Cortisol and 11 beta-hydroxysteroid dehydrogenase type 2 as potential determinants of renal citrate excretion in healthy children.

BACKGROUND: In patients with Cushing disease, renal citrate excretion is reduced. A low urinary citrate concentration is a risk factor for nephrolithiasis. Since higher acid loading is one major determinant of reduced citrate excretion, we aimed to examine whether glucocorticoids still within the physiological range may already impact on urinary citrate excretion independently of acid-base status. METHODS: Overall, 132 healthy prepubertal participants of the DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study who had collected two successive 24-h urine samples (at 1 and 2 years) before the start of their pubertal growth spurt were included in the study. Net acid excretion capacity (NAEC), urinary potential renal acid load (PRAL), creatinine, calcium, and various cortisol metabolites were measured in all samples. Glucocorticoid quantification was done by GC-MS and radioimmunoassay. RESULTS: In regression models multivariable-adjusted for 24-h urinary PRAL, NAEC, creatinine and calcium, urinary free cortisol (UFF), 6ß-hydroxycortisol, and 20α-dihydrocortisol showed significant inverse relationships (P ≤ 0.02) with 24-h renal citrate output. By contrast, the estimate of renal 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), i.e., the ratio of urinary free cortisone/UFF, associated positively with urinary citrate (P = 0.04). CONCLUSIONS: In line with studies in hypercortisolic state, even moderately high cortisol levels in healthy children, still within the physiological range, may negatively impact on the kidney's citrate excretion. Besides, a higher 11ß-HSD2 activity, favoring cortisol inactivation, is paralleled by an increased citrate excretion.

Temporal relationships between awakening cortisol and psychosocial variables in inpatients with anorexia nervosa - A time series approach.

OBJECTIVE: The aim of the study was to investigate the characteristics of the awakening salivary cortisol in patients with anorexia nervosa (AN) using a time series design. We included ten AN inpatients, six with a very low BMI (high symptom severity, HSS group) and four patients with less severe symptoms (low symptom severity, LSS group). METHODS: Patients collected salivary cortisol daily upon awakening. The number of collected saliva samples varied across patients between n=65 and n=229 (due to the different lengths of their inpatient stay). In addition, before retiring, the patients answered questions daily on the handheld regarding disorder-related psychosocial variables. The analysis of cortisol and diary data was conducted by using a time series approach. RESULTS: Time series showed that the awakening cortisol of the AN patients was elevated as compared to a control group. Cortisol measurements of patients with LSS essentially fluctuated in a stationary manner around a constant mean. The series of patients with HSS were generally less stable; four HSS patients showed a non-stationary cortisol awakening series. Antipsychotic medication did not change awakening cortisol in a specific way. The lagged dependencies between cortisol and depressive feelings became significant for four patients. Here, higher cortisol values were temporally associated with higher values of depressive feelings. CONCLUSIONS: Upon awakening, the cortisol of all AN patients was in the standard range but elevated as compared to healthy controls. Patients with HSS appeared to show less stable awakening cortisol time series compared to patients with LSS.

Glucocorticoid activity and metabolism with NaCl-induced low-grade metabolic acidosis and oral alkalization: results of two randomized controlled trials.

Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid-base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases.

Changes of Dietary Fat and Carbohydrate Content Alter Central and Peripheral Clock in Humans.

CONTEXT: The circadian clock coordinates numerous metabolic processes with light-dark and feeding regimens. However, in humans it is unknown whether dietary patterns influence circadian rhythms. OBJECTIVE: We examined the effects of switching from a high-carbohydrate, low-fat diet to a low-carbohydrate, high fat (LC/HFD) isocaloric diet on the central and peripheral circadian clocks in humans. DESIGN: Diurnal patterns of salivary cortisol and gene expression were analyzed in blood monocytes of 29 nonobese healthy subjects before and 1 and 6 weeks after the dietary switch. For this, we established a method of rhythm prediction by 3-time point data. RESULTS: The centrally driven cortisol rhythm showed a phase delay 1 and 6 weeks after the dietary switch to a LC/HFD as well as an amplitude increase. The dietary switch altered diurnal oscillations of core clock genes (PER1, PER2, PER3, and TEF) and inflammatory genes (CD14, CD180, NFKBIA, and IL1B). The LC/HFD also affected the expression of nonoscillating genes contributing to energy metabolism (SIRT1) and fat metabolism (ACOX3 and IDH3A). Expression of clock genes but not of salivary cortisol in monocytes tightly correlated with levels of blood lipids and with expression of metabolic and inflammatory genes. CONCLUSIONS: Our results suggest that the modulation of the dietary fat and carbohydrate content alters the function of the central and peripheral circadian clocks in humans.

