intracyclic bleeding rates were observed. [Copyright &y& Elsevier]

Abstract: Steroid sulfatase plays a pivotal role in regulating the formation of biologically active steroids from inactive steroid sulfates. It is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be subsequently reduced to steroids with estrogenic properties (i.e. estradiol and androstenediol) that can stimulate the growth of tumors in hormone-responsive tissues of the breast, endometrium and prostate. Hence, the action of steroid sulfatase is implicated in physiological processes and pathological conditions. It has been five years since our group last reviewed the important role of this enzyme in steroid synthesis and the progress made in the development of potent inhibitors of this important enzyme target. This timely review therefore concentrates on recent advances in steroid sulfatase research, and summarises the findings of clinical trials with Irosustat (BN83495), the only steroid sulfatase inhibitor that is being trialed in postmenopausal women with breast or endometrial cancer. [Copyright &y& Elsevier]

Abstract: The potent anti-inflammatory activity of exogenous dehydroepiandrosterone (DHEA) in rodents has not translated to humans. This disparity in pharmacological effects has been attributed to factors such as differences in expression and function of molecular targets and differential metabolism. Hepatocytes from rats, dogs, monkeys, and humans were used to measure species-specific metabolism of a related compound, androst-5-ene-3β,17β-diol (5-AED) using reversed-phase radio-HPLC, to explore the metabolic contribution to this interspecies disparity. We found that rat hepatocytes transformed 5-AED predominantly into an array of highly oxidized metabolites. Canine metabolites overlapped with rat, but contained a greater abundance of less hydrophilic species. Monkey and human metabolites were strikingly less hydrophilic, dominated by 5-AED and DHEA conjugates. From the accumulating evidence indicating that the DHEA anti-inflammatory activity may actually reside in its more highly oxidized metabolites, we advance a hypothesis that the virtual absence of these metabolites in humans is central to the failure of exogenous DHEA to produce a potent pharmacological effect in clinical investigations. Accordingly, emulation of its anti-inflammatory activity in humans will require administration of an active native metabolite or a synthetic pharmaceutical derivative. [Copyright &y& Elsevier]

Abstract: Doping control laboratories accredited by the World Anti-Doping Agency (WADA) require criteria that allow endogenous steroids to be distinguished from their synthetic analogues in urine. Methodology based on “looking outside the metabolic box” was used in this study to identify diagnostic urinary markers of 4-androstenediol (4-ADIOL) administration. Androst-2,4-diene-17-one and androst-3,5-diene-17-one are proposed to be formed in urine from acid-catalyzed hydrolysis of 4-ADIOL sulfoconjugate, a major phase II metabolic product of 4-ADIOL. The presence of these markers in the routine gas chromatography–mass spectrometry (GC–MS) steroid screen was suitable to identify samples requiring confirmation by gas chromatography–combustion-isotope ratio mass spectrometry (GC–C-IRMS) – to measure the carbon isotope ratio (δ 13C) of the androstdiene markers and confirm their likely synthetic origin based on depleted 13C content. [Copyright &y& Elsevier]

Summary: Microglia and astrocytes play essential roles in the maintenance of homeostasis within the central nervous system, but mechanisms that control the magnitude and duration of responses to infection and injury remain poorly understood. Here, we provide evidence that 5-androsten-3β,17β-diol (ADIOL) functions as a selective modulator of estrogen receptor (ER)β to suppress inflammatory responses of microglia and astrocytes. ADIOL and a subset of synthetic ERβ-specific ligands, but not 17β-estradiol, mediate recruitment of CtBP corepressor complexes to AP-1-dependent promoters, thereby repressing genes that amplify inflammatory responses and activate Th17 T cells. Reduction of ADIOL or ERβ expression results in exaggerated inflammatory responses to TLR4 agonists. Conversely, the administration of ADIOL or synthetic ERβ-specific ligands that promote CtBP recruitment prevents experimental autoimmune encephalomyelitis in an ERβ-dependent manner. These findings provide evidence for an ADIOL/ERβ/CtBP-transrepression pathway that regulates inflammatory responses in microglia and can be targeted by selective ERβ modulators. PaperClip: Display Omitted [ABSTRACT FROM AUTHOR]

