MetaboLights
NA
Identification
3alpha-hydroxy-5alpha-androstan-17-one
(3alpha,5alpha)-3-hydroxyandrostan-17-one
3-epihydroxyetioallocholan-17-one
3alpha-Hydroxy-5alpha-androstan-17-one
3alpha-hydroxyetioallocholan-17-one
5alpha-androstane-3alpha-ol-17-one
5alpha-androsterone
Androkinine
Androsterone
androsterone
Androtine
cis-androsterone
Species
homo sapiens
acropora digitifera
valsa sordida
malus domestica
reference compound
cladocopium goreaui
ahaetulla prasina
Europe PubMed Central results
Progressive Ureteropelvic Junction Obstruction and Renal Function Deterioration in Adult, Even in a Short Period of Time.
Author: Basiri A, Narouie B, Ghanbarizadeh SR, Rouientan H, Ahmadzade M.
Abstract: <h4>Introduction</h4>The ureteropelvic junction obstruction is more common in children; however, it can also affect adults. The management of this condition has shifted toward a nonoperative approach with serial ultrasonography and renography. <i>Case Presentation</i>. The ureteropelvic junction obstruction imaging with significant renal function deterioration in an adult patient is described in this report. Laparoscopic exploration revealed aberrant vessels that compress the ureteropelvic junction against the lower pole of the kidney.<h4>Conclusion</h4>It is important to consider that some of the ureteropelvic junction obstruction cases can get worse even in a short period of time.
DOI: 10.1155/2023/6855975
Analysis of tobacco exposures and high-risk HPV infection in American women: National Health and Nutrition Examination Survey.
Author: Jiang L, Ma S, Zhang G, Jiang L, Yan L.
Abstract: Nicotine is a known toxin, but its relationship with cervicovaginal high-risk human papillomavirus (HR-HPV) infection is uncertain. This study aimed to investigate whether tobacco exposure is associated with elevated cervicovaginal HR-HPV infection in US women, and if the strength of this association varies with the degree of exposure. Cross-sectional data from the 2011-2016 National Health and Nutrition Examination Survey (NHANES), which included a nationally representative sample of US women, were used for the study. Out of 12436 women aged 18-59 who participated in the interview, 3833 were ultimately enrolled in this study. Weighted logistic regression was used to estimate the link between tobacco exposure and cervicovaginal HR-HPV infection. The mean age of participants was 38.6 (SD 12.1) years, and non-Hispanic White individuals accounted for 37.3% of the sample. Those with any tobacco exposure tended to be younger (mean age 37.7 [SD 12.4] years vs 40.3 [11.2] years), non-Hispanic Black (27.8% vs. 15.1%), lower educated (41.8% vs. 29.4%), and have lower family income (39.9% vs. 23.5%). After adjustment, the odds of having HR-HPV infection were 1.32 (95% CI, 1.09-1.59) for those exposed to tobacco, remaining significant in multiple sensitivity analyses and across subgroups. This study, based on a nationally representative sample from the United States, suggests that tobacco exposure is a risk factor for elevated HR-HPV infection in women, highlighting the need for further research into reducing this modifiable risk factor.
Directed evolution approach to a structural genomics project: Rv2002 from Mycobacterium tuberculosis.
Author: Yang JK, Park MS, Waldo GS, Suh SW.
Abstract: One of the serious bottlenecks in structural genomics projects is overexpression of the target proteins in soluble form. We have applied the directed evolution technique and prepared soluble mutants of the Mycobacterium tuberculosis Rv2002 gene product, the wild type of which had been expressed as inclusion bodies in Escherichia coli. A triple mutant I6TV47MT69K (Rv2002-M3) was chosen for structural and functional characterizations. Enzymatic assays indicate that the Rv2002-M3 protein has a high catalytic activity as a NADH-dependent 3alpha, 20beta-hydroxysteroid dehydrogenase. We have determined the crystal structures of a binary complex with NAD(+) and a ternary complex with androsterone and NADH. The structure reveals that Asp-38 determines the cofactor specificity. The catalytic site includes the triad Ser-140Tyr-153Lys-157. Additionally, it has an unusual feature, Glu-142. Enzymatic assays of the E142A mutant of Rv2002-M3 indicate that Glu-142 reverses the effect of Lys-157 in influencing the pKa of Tyr-153. This study suggests that the Rv2002 gene product is a unique member of the SDR family and is likely to be involved in steroid metabolism in M. tuberculosis. Our work demonstrates the power of the directed evolution technique as a general way of overcoming the difficulties in overexpressing the target proteins in soluble form.
The cynomolgus monkey (Macaca fascicularis) is the best animal model for the study of steroid glucuronidation.
Author: Barbier O, Bélanger A.
