Urinary Metabolite Ratios Research Articles

Evaluation of urinary limonene metabolites as biomarkers of exposure to greenness

Exposure to plants is known to improve physical and mental health and living in areas of high vegetation is associated with better health. The addition of quantitative measures of greenness exposure at individual-level to other objective and subjective study measures will help establish cause-and-effect relationships between greenspaces and human health. Because limonene is one of the most abundant biogenic volatile organic compounds emitted by plants, we hypothesized that urinary metabolites of inhaled limonene can serve as biomarkers of exposure to greenness. To test our hypothesis, we analyzed urine samples collected from eight human volunteers after limonene inhalation or after greenness exposure using liquid chromatography-high resolution mass spectrometry-based profiling. Eighteen isomers of nine metabolites were detected in urine after limonene inhalation, and their kinetic parameters were estimated using nonlinear mixed effect models. Urinary levels of most abundant limonene metabolites were elevated after brief exposure to a forested area, and the ratio of urinary limonene metabolites provided evidence of recent exposure. The identities and structures of these metabolites were validated using stable isotope tracing and tandem mass spectral comparison. Together, these data suggest that urinary metabolites of limonene, especially uroterpenol glucuronide and dihydroperillic acid glucuronide, could be used as individualized biomarkers of greenness exposure.

Increased Excretion of Mast Cell Mediator Metabolites During Mast Cell Activation Syndrome.

One requirement for diagnosing mast cell activation syndrome (MCAS) is an increase, above an established baseline level, in serum tryptase by 20% plus 2 ng/mL. However, there is no consensus of what constitutes excretion of a substantial increase in metabolites from prostaglandin D2, histamine, or leukotriene E4 in MCAS. Ratios of acute/baseline levels for each urinary metabolite that accompanied tryptase increases of 20% plus 2 ng/mL were determined. Mayo Clinic databases of patients with systemic mastocytosis with or without MCAS were reviewed. Patients with the requisite increase in serum tryptase during MCAS were examined for those who also had acute/baseline measurements of urinary mediator metabolite(s). Ratios of acute/baseline levels for tryptase and for each urinary metabolite were calculated. For all patients, the average acute/baseline ratio (SD) for tryptase was 4.88 (3.77). Average ratios of urinary mediator metabolites were: leukotriene E4: 35.98 (50.59), 2,3-dinor-11β-prostaglandin F2α: 7.28 (6.89), and N-methyl histamine: 3.2 (2.31). The lowest acute-baseline ratios for each of the three metabolites accompanying a tryptase increase of 20% plus 2 ng/mL were similar, with values of about 1.3. To the author's knowledge, this is the largest series of mast cell mediator metabolite measurements during episodes of MCAS that were verified by the requisite tryptase increase above baseline. Unexpectedly, leukotriene E4 showed the greatest average increase. Acute/baseline increase of 1.3 or greater in any of these mediators could be useful for corroborating a diagnosis of MCAS.

The effect of etanercept therapy on adrenal steroid metabolism in juvenile idiopathic arthritis: a steroid metabolomics approach