Trajectories of the cortisol awakening responses during weight gain in anorexia nervosa patients with severe and less severe symptoms.

The aim of this study was to examine the features and changes of the cortisol awakening response (CAR) in patients with anorexia nervosa (AN) with severe and less severe symptoms over the course of inpatient treatment. Our study included n=20 AN patients who received treatment at the University Hospital, Heidelberg. N=11 patients were admitted at a psychosomatic and internal-medicine ward that specialized in the treatment of AN patients with a very low BMI (patient group with high symptom severity, HSS). The mean BMI of these patients was 13.2 kg/m(2) (SD=1.4) at the beginning of the study and 16.9 kg/m(2) (SD=1.7) at the end. N=9 patients were treated at a psychotherapeutic ward where AN patients with less severe symptoms are admitted (patient group with low symptom severity, LSS). The mean BMI of these latter patients was 16.3 kg/m(2) (SD=0.89) at the beginning of the study and 17.1 kg/m(2) (SD=0.65) at the end. Salivary cortisol was measured on two consecutive days respectively, both at the beginning and the end of the study. At the beginning of the study, patients with HSS had a significantly lower mean CAR compared to patients from the LSS group (3.4 nmol/l vs. 11.4 nmol/l). At the end of the study, the mean CAR of patients from the HSS group was still significantly lower compared to the mean CAR of patients with LSS (2.0 nmol/l vs. 9.2 nmol/l). Results indicate that AN patients with severe symptoms exhibit a lower CAR compared to AN patients with less severe symptoms.

Aldosterone augments Na+-induced reduction of cardiac norepinephrine reuptake.

Impairment of the cardiac norepinephrine (NE) reuptake by the neuronal NE transporter contributes to enhanced cardiac NE net release in congestive heart failure. Elevated plasma levels of aldosterone (AL) promote sympathetic overstimulation in failing hearts by unclear mechanisms. Our aim was to evaluate if elevated AL and/or alterations in Na(+) intake regulate cardiac NE reuptake. To test the effects of AL and Na(+) on cardiac NE reuptake, Wistar rats were fed a normal-salt (NS) diet (0.2% NaCl), a low-salt (LS) diet (0.015% NaCl), or a high-salt (HS) diet (8% NaCl). Another group of animals received AL infusion alone (0.75 µg/h) or AL infusion plus HS diet. Specific cardiac [(3)H]NE uptake via the NE transporter in a Langendorff preparation and AL plasma levels were measured at different time points between 5 and 42 days of treatment. To compare these findings from healthy animals with a disease model, Dahl salt-sensitive rats were investigated as a model of congestive heart failure with endogenously elevated AL. In summary, neither exogenous nor endogenous elevations of AL alone were sufficient to reduce cardiac NE reuptake. Only the HS diet induced a reduction of NE reuptake by 26%; additional infusion of AL augmented this effect to a further reduction of NE reuptake by 36%. In concordance, Dahl salt-sensitive rats treated with a HS diet displayed elevated AL and a marked reduction of NE reuptake. We conclude that exogenous or endogenous AL elevations alone do not reduce cardiac NE reuptake, but AL serves as an additional factor that negatively regulates cardiac NE reuptake in concert with HS intake.

11ß Hydroxysteroid dehydrogenase type 2 and dietary acid load are independently associated with blood pressure in healthy children and adolescents.