Abstract: Intense research efforts performed during the past decade clearly established the major role of glucuronidation and uridine-diphospho-glucuronosyltransferase (UGT) enzymes for steroid metabolism in humans. However, a clear understanding of the physiological importance of this metabolic process requires in vivo studies. Numerous evidences ascertain that simians are the most appropriate animal models for such studies. Indeed human and monkey have a similar pattern of steroidogenesis, unlike common laboratory mammals such as rat or mouse. Furthermore, human and monkey are unique in having high levels of circulating androsterone glucuronide and androstane-3alpha-diol glucuronide (3alpha-Diol-G). In addition, characterization of eight monkey UGT proteins demonstrated the similarity of their conjugation activity toward steroid hormones. Like human ones, monkey enzymes are expressed in steroid target tissues, where they preferentially glucuronidate androgen and estrogen metabolites. In monkey tissues, immunohistochemical studies demonstrated that UGT2B proteins are expressed in a cell-type specific manner in ovary and kidney, where they control androgens and aldosterone inactivation. These results identify the cynomolgus monkey as an appropriate animal model for the determination of cellular localization of UGT enzymes in steroid target tissues and for the identification of endogenous or exogenous stimuli affecting steroid glucuronidation.
Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans.
Author: Bélanger A, Pelletier G, Labrie F, Barbier O, Chouinard S.
Abstract: In humans, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17beta-HSD and 5alpha-reductase activities in androgen target tissues, such as the prostate and skin, convert dehydroepiandrosterone, androstenedione and testosterone into the most potent natural androgen dihydrotestosterone (DHT). This androgen is converted mainly in situ into two phase I metabolites, androsterone (ADT) and androstane-3alpha,17beta-diol (3alpha-DIOL), which might be back converted to DHT. Here, we discuss the recent findings regarding the characterization of specific UDP-glucuronosyltransferases (UGTs), UGT2B7, B15 and B17, responsible for the glucuronidation of these metabolites. The tissue distribution and cellular localization of the UGT2B transcripts and proteins in humans clearly indicate that these enzymes are synthesized in androgen-sensitive tissues. It is postulated that the conjugating activity of UGT enzymes is the main mechanism for modulating the action of steroids and protecting the androgen-sensitive tissues from deleteriously high concentrations of DHT, ADT and 3alpha-DIOL.
The structures of the unique sulfotransferase retinol dehydratase with product and inhibitors provide insight into enzyme mechanism and inhibition.
Author: Pakhomova S, Buck J, Newcomer ME.
Abstract: The structure of retinol dehydratase (DHR) from Spodoptera frugiperda, a member of the sulfotransferase superfamily, in complexes with the inactive form of the cofactor PAP 3'-phosphoadenosine 5'-phosphate (PAP) and (1) the product of the reaction with retinol anhydroretinol (AR), (2) the retinoid inhibitor all-trans-4-oxoretinol (OR), and (3) the potent steroid inhibitor androsterone (AND) have been determined and compared to the enzyme complex with PAP and retinol. The structures show that the geometry of the active-site amino acids is largely preserved in the various complexes. However, the beta-ionone rings of the retinoids are oriented differently with respect to side chains that have been shown to be important for the enzymatic reaction. In addition, the DHR:PAP:AND complex reveals a novel mode for steroid binding that contrasts significantly with that for steroid binding in other sulfotransferases. The molecule is displaced and rotated approximately 180 degrees along its length so that there is no acceptor hydroxyl in close proximity to the site of sulfate transfer. This observation explains why steroids are potent inhibitors of retinol dehydratase activity, rather than substrates for sulfonation. Most of the steroid-protein contacts are provided by the alpha-helical cap that distinguishes this member of the superfamily. This observation suggests that in addition to providing a chemical environment that promotes the dehydration of a sulfonated intermediate, the cap may also serve to minimize a promiscuous sulfotransferases activity.
DOI: 10.1110/ps.041061105
Fracture resistance in severely damaged primary maxillary central incisors restored with glass fiber and composite posts: An in vitro study.
Author: Kooshki F, Haeri Boroojeni HS, Shekarchi F, Rahimi R.
Abstract: <h4>Background</h4>A variety of non-metal prefabricated posts, including fiber posts, can be used as an alternative to metal posts due to their numerous feasible characteristics. Further research is necessary to assess physical and mechanical properties of restorations supported by intracanal posts in primary teeth.<h4>Objectives</h4>The aim of the study was to compare fracture resistance of maxillary central incisors that were extensively restored with glass fiber and composite posts.<h4>Material and methods</h4>A total of 40 primary maxillary central incisors were randomly divided into 4 equal groups. Group 1 received conventional intracanal composite posts, group 2 was treated with prefabricated intracanal glass fiber posts, group 3 received precured intracanal composite posts, and group 4 was treated with intracanal lucent glass fiber posts. Crowns were restored using composite resin, and the specimens were subsequently exposed to 5,000 thermal cycles and progressive load at a crosshead speed of 0.5 mm/min until fracture. The fracture resistance values were compared via one-way analysis of variance (ANOVA) followed by Tukey's test for pairwise comparisons (α = 0.05).<h4>Results</h4>The highest fracture resistance was observed in the lucent post group (343.2 N), followed by the prefabricated glass fiber post (284.8 N), conventional composite post (270.3 N) and precured composite post (261.1 N) groups, respectively. A statistically significant difference in the mean fracture resistance was observed among the 4 groups (p < 0.05). Pairwise comparisons revealed that the mean fracture resistance of the lucent post group was significantly higher than that of the other groups (p < 0.05).<h4>Conclusions</h4>All of the intracanal posts provided apt fracture resistance and can be used to restore severely damaged primary maxillary central incisors. However, lucent posts demonstrated significantly higher levels of fracture resistance.