ObjectiveTo evaluate the impact of anti-tumor necrosis factor-alpha (TNFα: etanercept [Etanercept ®]) therapy on adrenal activity in juvenile idiopathic arthritis (JIA) .MethodEleven JIA patients aged 12 ± 6.2 years with a disease duration of 6.3 ± 5.2 years were enrolled. They were treated once weekly with etanercept (0.8 mg/kg) for 3 ± 2.8 years. Urine samples for gas chromatography-mass spectrometry steroid hormone analysis were collected before, and 1 and 3 days after etanercept injection and compared to age- and sex-matched healthy controls.ResultsThe levels of 21 of the 31 metabolites were low before etanercept treatment. Those 21 metabolites included 4 C19 steroids (androgens), 5 C C21 steroid hormone intermediates, 10 cortisol metabolites, and 2 corticosterone metabolites. One day after treatment, only 5 of the 21 metabolite levels remained low. They included 2 C19 metabolites, 2 C21 steroid metabolites and 1 cortisol metabolite β –Cortol (β-Cl). Three days after treatment, the only metabolites levels that continued to be low were 2 C19 metabolite, 2 C21 steroid hormone intermediates and 1 cortisol metabolite α-Cortol (a-Cl), while the remaining 15 metabolites had already normalized after 1 day. Dehydroepiandrosterone-sulfate and 17-hydroxypregnenolone metabolite levels were the last ones to recover. Urinary metabolite ratios reflecting cytochrome P450 CYP21A2 (21-hydroxylase) and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzymatic activitieswere lower in JIA patients than in controls, although significant was not reached.ConclusionAlmost all of the pre-etanercept treatment cortisol urinary metabolite levels were significantly lower than normal, and almost all rose to normal values by 1 day after treatment. The therapeutic effect of anti-TNFα treatment in JIA may be related to its effect on the restoration of adrenal function and cortisol levels.

Sensitive detection of testosterone and testosterone prohormone administrations based on urinary concentrations and carbon isotope ratios of androsterone and etiocholanolone.

The testing strategy for the detection of testosterone (T) or T-prohormones is based on the longitudinal evaluation of urinary steroid concentrations accompanied by subsequent isotope ratio mass spectrometry (IRMS)-based confirmation of samples showing atypical concentrations or concentration ratios. In recent years, the IRMS methodology focussed more and more on T itself and on the metabolites of T, 5α- and 5β-androstanediol. These target analytes showed the best sensitivity and retrospectivity, but their use has occasionally been challenging due to their comparably low urinary concentrations. Conversely, the carbon isotope ratios (CIR) of the main urinary metabolites of T, androsterone (A) and etiocholanolone (EITO), can readily be measured even from low urine volumes; those however, commonly offer a lower sensitivity and shorter retrospectivity in uncovering T misuse. Within this study, the CIRs of A and ETIO were combined with their urinary concentrations, resulting in a single parameter referred to as 'difference from weighted mean' (DWM). Both glucuronidated and sulfated steroids were investigated, encompassing a reference population (n = 110), longitudinal studies on three individuals, influence of ethanol in two individuals, and re-analysis of several administration studies including T, dihydrotestosterone, androstenedione, epiandrosterone, dehydroepiandrosterone, and T-gel. Especially DWM calculated for the sulfoconjugated steroids significantly prolonged the detection time of steroid hormone administrations when individual reference ranges were applied. Administration studies employing T encompassing CIR common for Europe (-23.8‰ and -24.4‰) were investigated and, even though for a significantly shorter time period and less pronounced, DWM could demonstrate the exogenous source of T metabolites.

Multiethnic Prediction of Nicotine Biomarkers and Association With Nicotine Dependence.

IntroductionThe nicotine metabolite ratio and nicotine equivalents are measures of metabolism rate and intake. Genome-wide prediction of these nicotine biomarkers in multiethnic samples will enable tobacco-related biomarker, behavioral, and exposure research in studies without measured biomarkers.Aims and MethodsWe screened genetic variants genome-wide using marginal scans and applied statistical learning algorithms on top-ranked genetic variants, age, ethnicity and sex, and, in additional modeling, cigarettes per day (CPD), (in additional modeling) to build prediction models for the urinary nicotine metabolite ratio (uNMR) and creatinine-standardized total nicotine equivalents (TNE) in 2239 current cigarette smokers in five ethnic groups. We predicted these nicotine biomarkers using model ensembles and evaluated external validity using dependence measures in 1864 treatment-seeking smokers in two ethnic groups.ResultsThe genomic regions with the most selected and included variants for measured biomarkers were chr19q13.2 (uNMR, without and with CPD) and chr15q25.1 and chr10q25.3 (TNE, without and with CPD). We observed ensemble correlations between measured and predicted biomarker values for the uNMR and TNE without (with CPD) of 0.67 (0.68) and 0.65 (0.72) in the training sample. We observed inconsistency in penalized regression models of TNE (with CPD) with fewer variants at chr15q25.1 selected and included. In treatment-seeking smokers, predicted uNMR (without CPD) was significantly associated with CPD and predicted TNE (without CPD) with CPD, time-to-first-cigarette, and Fagerström total score.ConclusionsNicotine metabolites, genome-wide data, and statistical learning approaches developed novel robust predictive models for urinary nicotine biomarkers in multiple ethnic groups. Predicted biomarker associations helped define genetically influenced components of nicotine dependence.ImplicationsWe demonstrate development of robust models and multiethnic prediction of the uNMR and TNE using statistical and machine learning approaches. Variants included in trained models for nicotine biomarkers include top-ranked variants in multiethnic genome-wide studies of smoking behavior, nicotine metabolites, and related disease. Association of the two predicted nicotine biomarkers with Fagerström Test for Nicotine Dependence items supports models of nicotine biomarkers as predictors of physical dependence and nicotine exposure. Predicted nicotine biomarkers may facilitate tobacco-related disease and treatment research in samples with genomic data and limited nicotine metabolite or tobacco exposure data.