BACKGROUND: The reduced activity of 11ß hydroxysteroid dehydrogenase type 2 (11ßHSD2) contributes to elevated blood pressure (BP) in clinical syndromes, but its effect on BP in the physiologic range is unclear. OBJECTIVES: We examined the association of 11ßHSD2 activity with BP in healthy children independent of known BP-related dietary and other factors and determined whether the diet-dependent acid load may constitute a dietary factor related to BP. DESIGN: We conducted a cross-sectional analysis in 267 healthy children (age range: 4-14 y) who provided a 24-h urine sample, a parallel 3-d weighed dietary record, and 1-3 BP measurements ±1.5 y around the urine collection. The ratio of urinary free cortisone to cortisol measured by using a radioimmunoassay was used as an index for 11ßHSD2. Urinary net acid excretion and the urinary and dietary potential renal acid load (PRAL) were used to predict the diet-dependent acid load. The PRAL was calculated as the sum of major mineral nonbicarbonate anions minus the sum of mineral cations. Sex-, age- and height-independent SD scores (SDSs) of systolic and diastolic BP were used as outcomes in linear regression analyses. RESULTS: 11ßHSD2 was inversely associated with systolic BP SDSs in basic models and in analyses adjusted for body size, maternal BP, breastfeeding, and dietary intakes of total energy, salt, and fruit and vegetables (P = 0.03). In models that included indexes of dietary acid load instead of fruit and vegetables, all 3 acid-load biomarkers were significantly (P = 0.006-0.02) directly related to systolic BP. CONCLUSION: A lower 11ßHSD2 activity and higher dietary acid load may independently contribute to higher systolic BP in healthy children.

Alkaline salts to counteract bone resorption and protein wasting induced by high salt intake: results of a randomized controlled trial.

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 (KHCO(3)) 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 KHCO(3)/d were supplemented to counteract NaCl-induced LGMA, whereas the other campaign served as a control with only high NaCl intake. When KHCO(3) was ingested during high NaCl intake, postprandial buffer capacity ([HCO(3)(-)]) 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% [∑(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 KHCO(3) (P = 0.052). We conclude that during high salt intake, the KHCO(3)-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.

[Childhood temperament and maternal affectivity]. / Kindliches Temperament und müterliche Affektivität.

This study examines the question whether early childhood temperaments of children of mothers suffering from postnatal depression differs from children of non-depressed mothers. Children of clinically depressed mothers were assessed with regard to their temperament on two different dimensions and compared to a control group. The level of cortisol concentration in the children's saliva was the first variable. Saliva samples were gathered on three consecutive days to obtain a baseline, and before and after a mother-children interaction, which was interrupted by a still-face phase. As second variable the early childhood temperament was assessed with the Infant Behavior Questionnaire (IBQ). After the mother-children interaction the cortisol concentration levels of children of mothers suffering from postnatal depression were significantly lower. In the IBQ-Scales the children of depressed mothers showed significantly higher values on the scales Distress to Limitations and Activity. The significantly lower cortisol concentration in the saliva of children of mothers suffering from postpartum depression could be an indication that these children are already used to the fact that their mothers are not paying attention to them during the still-face phase. Overall, the results give rise to the assumption that postpartum depression does have an adverse impact on the development of affected children and that early intervention would be expedient to prevent the occurrence of pathological behavior characteristics and difficult mother-child relationships.

A functional Tph2 C1473G polymorphism causes an anxiety phenotype via compensatory changes in the serotonergic system.

The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg(447) substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [(35)S]GTP-γ-S binding assay and 5-HT(1A) receptor autoradiography, a functional desensitization of 5-HT(1A) autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety-related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT(1A) autoreceptors.

A new transgenic rat model overexpressing the angiotensin II type 2 receptor provides evidence for inhibition of cell proliferation in the outer adrenal cortex.

This study aimed to elucidate the role of the AT(2) receptor (AT(2)R), which is expressed and upregulated in the adrenal zona glomerulosa (ZG) under conditions of increased aldosterone production. We developed a novel transgenic rat (TGR; TGRCXmAT(2)R) that overexpresses the AT(2)R in the adrenal gland, heart, kidney, brain, skeletal muscle, testes, lung, spleen, aorta, and vein. As a consequence the total angiotensin II (Ang II) binding sites increased 7.8-fold in the kidney, 25-fold in the heart, and twofold in the adrenals. The AT(2)R number amounted to 82-98% of total Ang II binding sites. In the ZG of TGRCXmAT(2)R, the AT(2)R density was elevated threefold relative to wild-type (WT) littermates, whereas AT(1)R density remained unchanged. TGRCXmAT(2)R rats were viable and exhibited normal reproduction, blood pressure, and kidney function. Notably, a slightly but significantly reduced body weight and a moderate increase in plasma urea were observed. With respect to adrenal function, 24-h urinary and plasma aldosterone concentrations were unaffected in TGRCXmAT(2)R at baseline. Three and 14 days of Ang II infusion (300 ng·min(-1)·kg(-1)) increased plasma aldosterone levels in WT and in TGR. These changes were completely abolished by the AT(1)R blocker losartan. Of note, glomerulosa cell proliferation, as indicated by the number of Ki-67-positive glomerulosa cells, was stimulated by Ang II in TGR and WT rats; however, this increase was significantly attenuated in TGR overexpressing the AT(2)R. In conclusion, AT(2)R in the adrenal ZG inhibits Ang II-induced cell proliferation but has no obvious lasting effect on the regulation of the aldosterone production at the investigated stages.