DOI: 10.17219/dmp/158859
Formation of 19-norsteroids by in situ demethylation of endogenous steroids in stored urine samples.
Author: Grosse J, Anielski P, Hemmersbach P, Lund H, Mueller RK, Rautenberg C, Thieme D.
Abstract: The formation of 19-norsteroids by demethylation of endogenous steroids in stored urine samples was observed. Suspicious urine samples (i.e. containing trace amounts of 19-norandrosterone and 19-noretiocholanolone) were selected and spiked with deuterated analogues of androsterone and etiocholanolone at concentrations corresponding to high endogenous levels (4 microg/mL). After incubation, respective 19-norsteroids (19-norandrosterone-d4 and 19-noretiocholanolone-d5) were identified in these samples by high-resolution mass spectrometry. The transformation of the 5 beta-isomer (etiocholanolone) yields about three-fold higher concentrations, compared to the 5 alpha-isomer. A significant temperature dependence was observed by comparison of reaction kinetics at room temperature (23+/-2 degrees C) and 37 degrees C. Concentrations of 19-norandrosterone-d4 and 19-noretiocholanolone-d5, respectively, were 2.7 and 3.6 times higher at elevated temperature. The conversion of androsterone-d4 to 19-norandrosterone-d4 did not exceed a relative amount of 0.1%. Incubation of the urine samples with androsterone-d4-glucuronide led to the production of 19-norandrosterone-d4-glucuronoide. A partial stabilization was observed after addition of metabolic inhibitors (e.g. EDTA). The application of the incubation experiments described may contribute to the clarification of adverse analytical findings regarding low levels of 19-norsteroid metabolites.
Anticonvulsant activity of androsterone and etiocholanolone.
Author: Kaminski RM, Marini H, Kim WJ, Rogawski MA.
Abstract: <h4>Purpose</h4>Men with epilepsy often have sexual or reproductive abnormalities that are attributed to alterations in androgen levels, including subnormal free testosterone. Levels of the major metabolites of testosterone-androsterone (5alpha-androstan-3alpha-ol-17-one; 5alpha,3alpha-A), a neurosteroid that acts as a positive allosteric modulator of GABA(A) receptors, and its 5beta-epimer etiocholanolone (5beta-androstan-3alpha-ol-17-one; 5beta,3alpha-A)-also may be reduced in epilepsy. 5alpha,3alpha-A has been found in adult brain, and both metabolites, which also can be derived from androstenedione, are present in substantial quantities in serum along with their glucuronide and sulfate conjugates. This study sought to determine whether these endogenous steroid metabolites can protect against seizures.<h4>Methods</h4>The anticonvulsant activity of 5alpha,3alpha-A and 5beta,3alpha-A was investigated in electrical and chemoconvulsant seizure models in mice. The steroids also were examined for activity against extracellularly recorded epileptiform discharges in the CA3 region of the rat hippocampal slice induced by perfusion with 55 microM 4-aminopyridine (4-AP).<h4>Results</h4>Intraperitoneal injection of 5alpha,3alpha-A-protected mice in a dose-dependent fashion from seizures in the following models (ED50, dose in mg/kg protecting 50% of animals): 6-Hz electrical stimulation (29.1), pentylenetetrazol (43.5), pilocarpine (105), 4-AP (215), and maximal electroshock (224). 5beta,3alpha-A also was active in the 6-Hz and pentylenetetrazol models, but was less potent (ED50 values, 76.9 and 139 mg/kg, respectively), whereas epiandrosterone (5alpha,3beta-A) was inactive (ED50, <or=300 mg/kg). 5alpha,3alpha-A (10-100 microM) also inhibited epileptiform discharges in a concentration-dependent fashion in the in vitro slice model, whereas 5beta,3alpha-A was active but of lower potency, and 5alpha,3beta-A was inactive.<h4>Conclusions</h4>5alpha,3alpha-A and 5beta,3alpha-A have anticonvulsant properties. Although of low potency, the steroids are present in high abundance and could represent endogenous modulators of seizure susceptibility.
Determination of sulfates of androsterone and epiandrosterone in human serum using isotope diluted liquid chromatography-electrospray ionization-mass spectrometry.
Author: Mitamura K, Setaka M, Shimada K, Honma S, Namiki M, Koh E, Mizokami A.