Urinary Sex Steroid and Glucocorticoid Hormones Are Associated With Muscle Mass and Strength in Healthy Adults.

Sex steroid hormones exhibit anabolic effects whereas a deficiency engenders sarcopenia. Moreover, supraphysiological levels of glucocorticoids promote skeletal muscle atrophy, whereas physiologic levels of glucocorticoids may improve muscle performance. To study the relationship between both groups of steroid hormones at a physiological range with skeletal muscle mass and function in the general population. Cross-sectional analysis of the associations between urinary excreted androgens, estrogens, glucocorticoids, and steroid hormone metabolite ratios with lean mass and handgrip strength in a population-based cohort. Three centers in Switzerland including 1128 participants. Urinary steroid hormone metabolite excretion by gas chromatography-mass spectrometry, lean mass by bioimpedance analysis, and isometric handgrip strength by dynamometry. For lean mass a strong positive association was found with 11β-OH-androsterone and with most glucocorticoids. Androsterone showed a positive association in middle-aged and older adults. Estriol showed a positive association only in men. For handgrip strength, strong positive associations with androgens were found in middle-aged and older adults, whereas positive associations were found with cortisol metabolites in young to middle-aged adults. Sex steroids and glucocorticoids are strongly positively associated with skeletal muscle mass and strength in the upper limbs. The associations with muscle strength appear to be independent of muscle mass. Steroid hormones exert age-specific anabolic effects on lean mass and handgrip strength. Deficits in physical performance of aged muscles may be attenuated by androgens, whereas glucocorticoids in a physiological range increase skeletal muscle mass at all ages, as well as muscle strength in particular in younger adults.

Urinary metabolites predict prolonged duration of delayed graft function in DCD kidney transplant recipients.

Extending kidney donor criteria, including donation after circulatory death (DCD), has resulted in increased rates of delayed graft function (DGF) and primary nonfunction. Here, we used Nuclear Magnetic Resonance (NMR) spectroscopy to analyze the urinary metabolome of DCD transplant recipients at multiple time points (days 10, 42, 180, and 360 after transplantation). The aim was to identify markers that predict prolonged duration of functional DGF (fDGF). Forty-seven metabolites were quantified and their levels were evaluated in relation to fDGF. Samples obtained at day 10 had a different profile than samples obtained at the other time points. Furthermore, at day 10 there was a statistically significant increase in eight metabolites and a decrease in six metabolites in the group with fDGF (N=53) vis-à-vis the group without fDGF (N=22). In those with prolonged fDGF (≥21days) (N=17) urine lactate was significantly higher and pyroglutamate lower than in those with limited fDGF (<21days) (N=36). In order to further distinguish prolonged fDGF from limited fDGF, the ratios of all metabolites were analyzed. In a logistic regression analysis, the sum of branched-chain amino acids (BCAAs) over pyroglutamate and lactate over fumarate, predicted prolonged fDGF with an AUC of 0.85. In conclusion, kidney transplant recipients with fDGF can be identified based on their altered urinary metabolome. Furthermore, two ratios of urinary metabolites, lactate/fumarate and BCAAs/pyroglutamate, adequately predict prolonged duration of fDGF.