Alterations in the neuroendocrinological stress response to acute psychosocial stress in adolescents engaging in nonsuicidal self-injury.

OBJECTIVE: To investigate the neuroendocrinological stress response to acute psychosocial stress in a clinical sample of female adolescents engaging in nonsuicidal self-injury (NSSI). METHODS: The Trier Social Stress Test (TSST), a standardized psychosocial stress protocol, was performed in 14 female patients who engaged in NSSI and 14 healthy control subjects. NSSI was assessed by the Functional Assessment of Self-Mutilation (FASM). Salivary cortisol, heart rate, and affective states, assessed by the Positive and Negative Affect Schedule (PANAS), were measured during the TSST. RESULTS: We found an attenuated cortisol response to acute psychosocial stress in female adolescents with NSSI, whereas no group differences were observed in heart rate and emotional response to the TSST. CONCLUSIONS: These findings indicate that the HPA axis is hyporesponsive in adolescents with NSSI. Therefore, reduced secretion of cortisol could play a role in promoting vulnerability of these individuals to acute stress and maladaptive stress responses.

TAK1 in brain endothelial cells mediates fever and lethargy.

Systemic inflammation affects the brain, resulting in fever, anorexia, lethargy, and activation of the hypothalamus-pituitary-adrenal axis. How peripheral inflammatory signals reach the brain is still a matter of debate. One possibility is that, in response to inflammatory stimuli, brain endothelial cells in proximity to the thermoregulatory centers produce cyclooxygenase 2 (COX-2) and release prostaglandin E2, causing fever and sickness behavior. We show that expression of the MAP kinase kinase kinase TAK1 in brain endothelial cells is needed for interleukin 1ß (IL-1ß)-induced COX-2 production. Exploiting the selective expression of the thyroxine transporter Slco1c1 in brain endothelial cells, we generated a mouse line allowing inducible deletion of Tak1 specifically in brain endothelium. Mice lacking the Tak1 gene in brain endothelial cells showed a blunted fever response and reduced lethargy upon intravenous injection of the endogenous pyrogen IL-1ß. In conclusion, we demonstrate that TAK1 in brain endothelial cells induces COX-2, most likely by activating p38 MAPK and c-Jun, and is necessary for fever and sickness behavior.

Diagnosis of glucocorticoid-remediable aldosteronism in hypertensive children.

OBJECTIVE: Glucocorticoid-remediable aldosteronism (GRA) is caused by the presence of a chimeric gene originating from an unequal cross-over between the CYP11B1 and CYP11B2 genes. Aldosterone suppression by dexamethasone and high 18-hydroxycortisol (18-OHF) levels have been used to differentiate GRA from the other forms of primary aldosteronism. METHODS: A dexamethasone suppression test including serum 18-OHF determination and the measurement of urinary excretion of aldosterone, its metabolites and 18-OHF were performed in 3 children of a family with primary aldosteronism. Polymerase chain reactions were performed to identify the chimeric gene. RESULTS: The chimeric gene was identified in 2 children, their mother and grandmother. The affected children had an aldosterone-to-plasma renin activity ratio >30, elevated serum 18-OHF concentration and increased urinary excretion of aldosterone, its metabolites, and 18-OHF. Post-dexamethasone concentrations of serum aldosterone and 18-OHF concentrations were suppressed. CONCLUSION: Although very rare, the possible diagnosis of GRA should be considered in all children or young adults with low-renin hypertension. Since genetic testing is more specific than biochemical testing, a definitive diagnosis can only be obtained by identification of the CYP11B1/CYP11B2 chimeric gene.

Prepubertal glucocorticoid status and pubertal timing.