Abstract: A promising liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) for analysis of the sulfates of 5alpha-androgen, androsterone and epiandrosterone (A-S and EpiA-S) in human serum was developed. The method was used to assess one of the markers of 5alpha-reductase activity of males including patients with prostate cancer (PC). After deproteinization with acetonitrile, the androgen sulfates and the internal standard, [7,7,16,16-2H4]dehydroepiandrosterone-S, were extracted from human serum using a solid-phase extraction cartridge and washed with hexane. The extract was reconstituted and applied to the LC/ESI-MS system operated in the selected ion monitoring mode. The method was validated over the range 0.02-5 microg/mL (A-S) and 0.005-1.5 microg/mL (EpiA-S) using 10 microL of human serum. The method was a concise procedure without chemical or enzymatic hydrolysis of the conjugates, purification by high-performance liquid chromatography and/or derivatization, and proved to be satisfactory in its reproducibility and accuracy. The levels of these androgen sulfates tended to decrease during aging, and the A-S levels in the sera obtained from both healthy males and patients with PC were correlated with their EpiA-S levels.
DOI: 10.1002/bmc.522
Androsterone 3alpha-ether-3beta-substituted and androsterone 3beta-substituted derivatives as inhibitors of type 3 17beta-hydroxysteroid dehydrogenase: chemical synthesis and structure-activity relationship.
Author: Tchédam Ngatcha B, Luu-The V, Labrie F, Poirier D.
Abstract: Type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the biosynthesis of androgen testosterone. To produce potent inhibitors of this key steroidogenic enzyme, we prepared a series of androsterone (ADT) derivatives by adding a variety of substituents at position 3. The 3beta-substituted ADT derivatives proved to be good inhibitors (IC(50) = 57-147 nM) with better inhibitory activities obtained for compounds bearing a propyl, s-butyl, cyclohexylalkyl, or phenylalkyl group. With an IC(50) value of 57 nM, the 3beta-phenylmethyl-ADT was 6-fold more potent than ADT, the lead compound, and 13-fold more potent than 4-androstene-3,17-dione, the natural enzyme substrate used itself as inhibitor. The 3alpha-ether-3beta-substituted ADT derivatives had a lower inhibitory activity compared to the 3beta-substituted ADT analogues except for the 3beta-phenylethyl-3alpha-methl-O-ADT (IC(50) = 73 nM), which proved to be a more potent inhibitor than 3beta-phenylethyl-ADT (IC(50) = 99 nM). The results of our study identified potent type 3 17beta-HSD inhibitors for potential use in the treatment of androgen-sensitive diseases.
DOI: 10.1021/jm058179h
Monoamines and neurosteroids in sexual function during induced hypogonadism in healthy men.
Author: Bloch M, Rubinow DR, Berlin K, Kevala KR, Kim HY, Schmidt PJ.
Abstract: <h4>Context</h4>Although the behavioral effects of high-dose androgen administration may involve alterations in serotonergic activity, few studies have investigated the impact of androgen withdrawal on the central nervous system in humans.<h4>Objective</h4>To examine the effects of pharmacologically induced hypogonadism on several cerebrospinal fluid (CSF) systems that could mediate the behavioral concomitants of hypogonadism.<h4>Design</h4>Double-blind assessment of the effects of the short-term induction of hypogonadism and subsequent replacement with testosterone and placebo in a crossover design.<h4>Setting</h4>National Institutes of Health, Bethesda, Md.<h4>Participants</h4>Twelve healthy male volunteers.<h4>Interventions</h4>We administered the gonadotropin-releasing hormone agonist leuprolide acetate (7.5 mg intramuscularly every 4 weeks) to the healthy male volunteers, creating a hypogonadal state, and then either replaced testosterone (200 mg intramuscularly) or administered a placebo every 2 weeks for 1 month.<h4>Main outcome measures</h4>Mood and behavioral symptoms were monitored with daily self-ratings, and lumbar punctures were performed during both hypogonadal (placebo) and testosterone-replaced conditions for CSF levels of steroids and monoamine metabolites.<h4>Results</h4>The CSF testosterone, dihydrotestosterone, and androsterone levels were significantly lower during hypogonadism (P=.002, .04, and .046, respectively), but no significant changes were observed in CSF measures of 5-hydroxyindoleacetic acid, homovanillic acid, dehydroepiandrosterone, or pregnenolone. Decreased sexual interest was observed during the hypogonadal state compared with both baseline and testosterone replacement (P=.009) and correlated significantly with CSF measures of androsterone during both hypogonadism and testosterone replacement (r = -0.76 and -0.81, respectively; P<.01). Moreover, the change in severity of decreased sexual interest correlated significantly with the change in CSF androsterone levels between testosterone replacement and hypogonadism (r = -0.68; P<.05). The CSF 5-hydroxyindoleacetic acid and homovanillic acid levels did not correlate significantly with any behavioral or CSF measure.<h4>Conclusion</h4>These data suggest that the neurosteroid androsterone contributes to the regulation of sexual function in men.
The nuclear hormone receptor farnesoid X receptor (FXR) is activated by androsterone.
Author: Wang S, Lai K, Moy FJ, Bhat A, Hartman HB, Evans MJ.