Change of the 5α/5β ratio of urinary steroid metabolites in benign prostatic hyperplasia patients treated with dutasteride

BackgroundThe effects of the administration of dutasteride (DUT) on steroid metabolite pathways in BPH patients have not been examined. MethodsUrine and blood samples as well as clinical parameters were prospectively collected after the administration of DUT to 60 BPH patients, and after its withdrawal in another set of 25 BPH patients. Urine samples were assessed using gas chromatography/mass spectrometry for the urinary steroid profile (USP), which simultaneously measures 63 steroid metabolites. We examined pharmacological changes in the 5α/5β ratio of urinary metabolites and their relationships with clinical parameters in patients treated with DUT. ResultsThe mean urinary androsterone/etiocholanolone (An/Et) ratio in sex-steroid pathways significantly decreased from 1.39 to 0.02 (p < 0.01). Urinary metabolites in other steroid pathways such as 5αTHF/5βTHF in the glucocorticoid pathway and 5αTHB/5βTHB in the mineralocorticoid pathway also significant decreased after the DUT treatment. As compared to baseline level, the mean An/Et ratios in patients with the withdrawal of DUT were 0.7%, 1.4%, 12.6%, and 82.4% at just before, one month, 3 months, and 6 months after the withdrawal of DUT, respectively. All other steroid pathways changed in a similar manner without the aggravation of urinary symptoms. The recovery ratio of An/Et in USP before and 3 months after the withdrawal of DUT correlated with the recovery ratio of serum PSA levels (ρ = 0.61, p < 0.01). ConclusionUrinary 5α/5β metabolites in all pathways were strongly suppressed after the administration of DUT for one month and the pharmacological effect of DUT prolonged even after withdrawal of DUT.

Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms.

Background The kidneys have a central role in the generation, turnover, transport, and excretion of metabolites, and these functions can be altered in CKD. Genetic studies of metabolite concentrations can identify proteins performing these functions.Methods We conducted genome-wide association studies and aggregate rare variant tests of the concentrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and fractional excretions in up to 1168 patients with CKD.Results After correction for multiple testing, genome-wide significant associations were detected for 25 serum metabolites, two urine metabolites, and 259 serum and 14 urinary metabolite ratios. These included associations already known from population-based studies. Additional findings included an association for the uremic toxin putrescine and variants upstream of an enzyme catalyzing the oxidative deamination of polyamines (AOC1, P-min=2.4×10-12), a relatively high carrier frequency (2%) for rare deleterious missense variants in ACADM that are collectively associated with serum ratios of medium-chain acylcarnitines (P-burden=6.6×10-16), and associations of a common variant in SLC7A9 with several ratios of lysine to neutral amino acids in urine, including the lysine/glutamine ratio (P=2.2×10-23). The associations of this SLC7A9 variant with ratios of lysine to specific neutral amino acids were much stronger than the association with lysine concentration alone. This finding is consistent with SLC7A9 functioning as an exchanger of urinary cationic amino acids against specific intracellular neutral amino acids at the apical membrane of proximal tubular cells.Conclusions Metabolomic indices of specific kidney functions in genetic studies may provide insight into human renal physiology.