CONTEXT: Whether prepubertal glucocorticoid status impacts on the timing of puberty is not clear. OBJECTIVE: The objective of the study was to examine the relationship between prepubertal glucocorticoid status and early or late pubertal markers, independent of adrenarchal and nutritional status. DESIGN AND PARTICIPANTS: Prospective cohort study of healthy Caucasian children (n = 111, 56 boys) who provided both 24-h urine samples and weighed dietary records 1 and 2 yr before the start of pubertal growth spurt [age at take-off (ATO)]. MEASUREMENTS: Major urinary glucocorticoid and androgen metabolites determined by gas chromatography-mass spectrometry analysis were summed to assess daily overall cortisol (ΣC21) and adrenal androgen secretion; urinary free cortisol and cortisone measured by RIA were summed (UFF+UFE) as an indicator of potentially bioactive free glucocorticoids. MAIN OUTCOMES: The main outcomes included ATO, age at peak height velocity, age at menarche/voice break, ages at Tanner stage 2 for breast (girls) and genital (boys) development, and pubic hair. RESULTS: In girls ΣC21, but not UFF+UFE, was associated with pubertal markers after adjusting for overall adrenal androgen, urinary nitrogen, and body fat. Girls with higher ΣC21 (fourth quartile) reached ATO 0.7 yr (P = 0.01) and menarche 0.9 yr later (P = 0.006) than girls with lower ΣC21 (first quartile). The ΣC21 tended to be also positively associated with age at Tanner stage 2 for breast (P = 0.1), Tanner stage 2 for pubic hair (P = 0.1), and age at peak height velocity (P = 0.06). In boys, neither the ΣC21 nor UFF+UFE was related to pubertal timing. CONCLUSION: An individually higher prepubertal glucocorticoid secretion level, even in physiological range, appears to delay early and late pubertal timing of healthy girls, particularly their onset of pubertal growth spurt and menarche.

Comparison of two different radioimmunoassays to measure 17-hydroxyprogesterone during treatment monitoring of children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Accurate measurement of 17-hydroxyprogesterone (17-OHP) concentrations is essential for the correct diagnosis and treatment management of children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21 OHD). METHODS: We analysed 102 serum samples from 15 children with known 21 OHD twice using two different 17-OHP assays. 17-OHP concentrations were measured by an in-house radioimmunoassay (RIA) after recovery-corrected extraction and chromatographic purification and by a commercially available RIA without extraction (Immunotech). RESULTS: The correlation coefficient for results of pairs of 17-OHP concentrations was 0.974. The median ratio (17-OHP concentration measured with the commercial assay/17-OHP concentration measured with the in-house assay) was 0.593 with a 95% confidence interval ranging from 0.258 to 1.370. The ratio was constant throughout the average 17-OHP concentrations ranging from 0.24 to 149.2 nmol/L, as well as throughout the age range from 0.3 to 16.4 years. CONCLUSIONS: Despite good overall correlation, absolute 17-OHP concentrations differed dramatically. This could lead to misclassification of patients suspected for 21 OHD on the basis of the hormonal profile and to a reduced quality during treatment monitoring of patients with 21 OHD with the risk of under- and overtreatment.

Urine volume dependency of specific dehydroepiandrosterone (DHEA) and cortisol metabolites in healthy children.

Urine volume should be considered as a confounder when using urinary free cortisol (UFF) and cortisone (UFE) to assess glucocorticoid (GC) status. We aimed to examine whether adrenal androgen (AA) metabolites may be also affected by urine volume in healthy children. To compare the flow dependence of GC and AA metabolites, specific GC metabolites were examined. In 24-h urine samples of 120 (60 boys) healthy children (4-10 yr), steroid profiles were determined by GC-MS analysis, UFF and UFE by radioimmunoassay. To assess daily AA and GC secretion rates, 7 quantitatively most important AA (∑C19) and GC (∑C21) metabolites were summed. Sum of DHEA and its 16α-hydroxylated metabolites were denoted as DHEA&M. Association of urine volume with AA (∑C19, DHEA&M, DHEA, 16α-hydroxy-DHEA, 3ß,16α,17ß-androstenetriol) and GC (∑C21, UFF, UFE, 6ß-hydroxycortisol, 20α-dihydrocortisol) were examined in linear regression models. Among the examined AA metabolites, 16α-hydroxy-DHEA (ß=0.56, p<0.0001) and DHEA (ß=0.43, p=0.05) showed relatively strong association with urine volume. A trend was seen for ∑C19 (ß=0.23, p=0.08), but not for DHEA&M (p>0.1). Regarding GC metabolites, urine volume showed a stronger association with cortisol's direct metabolites, i.e., cortisone, 6ß-hydroxycortisol and 20α-dihydrocortisol (ß=0.4-0.6, p<0.01) than with cortisol itself (ß=0.28, p<0.05). ∑C21 was not associated with urine volume. In conclusion, like UFF and UFE, renal excretion of DHEA, 16α-hydroxy-DHEA, 6ß-hydroxycortisol, and 20α-dihydrocortisol may also depend on urine volume. The intrarenal production of the latter three and cortisone might explain their relative strong water-flow-dependency. Total AA or GC secretion marker appears not to be relevantly confounded by urine volume.