Abstract: Farnesoid X receptor (FXR) uses bile acids as endogenous ligands. Here, we demonstrate that androsterone, a metabolic product of testosterone, is also an FXR ligand. Treatment of castrated male mice with androsterone induced expression of the FXR target gene small heterodimer partner (SHP). In mouse AML-12 hepatocytes, chenodeoxycholic acid (CDCA) or androsterone induced SHP expression with a similar kinetic pattern. The FXR antagonist guggulsterone blocked the induction of SHP by androsterone in AML-12 cells. Nuclear magnetic resonance spectroscopy demonstrated the direct binding of androsterone to purified human FXR (hFXR) ligand-binding domain (LBD) protein, resulting in the recruitment of steroid receptor coactivator protein-1 (SRC-1) coactivator peptide. In HEK293 cells, androsterone activated gal4-mouse FXR-LBD and gal4-hFXR-LBD fusion proteins, although in contrast to CDCA, androsterone activation was significantly greater for the mouse FXR-LBD than for the hFXR-LBD. Site-directed mutagenesis of the hFXR-LBD defined amino acids Asn354 and Ser345 as critical for differential species sensitivity to CDCA and androsterone, respectively. Crystal structure studies suggest that the orientation of the steroid nucleus of bile acids within the binding pocket of FXR is reversed from all other nuclear hormone receptors. In support of this model, we show here that mutations M265I or R331H, residues predicted by crystal structure to interact with the carboxylic acid tail of CDCA but not with androsterone, altered CDCA activation but had no effect on androsterone activation. Activation of FXR by androsterone may provide an additional means for physiological or pharmacological modulation of FXR.
DOI: 10.1210/en.2005-1485
Dehydroepiandrosterone and its derivatives: potentially novel anti-proliferative and chemopreventive agents.
Author: Matsuzaki Y, Honda A.
Abstract: Dehydroepiandrosterone (DHEA) is the most abundant adrenal androgenic steroid in young adult humans. The physiological functions of DHEA in preventing human carcinogenesis are still controversial, but a lot of reports have shown that pharmacological doses of DHEA show chemopreventive and anti-proliferative effects on tumors in rodents. Although a therapeutic dose of DHEA has been reported to promote hepatocarcinogenesis in rats due to peroxisomal proliferation, it remains unclear whether DHEA is a peroxisome proliferator in human liver. The chemopreventive and anti-proliferative effects of DHEA are not explained by a single mechanism, and at least four mechanisms seem to contribute to these effects: 1) depletion of NADPH and ribose-5-phosphate due to the inhibition of glucose-6-phosphate dehydrogenase activity, 2) suppression of cholesterol biosynthetic pathway by inhibition of HMG-CoA reductase, 3) interference with cell proliferation signaling pathways, and 4) suppression of nitric oxide generation through down-regulation of nitric oxide synthase II. In addition to studies of the mechanisms underlying the anti-neoplastic effects, searches for more potent and less androgenic DHEA derivatives are ongoing. A small amount of DHEA is endogenously metabolized to 7-oxygenated DHEA, and this may represent a metabolic pathway to more potent steroid hormones. Androsterone, epiandrosterone and etiocholanolone have been considered to be merely inactive end products of DHEA, but may in fact be physiological effectors in their own right. In addition, DHEA analogs such as 3beta-methyl-5-androsten-17-one, 16alpha-fluoro-5-androsten-17-one and 16alpha-fluoro-5alpha-androstan-17-one have been synthesized and shown to be more effective inhibitors of tumor growth, compared with DHEA itself. However, to design potent and safe DHEA derivatives, identification of the DHEA receptor and clarification of the mechanisms of DHEA action are required.
Detection of manipulation in doping control urine sample collection: a multidisciplinary approach to determine identical urine samples.
Author: Thevis M, Geyer H, Mareck U, Sigmund G, Henke J, Henke L, Schänzer W.
Abstract: Manipulation of urine sampling in sports drug testing is considered a violation of anti-doping rules and is consequently sanctioned by regulatory authorities. In 2003, three identical urine specimens were provided by three different athletes, and the identity of all urine samples was detected and substantiated using numerous analytical strategies including gas chromatography-mass spectrometry with steroid and metabolite profiling, gas chromatography-nitrogen/phosphorus detector analysis, high-performance liquid chromatography-UV fingerprinting, and DNA-STR (short tandem repeat) analysis. None of the respective athletes was the donor of the urine provided for doping analysis, which proved to be a urine sample collected from other unidentified individual(s). Samples were considered suspicious based on identical steroid profiles, one of the most important parameters for specimen individualization in sports drug testing. A database containing 14,224 urinary steroid profiles of athletes was screened for specific values of 4 characteristic parameters (ratios of testosterone/epitestosterone, androsterone/etiocholanolone, androsterone/testosterone, and 5alpha-androstane-3alpha,17beta-diol/5beta-androstane-3alpha,17beta-diol) and only the three suspicious samples matched all criteria. Further metabolite profiling regarding indicated medications and high-performance liquid chromatography-UV fingerprinting substantiated the assumption of manipulation. DNA-STR analyses unequivocally confirmed that the 3 urine samples were from the same individual and not from the athletes who provided DNA from either buccal cell material or blood specimens. This supportive evidence led to punishment of all three athletes according to the rules of the World Anti-Doping Agency. Application of a new multidisciplinary strategy employing common and new doping control assays enables the detection of urine substitution in sports drug testing.