Abstract: Two natural 5-androstene steroid tetrols, androst-5-ene-3β,7β,16α,17β-tetrol (HE3177) and androst-5-ene-3α,7β,16α,17β-tetrol (HE3413), were discovered in human plasma and urine. These compounds had significant aqueous solubility, did not bind or transactivate steroid-binding nuclear hormone receptors, and were not immunosuppressive in murine mixed-lymphocyte studies. Both compounds appear to be metabolic end products, as they were resistant to primary and secondary metabolism. Both were orally bioavailable, and were very well tolerated in a two-week dose-intensive toxicity study in mice. Anti-inflammatory properties were found with exogenous administration of these compounds in rodent disease models of multiple sclerosis, lung injury, chronic prostatitis, and colitis. [Copyright &y& Elsevier]

It has been established that carrying a pregnancy to full-term at an early age can protect against contracting cancer by up to 50% in later life. The trophoblast theory of cancer states that trophoblast and cancer tissue are very similar. New findings suggest that the loss of fetal cells during pregnancy resemble those cells responsible for causing metastasis in cancer. Fetal cells and spreading cancer cells are highly proliferative. They are similar to stem cells, exhibiting no or low hormone receptor expression, and require a hormone receptor independent mechanism for control. Control of membrane stability during pregnancy is of vital importance for a successful pregnancy and is mediated by androstenediol and 2-methoxyestradiol. 2-Methoxyestradiol has no hormone receptor affinity and elicits strong anticancer effects particularly against cancer stem cells and fetal cells, for which currently no treatment has yet been established. There is a discussion whether pregnancy reduces cancer stem cells in the breast. Soy isoflavones are structurally similar to both hormones, and elicit strong anticancer effects and antiangiogenesis via inhibition of NF-κB, even in hormone receptor independent breast cancers seen in epidemiologic studies. The trophoblast theory of cancer could help to explain why soy baby nutrition formulas have no effect on baby physiology, other than the nutritional aspect, although soy elicits many effects on the adult immune system. To survive the immune system of the mother, the immune system of the fetus has to be separated; otherwise, the reduction of the immune system in the mother, a necessary feature for the blastocyst to grow, would immediately reduce the immunity for the fetus and endanger its survival. Similar to a fetus, newly born babies show immune insensitive to Th1 and Th2 cytokines, which are necessary and crucial for regulating the immune system of the mother, thus raising the risk of the baby of developing allergies and neurodermatitis. Gene expression studies in vitro as well as in circulating tumor cells from patients consuming a fermented soy product support the antiangiogenic as well as antiproliferative effects of soy. [ABSTRACT FROM AUTHOR]

Abstract: The changes in endometrial homeostasis found in women with polycystic ovarian syndrome (PCOS) could be associated with alterations in the intracrine metabolism of steroid hormones. The uptake of dehydroepiandrosterone-sulphate (DHEA-S), precursor of the intracrine pathway, is achieved by transporters, such as organic anion transporter polypeptides (OATPs), and molecules with oestrogenic activity, such as androst-5-ene-3β,17β-diol (androstenediol), can be generated. We aimed to determine androstenediol generation and the expression of OATPs in human endometria throughout the menstrual cycle and in endometria from PCOS women. Endometrial samples were obtained from control women in the proliferative phase (control endometria (CEp), n =7), secretory phase (CEs, n =7), and from PCOS patients (PCOSEp, n =7). The mRNA levels of OATP-B, OATP-D and OATP-E were measured by reverse transcriptase polymerase chain reaction (RT-PCR) and protein levels of OATP-E by immunofluorescence; 3β-hydroxysteroid dehydrogenase (HSD) by immunohistochemistry/Western blot; the metabolism of DHEA to androstenediol was evaluated by thin layer chromatography–high-performance liquid chromatography (TLC–HPLC). Lower levels of OATP-E transcript were obtained in PCOSEp (p <0.05) compared with CEp, while OATP-E protein levels (p <0.05) and DHEA conversion to androstenediol (p <0.01) were higher in PCOSEp. Lower 3β-(hydroxysteroid dehydrogenase) HSD protein levels were found in PCOSEp (p <0.05) (Western blot, immunohistochemistry). These results reveal a higher capacity of the endometria from PCOS women to metabolise DHEA to androstenediol, which, coupled with the high oestrogen sensitivity previously found in these endometria, may account for the increase in cell proliferation in PCOSEp already reported. [ABSTRACT FROM AUTHOR]

