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Kamrath C.,Justus Liebig University | Hartmann M.F.,Justus Liebig University | Remer T.,Research Institute of Child Nutrition | Wudy S.A.,Justus Liebig University
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Background: 17-Hydroxyprogesterone (17-OHP) can be converted to dihydrotestosterone (DHT) via an alternative "backdoor" route that bypasses the conventional intermediates androstenedione and testosterone. In this backdoor pathway, 17-OHP is converted to 5α-pregnane-3α, 17α-diol-20-one (pdiol), which is an excellent substrate for the 17,20 lyase activity of CYP17A1 to produce androsterone. Objective and Hypotheses: The objective of this study was to obtain evidence for the presence of the backdoor pathway in patients with 21-hydroxylase deficiency (21-OHD). Methods: We compared urinary steroid hormone profiles determined by gas chromatography-mass spectrometry of 142 untreated 21-OHD patients (age range, 1 d to25.4 yr; 51 males) with 138 control subjects. The activity of the backdoor pathway was assessed using the ratios of the urinary concentrations of pdiol to those of the metabolites of the classic Δ 4 and Δ 5 pathways. In contrast to etiocholanolone, which originates almost exclusively from the classic pathways, androsterone may be derived additionally from the backdoor pathway. Therefore, the androsterone to etiocholanolone ratio can be used as an indicator for the presence of the backdoor pathway. Results: Untreated 21-OHD subjects showed increased urinary ratios of pdiol to the Δ 4 and Δ 5 pathway metabolites and a higher androsterone to etiocholanolone ratio. Conclusions: The elevated ratios of pdiol to the Δ 4 and Δ 5 pathway metabolites as well as the higher androsterone to etiocholanolone ratio in patients with 21-OHD indicate postnatal activity of the backdoor pathway with maximum activity during early infancy. Our data provide new insights into the pathophysiology of androgen biosynthesis of 21-OHD. Copyright © 2012 by The Endocrine Society. Source


Mussig K.,University of Tubingen | Remer T.,Research Institute of Child Nutrition | Maser-Gluth C.,University of Heidelberg
Journal of Steroid Biochemistry and Molecular Biology | Year: 2010

Cortisol secretion and glucocorticoid excretion rates are regularly increased in obesity and associate with indices of body size and visceral adiposity. Different mechanisms may underlie the elevated urinary excretion rates of cortisol metabolites in obesity. In the present brief overview, potential mechanisms are discussed, paying special attention to cortisol metabolism. Besides, potential confounding factors in the evaluation of urinary glucocorticoid excretion are highlighted. © 2010 Elsevier Ltd. Source


Hoffmann P.,Justus Liebig University | Hartmann M.F.,Justus Liebig University | Remer T.,Research Institute of Child Nutrition | Zimmer K.-P.,Justus Liebig University | Wudy S.A.,Justus Liebig University
Steroids | Year: 2010

Oestrogens, such as oestrone (E1), 17β-oestradiol (E 2), oestriol (E3) and their biologically active metabolites 2-methoxyoestrone (2-MeOE1), 2-hydroxyoestradiol (2-OHE2) 16-ketooestradiol (16-OE2), 16-epioestriol (16-epiE3), as well as testosterone (T) play an important role in physiological and pathological developmental processes during human development. We therefore aimed at developing an isotope dilution/bench top gas chromatography-mass spectrometry (ID/GC-MS) method, based on benchtop GC-MS, for the simultaneous determination ('profiling') of the above analytes in children. The method consisted of equilibration of urine (5 ml) with a cocktail containing stable isotope-labelled analogues of the analytes as internal standards ([2,4-2H2]E1, [2,4,16,16- 2H4]E2, [2,4,17-2H 3]E3, [16,16,17-2H3]T, [1,4,16,16-2H4]2-MeOE1, [1,4,16,16,17- 2H5]2-OHE2, [2,4,15,15,17-2H 5]16-OE2 and [2,4-2H2]16-epiE 3). Then, solid-phase extraction (C18 cartridges), enzymatic hydrolysis (sulphatase from Helix pomatia (type H-1)), re-extraction, purification by anion exchange chromatography and derivatisation to trimethylsilyl ethers followed. The samples were analysed by GC-MS (Agilent GC 6890N/5975MSD; fused silica capillary column 25 m × 0.2 mm i.d., film 0.10 μm). Calibration plots were linear and showed excellent reproducibility with coefficients of determination (r2) between 0.999 and 1.000. Intra- and inter-assay coefficients of variation (CV) were <2.21% for all quantified metabolites. Sensitivity was highest for 2-OHE2 (0.25 pg per absolute injection: signal-to-noise ratio (S/N) = 3) and lowest for 16-epiE 3 (2 pg per absolute injection: S/N = 2.6), translating into corresponding urine sample analyte concentrations of 0.025 ng ml-1 and 0.2 ng ml-1, respectively. Accuracy - determined in a two-level spike experiment - showed relative errors ranging between 0.15% for 16-OE 2 and 11.63% for 2-OHE2. Chromatography showed clear peak shapes for the components analysed. In summary, we describe a practical, sensitive and specific ID/GC-MS assay capable of profiling the above-mentioned steroids in human urine from childhood onwards. © 2010 Elsevier Inc. All rights reserved. Source