The identification and simultaneous quantification of neuroactive androstane steroids and their polar conjugates in the serum of adult men, using gas chromatography-mass spectrometry.
Author: Kancheva L, Hill M, Vceláková H, Vrbíková J, Pelikánová T, Stárka L.
Abstract: Certain androstane steroids (AS) modulate ionotropic receptors, as do the pregnane steroids. Whereas women produce significant amounts of neuroactive progesterone metabolites, the steroid neuromodulators in men originate mainly from the 3-oxo-4-ene C(19)-steroids, which are converted to their 3alpha- and 3beta-hydroxy-5alpha/5beta-reduced metabolites. The neuromodulating effects of AS prompted us to monitor circulating levels of the steroids to estimate metabolic pathways in the periphery that may influence brain concentrations of AS. Hence, the serum levels of 20 steroids and 16 steroid polar conjugates including 17-oxo- and 17beta-hydroxy-derivatives of 5alpha/beta-androstane-3alpha/beta-hydroxy-androstane steroids were quantified in 15 men (16-62 years of age) using GC-MS. The conjugated AS for the most part reached micromolar concentrations, these being two or three orders of magnitude higher than those of the free steroids. The ratios of conjugates to free steroids were one to two orders of magnitude higher than the values for the corresponding pregnane steroids. This data suggested that conjugation may considerably restrain the transport of free AS from the periphery into the central nervous system.
The neurosteroid dehydroepiandrosterone (DHEA) and its metabolites alter 5-HT neuronal activity via modulation of GABAA receptors.
Author: Gartside SE, Griffith NC, Kaura V, Ingram CD.
Abstract: Dehydroepiandrosterone (DHEA) and its metabolites, DHEA-sulphate (DHEA-S) and androsterone, have neurosteroid activity. In this study, we examined whether DHEA, DHEA-S and androsterone, can influence serotonin (5-HT) neuronal firing activity via modulation of γ-aminobutryic acid (GABA(A)) receptors. The firing of presumed 5-HT neurones in a slice preparation containing rat dorsal raphe nucleus was inhibited by the GABA(A) receptor agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridinyl-3-ol (THIP) (25 μM) and GABA (100 μM). DHEA (100 and 300 μM) and DHEA-S (1, 10 and 100 μM) caused a rapid and reversible attenuation of the response to THIP. DHEA (100 μM) and DHEA-S (100 μM) also attenuated the effect of GABA. Androsterone (10 and 30 μM) markedly enhanced the inhibitory response to THIP (25 μM). The effect was apparent during androsterone administration but persisted and even increased in magnitude after drug wash-out. The data indicate that GABA(A) receptor-mediated regulation of 5-HT neuronal firing is sensitive to negative modulation by DHEA and its metabolite DHEA-S is sensitive to positive modulation by the metabolite androsterone. The effects of these neurosteroids on GABA(A) receptor-mediated regulation of 5-HT firing may underlie some of the reported behavioural and psychological effects of endogenous and exogenous DHEA.
[Androsterone, etiocholanolone].
Author: Shibata Y.
Abstract: NA
Anticonvulsant potencies of the enantiomers of the neurosteroids androsterone and etiocholanolone exceed those of the natural forms.
Author: Zolkowska D, Dhir A, Krishnan K, Covey DF, Rogawski MA.
Abstract: <h4>Rationale</h4>Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABAA receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5β,3α-A, the unnatural enantiomers are more potent at GABAA receptors than the natural forms.<h4>Objectives</h4>The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5β,3α-A with their enantiomers in mouse seizure models.<h4>Methods</h4>Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ).<h4>Results</h4>In the 6-Hz test, the ED50 values of ent-5α,3α-A was 5.0 mg/kg whereas the value for 5α,3α-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABAA receptor-positive allosteric modulators are generally weak in the MES seizure test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5α,3α-A and 5α,3α-A, respectively. Similar relationships were obtained for the 5β-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5β,3α-A were 11.8 and 20.4 mg/kg whereas the values for 5β,3α-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5α,3α-A persisted for somewhat longer (~5 h) than for 5α,3α-A (~4 h); protection by ent-5β,3α-A also persisted longer (~3 h) than for 5β,3α-A (~2 h).<h4>Conclusions</h4>The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics.
DHEA metabolism to the neurosteroid androsterone: a possible mechanism of DHEA's antidepressant action.
Author: Ben Dor R, Marx CE, Shampine LJ, Rubinow DR, Schmidt PJ.