5-androstenediol (5-AED) has been advanced as a possible countermeasure for treating the haematological component of acute radiation syndrome (ARS). It has been used in animal models to stimulate both innate and adaptive immunity and treat infection and radiation-induced immune suppression. We here report on the safety, tolerability and haematologic activity of 5-AED in four double-blinded, randomized, placebo-controlled studies on healthy adults including elderly subjects. A 5-AED injectable suspension formulation (NEUMUNE) or placebo was administered intramuscularly as either a single injection, or once daily for five consecutive days at doses of 50, 100, 200 or 400 mg. Subjects (n = 129) were randomized to receive NEUMUNE (n = 95) or the placebo (n = 34). NEUMUNE was generally well-tolerated; the most frequent adverse events were local injection site reactions (n = 104, 81%) that were transient, dose-volume dependent, mild to moderate in severity, and that resolved over the course of the study. Blood chemistries revealed a transient increase (up to 28%) in creatine phosphokinase and C-reactive protein levels consistent with intramuscular injection and injection site irritation. The blood concentration profile of 5-AED is consistent with a depot formulation that increases in disproportionate increments following each dose. NEUMUNE significantly increased circulating neutrophils (p < 0.001) and platelets (p < 0.001) in the peripheral blood of adult and elderly subjects. A dose-response relationship was identified. Findings suggest that parenteral administration of 5-AED in aqueous suspension may be a safe and effective means to stimulate innate immunity and alleviate neutropenia and thrombocytopenia associated with ARS. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we identified a mechanism by which the neuro-steroid, 5-androstene 3β,17α diol (17α-AED) induces autophagy in human malignant glioma cells and transformed fibroblasts. 17α-AED treatment induced endoplasmic reticulum (ER) stress, identified by the partial activation of an unfolded protein response in T98G, U87MG, U251MG, LN-18, LN-229 and LN-Z308 glioma cell lines. In this regard, there were increased levels of CCAAT/enhancer-binding protein homologous protein (CHOP) and glucose-regulated protein of 78kDa transcripts but no splicing of X-box-binding protein 1 mRNA or processing of activating transcription factor-6 in glioma cells treated with the neuro-steroid. 17α-AED induced eukaryotic translational initiation factor 2α (eIF2α) phosphorylation in glioma cells which correlated with microtubule-associated protein-light chain 3 (LC3) conversion from LC3-I to -II. In transformed murine embryonic fibroblasts (MEFs) that are deficient of eIF2α function or T98G glioma cells transfected with a dominant-negative eIF2α construct, 17α-AED induced LC3 conversion was significantly reduced as compared to control cells. Neuro-steroid treatment caused the activation of the eIF2α kinase, protein kinase-like ER kinase (PERK) but not other eIF2α kinases in glioma cells. Moreover, eIF2α phosphorylation and LC3 conversion, in response to 17α-AED treatment, was blocked in MEFs that lacked PERK activity. T98G cells transfected with a dominant-negative PERK construct exhibited an attenuated response to neuro-steroid treatment in terms of decreases in: eIF2α activation; CHOP expression; the incidence of autophagy; and cytotoxicity. These results demonstrate that ER stress is linked to 17α-AED induced autophagy by PERK/eIF2α signaling in human malignant glioma cells and transformed fibroblasts. [Copyright &y& Elsevier]