MP09-18 CHANGE OF URINARY STEROID METABOLITES IN BPH PATIENTS TREATED WITH DUTASTERIDE

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Medical & Non-surgical Therapy1 Apr 2017MP09-18 CHANGE OF URINARY STEROID METABOLITES IN BPH PATIENTS TREATED WITH DUTASTERIDE Yota Yasumizu, Eiji Kikuchi, Takahiro Maeda, Masanori Hasegawa, Akira Miyajima, and Mototsugu Oya Yota YasumizuYota Yasumizu More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , Takahiro MaedaTakahiro Maeda More articles by this author , Masanori HasegawaMasanori Hasegawa More articles by this author , Akira MiyajimaAkira Miyajima More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.326AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES So far no studies have investigated whether administration of dutasteride (DUT) could affect the steroid metabolite pathway in symptomatic BPH patients. METHODS Urine and blood samples, and clinical parameters such as IPSS, QoL score and prostate volume were prospectively collected before and after 0.5 mg daily DUT administration in 60 symptomatic BPH patients. Among the 60 patients, 25 discontinued DUT after treatment at 12 months and urine samples after the withdrawal of DUT treatment were also prospectively collected. Urine samples were evaluated by urinary steroid profile (USP), which could measure all 63 urinary steroid metabolites at a same time. The USP analysis was determined by gas chromatography/mass spectrometry. We evaluated the pharmacological changes in urinary metabolites in USP and their correlations with clinical parameters in BPH patients treated with DUT. RESULTS The urinary androsterone/etiocholanolone (An/Et) ratio in the sex-steroid pathway was significantly decreased from 1.39 ± 0.62 to 0.02 ± 0.01 (p<0.01). Urinary metabolites in other steroid pathways such as 5αTHF/5βTHF in the glucocorticoid pathway and 5αTHB/βTHB in the mineralocorticoid pathway were also significantly decreased after DUT treatment. In the 25 patients who discontinued DUT treatment, the mean An/Et ratio at baseline before DUT treatment, just before withdrawal of DUT, one month, 3 months, and 6 months after withdrawal of DUT treatment were 0.01, 1.42, 0.02, 0.18, and 1.17, respectively. All other urinary metabolite ratios such 5αTHF/5βTHF and 5αTHB/βTHB were also changed in a similar manner. Prostate volume, IPSS, and QoL score just before withdrawal of DUT treatment (12 months after DUT treatment) were significantly lower than those at baseline before DUT treatment, but these parameters 3 months and 6 months after withdrawal of DUT were not significantly different from those just before withdrawal of DUT treatment. The mean PSA level at baseline before DUT treatment, just before withdrawal of DUT, and 3 months, and 6 months after withdrawal of DUT treatment were 5.6, 2.3, 3.7, and 5.2 ng/ml, respectively. Significant correlation was observed between the recovery rate of PSA level and the recovery rate of An/Et in USP before and 3 months after withdrawal of DUT (ρ=0.61, p<0.01). CONCLUSIONS The urinary 5α/5β metabolites in all steroid pathways were strongly suppressed after daily 0.5 mg DUT administration for one month. The recovery rate of PSA after withdrawal of DUT treatment might reflect the recovery rate of 5α/5β steroid metabolites. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e107 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Yota Yasumizu More articles by this author Eiji Kikuchi More articles by this author Takahiro Maeda More articles by this author Masanori Hasegawa More articles by this author Akira Miyajima More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Cortisol metabolism, postnatal depression and weight changes in the first 12 months postpartum.

Postnatal depression correlates with postpartum weight retention, and dysregulated cortisol metabolism is evident in depressed individuals. Cortisol metabolism, BMI and metabolic phenotype are robustly associated, but the role of cortisol metabolism in postnatal mental health and weight loss has never been examined. A longitudinal observation. Forty nine healthy women with uncomplicated pregnancy. BMI and urinary steroid metabolites at 1 week and 1, 3, 6 and 12 months postpartum. Validated urinary steroid metabolite ratios were measured to determine the activities of 11β-hydroxysteroid dehydrogenases (11β-HSD) that interconvert inactive cortisone and active cortisol and the 5α-reductases that clear cortisol to its inactive metabolites. Postnatal depression symptoms were measured at 1, 6 and 12 months. Low 5α-reductase activity was associated with greater weight loss across the first year, independent of demographics, breastfeeding and depression. Postpartum BMI change was unrelated to postnatal depression at any time. Symptoms of postnatal depression were related to higher cortisol metabolite production at 12 months, independent of demographics and breastfeeding. Greatest weight loss in the postpartum year was associated with lower conversion of cortisone to cortisol and lower conversion of cortisol to its metabolites, supporting previous work that demonstrates the facilitative role of lower 5α-reductase and 11β-HSD-1 in weight loss. Greater depression symptoms were associated with higher cortisol metabolite production rates. Whilst weight and mental health are both associated with dysregulation of the HPA axis, there may be different pathways towards depressed and obese phenotypes in healthy postpartum samples.