Buehlmeier J.,German Aerospace Center | Frings-Meuthen P.,German Aerospace Center | Remer T.,Research Institute of Child Nutrition | Maser-Gluth C.,University of Heidelberg | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

High sodium chloride (NaCl) intake can induce low-grade metabolic acidosis (LGMA) and may thus influence bone and protein metabolism. We hypothesized that oral potassium bicarbonate (KHCO3) supplementation may compensate for NaCl-induced, LGMA-associated bone resorption and protein losses. Eight healthy male subjects participated in a randomized trial with a crossover design. Each of two study campaigns consisted of 5 d of dietary and environmental adaptation followed by 10 d of intervention and 1.5 d of recovery. In one study campaign, 90 mmol KHCO3/d were supplemented to counteract NaCl-induced LGMA, whereas the other campaign served as a control with only high NaCl intake. When KHCO3 was ingested during high NaCl intake, postprandial buffer capacity ([HCO3-]) increased (P = 0.002). Concomitantly, urinary excretion of free potentially bioactive glucocorticoids [urinary free cortisol (UFF) and urinary free cortisone (UFE)] was reduced by 14% [Σ(UFF,UFE); P =0.024]. Urinary excretion of calcium and bone resorption marker N-terminal telopeptide of type I collagen was reduced by 12 and 8%, respectively (calcium, P = 0.047; N-terminal bone collagen telopeptide, P = 0.044). There was a trend of declining net protein catabolism when high NaCl was combined with KHCO3 (P = 0.052). We conclude that during high salt intake, the KHCO3-induced postprandial shift to a more alkaline state reduces metabolic stress. This leads to decreased bone resorption and protein degradation, which in turn might initiate an anticatabolic state for the musculoskeletal system in the long run. Copyright © 2012 by The Endocrine Society. Source


Alexy U.,University of Bonn | Schwager V.,Research Institute of Child Nutrition | Kersting M.,Research Institute of Child Nutrition
European Journal of Clinical Nutrition | Year: 2014

We examined the association between diet costs and diet quality in a sample of children and adolescents using data from the ongoing longitudinal (open cohort) DONALD (Dortmund Nutritional and Anthropometric Longitudinally Designed) study. Children and adolescents aged 4-18 years (255 boys and 239 girls) provided 1100 yearly collected 3-day weighted dietary records. Linear mixed (effects) models were used to analyze the association between diet costs ([euro;[sol;day, estimated using retail food prices) and the Nutrient Quality Index (NQI) and the Healthy Nutrition Score for Kids and Youth (HuSKY). Analysis were stratified for low-quality records (scoremedian). No significant association was found in the low-quality records, whereas in the high-quality records the association was significantly positive for both scores (HuSKY P=0.016, NQI P<0.0001). In conclusion, a substantial part of our sample could increase their diet quality without a noteworthy increase of expenditure. © 2014 Macmillan Publishers Limited. Source

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