The aim of this review is to identify circulating steroids associated with prostate cancer (PCa) in bibliographic reports. First, we summarize chronological reports comparing circulating steroid levels in men with a high risk of PCa, such as African-Americans (AAs), with men having a lower risk. Higher testosterone plasma levels in young AA men have been reported. However, the difference between AAs and Caucasians decreases with age. When measured, dihydrotestosterone (DHT) was found to be higher in AAs; however, these results must be taken with caution, as immunological assay of this steroid is difficult. Second, we summarize chronological reports concerning circulating steroids assayed in blood samples drawn several years before a diagnosis of PCa was made, compared to controls. These nested case-control studies did not lead to straightforward conclusions regarding an increase in circulating testosterone. However, large collaborative studies showed a trend of a decrease in plasma sex hormone binding globulin, consequently an increase in bioavailable plasma testosterone in PCa. These nested case-control studies failed to associate plasma DHT levels with PCa risk. Third, we summarize numerous chronological publications relating plasma concentrations, measured at the time of PCa diagnosis. Numerous results showed a decrease in plasma testosterone levels in aggressive PCa (high Gleason score, advanced stage with positive surgical margins). Testosterone levels returned to normal several months after prostatectomy. All plasma hormone assay levels were always carried out using immunological methods. We recommend replacing this methodology by mass spectrometry coupled with gas chromatography or liquid chromatography in these epidemiologic studies. [ABSTRACT FROM AUTHOR]

The term catamenial epilepsy is used to describe the cyclical occurrence of seizure exacerbations during particular phases of menstrual cycle in women with preexisting epilepsy. Recent investigations have demonstrated the existence of at least three patterns of catamenial seizure exacerbation: perimenstrual and periovulatory in ovulatory cycle and entire luteal phase in anovulatory cycle. Cyclical changes in the circulating levels of estrogens (proconvulsant) and progesterone (anticonvulsant) play a central role in the development of catamenial epilepsy. Also, variations in concentrations of antiepileptic drugs across the menstrual cycle may contribute to increased seizure susceptibility. A variety of approaches have been proposed for the treatment of catamenial epilepsy. [ABSTRACT FROM AUTHOR]

Androstenediol (androst-5-ene-3β,17β-diol; 5-AED), a natural adrenal steroid, has been shown to suppress experimental autoimmune encephalomyelitis (EAE) in female SJL/Jmice. We here report that 5-AED limits inflammation and proinflammatory cytokines including TNFα inmurine models of carrageenan-induced pleurisy and lippopolysaccaride- (LPS) induced septic shock. 5-AED binds to and transactivates sex steroid receptors with the same general rank order of potency (ERβ > ERα ⪢AR). 5-AED provides benefit in EAE in a dose-dependent fashion, even when treatment is delayed until onset of disease. The minimally effective dose may be as low as 4mg/kg in mice. However, benefit was not observed when 5-AED was given in soluble formulation, leading to a short half-life and rapid clearance. These observations suggest that treatment with 5-AED limits the production of proinflammatory cytokines in these animal models and, ultimately, when formulated and administered properly, may be beneficial for patients with multiple sclerosis and other Th1-driven autoimmune diseases. [ABSTRACT FROM AUTHOR]

Treatments for advanced prostate cancer (CaP) typically involve androgen deprivation therapy. However, most patients eventually develop castration-resistant CaP (CRPC) for which highly effective therapies are limited. We explored the efficacy of a novel agent, HE3235, in inhibiting growth of CRPC in preclinical models. Castrated male mice were implanted subcutaneously with LuCaP35V CaP xenografts in the presence and absence of 5'-androstenediol (AED) and treated with HE3235. To investigate the effect of HE3235 on CaP tumor in the bone, castrated mice were injected intratibially with C4-2B CaP cells and treated with HE3235. Serum prostate-specific antigen (PSA) levels, tumor volume, immunohistochemistry, gene expression, and levels of intratumoral androgens were analyzed. HE3235 significantly prolonged the tumor doubling time of LuCaP35V, decreased androgen receptor expression, and lowered levels of intratumoral testosterone by ~89% and dihydrotestosterone by ~63% in both the presence and the absence of AED. HE3235 inhibited tumor growth in the bone environment. Weights of tumored tibiae of HE3235-treated animals were lower than those of control (P = .031), and normalized PSA levels were also significantly decreased at the end of study by HE3235 treatment (P = .0076). HE3235 inhibits the growth of subcutaneous CRPC as well as CRPC in the bone environment. Our data show that HE3235 exhibits a wide range of effects, including alteration of androgen receptor signaling and reductions in levels of intratumoral androgens. Our results support ongoing clinical investigations into the effectiveness of HE3235 in the setting of CRPC and warrants further studies into the mechanisms behind the effects of HE3235. [ABSTRACT FROM AUTHOR]