Diagnosis of 21-hydroxylase deficiency by urinary metabolite ratios using gas chromatography–mass spectrometry analysis: Reference values for neonates and infants

One major issue of newborn screening programs for 21-hydroxylase deficiency (21OHD) is the high rate of false-positive results, especially in preterm neonates. Urinary steroid metabolite analysis using gas chromatography–mass spectrometry (GC–MS) is suitable as a confirmatory diagnostic tool.The objective of this study was to analyze retrospectively diagnostic metabolite ratios in neonates and infants with and without 21OHD using GC–MS with emphasis on glucocorticoid metabolism, and to develop reference values for the steroid metabolite ratios for the diagnosis of 21OHD.We retrospectively analyzed urinary steroid hormone metabolites determined by GC–MS of 95 untreated neonates and infants with 21OHD (1–148 days), and 261 neonates and infants (100 preterms) without 21OHD (0–217 days).Metabolites of 17α-hydroxyprogesterone showed specificities below 98%, whereas the 21-deoxycortisol metabolite pregnanetriolone clearly separated 21OHD from non-21OHD subjects. The best diagnostic ratio for 21OHD was pregnanetriolone to 6α-hydroxy-tetrahydrocortisone. The lowest value of this ratio in the 21OHD group (0.47) was at least eight times higher than the highest values in the non-21OHD group (0.055).We have given appropriate reference values for steroid metabolite ratios in the largest 21OHD cohort so far described. Consideration of glucocorticoid metabolism, especially the use of typical neonatal 6α-hydroxylates metabolites, leads to improvement of diagnostic metabolite ratios.

CYP17A1 Enzyme Activity Is Linked to Ambulatory Blood Pressure in a Family-Based Population Study.

Genome-wide association studies have linked CYP17A1 coding for the steroid hormone synthesizing enzyme 17α-hydroxylase (CYP17A1) to blood pressure (BP). We hypothesized that the genetic signal may translate into a correlation of ambulatory BP (ABP) with apparent CYP17A1 activity in a family-based population study and estimated the heritability of CYP17A1 activity. In the Swiss Kidney Project on Genes in Hypertension, day and night urinary excretions of steroid hormone metabolites were measured in 518 participants (220 men, 298 women), randomly selected from the general population. CYP17A1 activity was assessed by 2 ratios of urinary steroid metabolites: one estimating the combined 17α-hydroxylase/17,20-lyase activity (ratio 1) and the other predominantly 17α-hydroxylase activity (ratio 2). A mixed linear model was used to investigate the association of ABP with log-transformed CYP17A1 activities exploring effect modification by urinary sodium excretion. Daytime ABP was positively associated with ratio 1 under conditions of high, but not low urinary sodium excretion (P interaction <0.05). Ratio 2 was not associated with ABP. Heritability estimates (SE) for day and night CYP17A1 activities were 0.39 (0.10) and 0.40 (0.09) for ratio 1, and 0.71 (0.09) and 0.55 (0.09) for ratio 2 (P values <0.001). CYP17A1 activities, assessed with ratio 1, were lower in older participants. Low apparent CYP17A1 activity (assessed with ratio 1) is associated with elevated daytime ABP when salt intake is high. CYP17A1 activity is heritable and diminished in the elderly. These observations highlight the modifying effect of salt intake on the association of CYP17A1 with BP.