Abstract: <h4>Background</h4>Alterations in neurosteroid secretion have been implicated in the efficacy of antidepressants. In a previous study, the adrenal androgen DHEA, a precursor of the neurosteroid androsterone, produced antidepressant and libido-enhancing effects in patients with midlife depression. To investigate the mechanisms underlying DHEA's behavioral effects in this same patient group, we examined plasma levels of four additional neurosteroids implicated in the regulation of affective behavior.<h4>Methods</h4>Blood samples were assayed for neurosteroids in men (n = 13) and women (n = 10) with midlife depression who previously participated in a crossover study in which DHEA and placebo were administered for 6 weeks each. Depression severity was measured by the Center for Epidemiologic Studies Depression Scale (CES-D). Plasma levels of androsterone (ADT), allopregnanolone, pregnanolone, and pregnenolone were measured by GC-MS at baseline and week 6 of each treatment phase. Data were analyzed with repeated measures analysis of variance (ANOVA-R) and Bonferroni t tests.<h4>Results</h4>ADT levels (but not allopregnanolone, pregnanolone, and pregnenolone) increased after DHEA but not after placebo (F 2,42 = 3.3, p < 0.05). Post-DHEA ADT levels were higher in women than men [t 63 = 2.9, p < 0.05]. However, in both men and women who met criteria for clinical response on the CES-D, baseline ADT levels significantly increased post-DHEA, and the magnitude of the ADT increase post-DHEA treatment was similar in men and women. Consequently, it was the non-responders who accounted for the sex difference in post-DHEA plasma ADT levels, a difference that was driven by values in two women (the only female non-responders).<h4>Conclusions</h4>The small sample size notwithstanding, these data emphasize the potential behavioral relevance of ADT in humans, which may include contribution to the antidepressant effects of DHEA.
Neuroanatomy Through Clinical Cases
Author: NA
Abstract: NA
Effects of androsterone on the protective action of various antiepileptic drugs against maximal electroshock-induced seizures in mice.
Author: Tutka P, Mróz K, Mróz T, Buszewicz G, Aebisher D, Bartusik-Aebisher D, Kołodziejczyk P, Łuszczki JJ.
Abstract: This study evaluated the effect of androsterone (AND), a metabolite of testosterone, on the ability of selected classical and novel antiepileptic drugs to prevent seizures caused by maximal electroshock (MES), which may serve as an experimental model of human generalized tonic-clonic seizures in mice. Single intraperitoneal (i.p.) administration of AND (80 mg kg<sup>-1</sup>) significantly raised the threshold for convulsions in the MES seizure threshold test. Lower doses of AND (5, 10, 20, and 40 mg kg<sup>-1</sup>) failed to change the threshold. AND at a subthreshold dose of 40 mg kg<sup>-1</sup> significantly enhanced the protective activity of carbamazepine, gabapentin, and phenobarbital against MES-induced seizures decreasing their median effective doses (ED<sub>50</sub>) values ± SEM from 8.59 ± 0.76 to 6.05 ± 0.81 mg kg<sup>-1</sup> (p = 0.0308) for carbamazepine, from 419.9 ± 120.6 to 111.5 ± 41.1 mg kg<sup>-1</sup> (p = 0.0405) for gabapentin, and from 20.86 ± 1.64 to 10.0 ± 1.21 mg kg<sup>-1</sup> (p = 0.0007) for phenobarbital. There were no significant changes in total brain concentrations of carbamazepine, gabapentin, and phenobarbital following AND administration. This suggests that the enhancing effects of AND on the protective activity of these antiepileptic drugs are not related to pharmacokinetic factors. A lower dose of AND (20 mg kg<sup>-1</sup>) had no effect on the protective activity of carbamazepine, gabapentin, and phenobarbital. AND administered at a dose of 40 mg kg<sup>-1</sup> failed to change the anticonvulsant activity of lamotrigine, oxcarbazepine, phenytoin, topiramate, and valproate in the MES test. In the chimney test, AND given at a dose enhancing the protective activity of carbamazepine, gabapentin, and phenobarbital (which alone was without effect on motor performance of mice) did not affect impairment of motor coordination produced by the antiepileptics. Our findings recommend further preclinical and clinical research on AND in respect of its use as adjuvant therapy in the management of epilepsy in men with deficiency of androgens.
Authors' response
Quantification of 5 alpha- and 5 beta-androstanediols in urine by gas chromatography-mass spectrometry.
Author: Muller L, Phillipou G.
Abstract: We measured concentrations of 5 alpha-androstane-3 alpha,17 beta-diol (Ad) and 5 beta-androstane-3 alpha,17 beta-diol (beta-Ad) in urine by specific capillary gas chromatography-mass spectrometry, with [16,16,17 alpha-2H3]-5 alpha-androstane-3 alpha,17 beta-diol as the internal standard. Comparison of the so-derived reference intervals for Ad and beta-Ad in men and women with those previously published indicates a significant positive bias for many of the previous assays in comparison with our procedure. Both Ad and beta-Ad have a pronounced diurnal rhythm, with maximum excretion in the interval 2300-0700 hours. Concentrations of Ad and beta-Ad were significantly correlated (r = 0.786, p less than 0.001), but the ratio of Ad to beta-Ad was not correlated to that for androsterone to etiocholanolone, the major 5 alpha and 5 beta metabolites of androgens in urine.
Complete Genome Sequence of Lactobacillus curvatus NFH-Km12, Isolated from the Japanese Traditional Fish Fermented Food Kabura-zushi.
Author: Kyoui D, Mikami N, Yamamoto H, Kawarai T, Ogihara H.