Breast Cancer Association with CYP1A2 Activity and Gene Polymorphisms--a Preliminary Case-control Study in Tunisia.

The aim of the present study was to evaluate the relative contribution of CYP1A2 isoforms (-3860 G/A, -2467T/delT and -163C/A) in control subjects and breast cancer patients to the metabolism of caffeine in human liver. Restriction fragment length polymorphism analysis of PCR-amplified Fragments (PCR-RFLP) was used for the genotyping of CYP1A2 SNPs and HPLC allowed the phenotyping through the measurement of CYP1A2 activity using the 17X + 13X + 37X/137X urinary metabolite ratio (CMR) and plasma caffeine half life (T1/2). The CYP1A2 -3860A genotype was associated with a decreased risk of breast cancer. In contrast, distributions of the CYP1A2 -2467T/delT or -2467delT/delT and -163A/C or A/A genotypes among breast cancer patients and controls were similar. When the genotype and phenotype relationship was measured by comparing the mean CMR ratios and caffeine half life within the genotype groups between subjects and breast cancer patients, there were no significant differences except for -3860 A, most of them being homozygous for the -3860 G/G SNP and had a significant higher mean CMR ratio and half life than those with -3860 G/A (P=0.02). The results of this preliminary study show a significant association between CP1A2 -3860 G variant and CYP1A2 phenotype which must be confirmed by further large-size case-control studies.

The pitfalls associated with urinary steroid metabolite ratios in children undergoing investigations for suspected disorders of steroid synthesis.

BackgroundUrinary steroid metabolite ratios may improve the diagnostic yield of potential disorders of steroid hormone synthesis.ObjectivesTo investigate the range of ratios and their predictive value in children with suspected disorders of steroid synthesis.Design and methodsTwelve ratios were calculated on steroid metabolite data analysed by gas chromatography–mass spectrometry in urine samples collected between 2008–2010 from 93 children. Urine samples were also analysed in 252 children with no known endocrine concerns.ResultsOf the 252 controls, 115 (46%) were male with a median age of 10 yr (range 1 month,18.5 years). Of the 93 cases, 38 (41%) were male with a median age of 6.5 yr (1 day,18.5 yrs). Of these, 41 (44%) had at least one ratio greater than the 95% percentile for controls. The most frequently abnormal ratio, found in 18/93 (19%) cases was (THS/(THE + THF + 5αTHF)) suggestive of 11β-hydroxylase deficiency. Over this period, 8 (9%) children were subsequently diagnosed with a steroid hormone disorder; 4 with 21-hydroxylase deficiency, 2 with11β-hydroxylase deficiency and 2 with 5α-reductase deficiency. All except one of these children had at least 1 raised ratio.ConclusionsUrinary steroid metabolite ratios in suspected disorders of hormone synthesis often exceed the reference range for normal children. The predictive value of steroid metabolite ratios in identifying a genetic abnormality may be condition specific and needs further study to improve its clinical utility.

The balance of estrogen metabolites in breast cancer and the ways of its correction

Background. A clear relationship is now found between the activity of estrogen metabolites and the development of tumors in estrogen-dependent tissues. Many international and Russian studies could identify a number of compounds involved in the regulation of estrogen metabolites. Indole-3-carbinol is one of these compounds that correct a ratio of 2-hydroxyestrone (2-OHE1) to 16-OHE1. It is a phytonutrient that is contained in Cruciferous vegetables and has antitumor activity. Our investigations used highly purified indole-3-carbinol (Indinol). The ability to identify the role of metabolic syndrome, by applying the current methodological approaches, allowed us to study the effect of highly purified indole-3-carbinol on the level of expression of estrogen metabolites and to attempt to expand views on procedures to prevent and treat breast tumors. Materials and methods. A total of 136 women were comprehensively examined; of them 44 patients formed a group of those with morphologically verified hormone-independent breast cancer (BC) and 42 patients were a group of those with hormone-dependent BC. A control group included 50 women without signs of breast disease. In all the patients, body mass index was calculated; the ratio of urinary estrogen metabolites (2-ОНЕ1/16α-ОНЕ1) was quantified; and biopsy specimens and operative material were histologically and immunohistologically studied. Results. The BC patients were noted to have the high expression of 16α-OHE1 and the low values of 2-OHE1 (ratio, 0.42) as compared to the control group (2.09), which was an important component of metabolic syndrome. The BC patients had the high level of concomitant endocrine metabolic disturbances with the high body mass index, which reflected the clinical manifestation of metabolic syndrome. Indinol used to treat both hormone-dependent and hormone-independent BC showed an antimetabolic effect that was most pronounced 6 months later. Conclusion. Thus, early correction of metabolic disturbances with antimetabolites is one of the important, pathogenetically sound areas in the prevention of BC.

Effects of Genotype on Metabolic Activities of CYP1A2, CYP2A6, XO, and NAT in Adults and Children as Determined by Caffeine Urinary Metabolite Ratios

Caffeine is metabolized by cytochrome P450 1A2 (CYP1A2), CYP2A6, xanthine oxidase (XO), and N-acetyltransferase 2 (NAT2) and is a commonly used probe substrate for phenotyping these enzymes. Differ...

G97 RANGE OF URINARY STEROID METABOLITE RATIOS IN CHILDREN UNDERGOING INVESTIGATION FOR SUSPECTED DISORDERS OF STEROID SYNTHESIS

BackgroundCalculation of a urinary steroid metabolite ratio (uSMR) may be a useful method of improving diagnostic yield when investigating disorders of steroid hormone synthesis.Objective and hypothesis:To investigate the range of...

Range of urinary steroid metabolite ratios in children undergoing investigation for suspected disorder of steroid synthesis

Range of urinary steroid metabolite ratios in children undergoing investigation for suspected disorder of steroid synthesis

Exploring the utility of urine steroid metabolite ratios in evaluating over 500 suspected cases of disorders of sex hormone synthesis

<h3>Background</h3> Calculation of a urinary steroid metabolite ratio (uSMR) may be a useful method of improving diagnostic yield when investigating disorders of steroid hormone synthesis. <h3>Objective and hypothesis</h3> To determine the range of uSMR and the relationship between the uSMR and the diagnostic outcome in abnormal cases. <h3>Population/methods</h3> Ten ratios were calculated on steroid metabolite data previously analysed by GC-MS in urine samples from 544 patients under 18 years collected between 2008-2010. <h3>Results</h3> Out of 544 patients, 337 (62%) were female, 189 (35%) were male and in 18 (3%) the sex was not documented. Indications for performing the test included adrenarche or XX virlisation in 239 (44%) cases and XY DSD in 68 (13%) cases. Median age at test was 7.4 years (r, 1 day,18 years) with 11%, 4%, 3%, 3%, 7%, 16%, 40%, 6%, 6% and 4% of tests performed in the following age bands, &lt;1 week, 2 weeks-2 months, 3-5 months, 6-11 months, 1-3 years, 4-6 years, 7-9 years, 10-12 years, 13-15 years and 16-18 years, respectively. In 97 (18%) patients, one or more uSMR was above the 97th centile. The proportion of high uSMR according to the above age bands, was 0%, 0%, 2%, 11%, 33%, 6%, 16%, 8%, 7% and 17%, respectively. Out of these 97, case notes were reviewed in 28/32 cases from Glasgow. 5 (18%) patients had a confirmed steroid disorder (true positives), 8 (29%) had uSMR performed due to concerns such as ambiguous genitalia, premature adrenarche or cryptorchidism (possible true positives) and in the remaining 15 cases the tests were performed for a variety of reasons which resolved at a later stage (false positives). <h3>Conclusions</h3> Applying simplified diagnostic ratios to urinary steroid profile data results in a yield of about 20% cases being abnormal. There is a need to improve the sensitivity and specificity of the uSMR and the reference ranges for these ratios.