Abstract: Kabura-zushi is a traditional Japanese fermented food made from yellowtail, rice, salt, and kōji. In this study, the complete genomic sequence of Lactobacillus curvatus NFH-Km12, isolated from this unique food, is reported. NFH-Km12 has a 1.9-Mbp chromosome and contains 5 plasmids.
DOI: 10.1128/mra.00823-18
Time course of lung changes on thoracic ultrasound of mild COVID-19 patients.
Author: Tung-Chen Y, Marín-Baselga R, Soriano-Arroyo R, Muñoz-Del Val E.
Abstract: NA
Morphological Variations of the Mandibular Lingula: Clinical Implications for Surgical and Anesthetic Strategies in Adult Patients.
Author: Elhassan YH.
Abstract: <h4>Background</h4>The mandibular lingula is an important anatomical landmark. It is also of dental, surgical, and radiological importance due to the existence of the inferior alveolar nerve and the mandibular foramen. Therefore, studies about morphological variations significantly improve the quality of surgical and anesthetic interventions.<h4>Objective</h4>This study explores the lingula's morphological variations in adult human mandibles and their importance in surgical and anesthetic procedures.<h4>Materials and methods</h4>A descriptive anatomical study was performed using 100 dry adult human mandibles (200 sides) obtained from three different Saudi university museums; all mandibles are of Indian origin. The sample consisted of 80 male and 20 female mandibles. Using visual assessment and statistical evaluation, lingulae were classified into four types: triangular, truncated, nodular, and assimilated.<h4>Results</h4>Among the 200 mandibular sides examined, the triangular lingula was identified in 108 (54%) sides, with a variant exhibiting a narrow, flat, and more pointed apex observed unilaterally in 10 (5%) sides. The truncated, nodular, and assimilated types were present in 44 (22%), 26 (13%), and 12 (6%) sides, respectively. A male predisposition was noted for bilateral occurrences of the triangular subtype, whereas a statistically significant higher incidence of the nodular type was observed among females. Furthermore, the lingula tips were predominantly directed posterosuperiorly toward the condyle, being observed in 183 (91.5%) of the 200 sides.<h4>Conclusion</h4>In conclusion, we note the uniqueness of the lingula variations found, emphasizing the importance of these considerations to practitioners during surgical procedures. A better understanding of anatomy will be essential when performing surgery and providing anesthesia. Future studies should involve sophisticated imaging methods to better explain lingula morphology.
DOI: 10.7759/cureus.79632
The Potential Use of Orange and Banana Peels to Minimize the Toxicological Effects of Silver Nanoparticles in Oreochromis Niloticus.
Author: Abdel-Khalek AA, Hamed A, Hasheesh WSF.
Abstract: To evaluate the effectiveness of orange peels (OP) and banana peels (BP) in reducing the toxicity of silver nanoparticles (Ag-NPs), Oreochromis niloticus were exposed to Ag-NPs, Ag-NPs + OP, and Ag-NPs + BP for 24, 48, and 96 h. Time-dependent toxicological impacts of Ag-NPs were recorded. The maximum Ag accumulation was in hepatic and renal tissues after 96 h. A marked decrease in red blood cell count, hemoglobin content, hematocrit ratio, and mean corpuscular hemoglobin concentration was observed after 48 and 96 h of Ag-NPs exposure. Silver accumulation resulted in severe histological alterations (ex: congestion, vacuolization, and necrotic degeneration) in gills, livers, and kidneys. The adsorptive capacity of both peels could reduce the bioavailability of Ag-NPs as indicated by decreased Ag content in tissues, insignificant change in the hematological parameters with control groups, and regressive histological alterations based on the frequency of alterations' existence and the extent of affected parts.
[Transnasal endoscopic skull base surgery: analysis of complications in the first 120 procedures].
Author: Rojas HP, José PH, Herrera RR, Ledesma JL, Rubín E, Stieben LAR.
Abstract: <h4>Background</h4>The endonasal endoscopic approach (EEA) has potential advantages over traditional open approaches. However, complications such as cerebrospinal fluid (CFS) leak, visual disturbances, and postoperative meningitis have been described. The aim was to present the experience accumulated in 120 cases of skull base EEA performed by the same surgical team and describe and analyze the main postoperative complications according to the complexity of the cases.<h4>Methods</h4>Retrospective study on our database of patients undergoing skull base EEA for various pathologies between July 2011 and March 2022.<h4>Results</h4>120 skull base EEA surgeries were analyzed. 57.14% were performed on women. The median age was 44 years. 26.66% were reinterventions. The most frequent pathology was pituitary adenoma (49.17%) followed by CSF leak (8.33%). The most used EEA was the transelar 65.83%. 26 complications were recorded, with no differences according to complexity. There were 13 cases of diabetes insipidus (DI) and 8 of CSF leak. This was more frequent in patients with intraoperative CSF leak. The median hospital stay was 5.5 days.<h4>Conclusion</h4>Skull base EEA has become increasingly common for the surgical management of skull base pathology, with a low frequency of immediate postoperative complications and low mortality. The improvement of the technique and the improvement in postoperative care are associated with a shorter hospital stay.