Indicators of mineralocorticoid excess in the evaluation of primary aldosteronism.

It is suggested to use the aldosterone-to-renin ratio (ARR) as a first test in the screening for primary aldosteronism (PA). However, many groups rather rely on the determination of urinary tetrahydroaldosterone secretion; others calculate a ratio of urinary aldosterone to plasma renin activity. The aim of the present study was to evaluate the usefulness of different parameters of aldosterone excess in the case finding of PA. The study included 28 patients with PA and 33 subjects with essential hypertension. Clinical data, which included the hormonal parameters, serum aldosterone, plasma renin concentration, urinary free aldosterone and metabolites and serum and urinary electrolyte levels were analyzed. These indices of aldosterone excess, the ARR, serum sodium to urinary sodium to (serum potassium)(2) to urinary potassium (SUSPPUP) ratio and combinations of these parameters were compared between the groups. Receiver-operating curve analysis revealed that the ARR multiplied by the SUSPPUP ratio (ARR x SUSPPUP) is the most reliable screening test, with a sensitivity of 92.3% and a specificity of 93.9% (cutoff point 199.2 (mmol l(-1))(-1)). The combination of ARR x SUSPPUP ratio with urinary free aldosterone divided by the plasma renin concentration rendered a specificity of 100%. Less useful was the correction of urinary free aldosterone and its metabolites for sodium excretion. Although the ARR and urinary free aldosterone divided by renin are good tests in the screening for PA, the combination of ARR with SUSPPUP ratio is a better indicator of an aldosterone excess and aldosterone action in patients with ongoing antihypertensive medication. Antihypertensive drugs only marginally interfere with the SUSPPUP ratio, but they may influence the ARR, whereby the effects in PA patients seem to be negligible.

Prepubertal adrenarchal androgens and animal protein intake independently and differentially influence pubertal timing.

CONTEXT: Whether adrenarche impacts on pubertal development is controversial. OBJECTIVE: The objective of the study was to examine the associations of adrenal androgen (AA) secretion with early and late pubertal markers, independent of potential influences of dietary animal protein intake. DESIGN AND PARTICIPANTS: This was a prospective cohort study of healthy free-living Caucasian children (n = 109) who provided both 24-h urine samples and 3-d weighed dietary records 1 and 2 yr before the biological age at take-off of the pubertal growth spurt (ATO). MEASUREMENTS: Twenty-four-hour excretion rates of androgen (C19) metabolites quantified by gas chromatography-mass spectrometry were measured. MAIN OUTCOMES: ATO, age at peak height velocity (APHV), age at menarche/voice break, duration of pubertal growth acceleration, and ages at Tanner stage 2 for breast (girls) and genital (boys) development (B2-G2) and pubic hair (PH2). RESULTS: Higher adrenarchal C19 steroids predicted earlier ages at Tanner stage 2 for pubic hair (P < 0.0001) and B2-G2 (P = 0.009) as well as a shorter pubertal growth acceleration period (P = 0.001), independently of animal protein intake. Children with a higher AA secretion had a 1.5-yr earlier beginning of pubarche and a 0.8-yr earlier beginning of B2-G2 than those with a lower AA excretion. Furthermore, animal protein intake was independently negatively associated with ATO and APHV (P < 0.05 each) and tended to be negatively associated with age at menarche/voice break (P = 0.07). CONCLUSION: A higher animal protein intake may be involved in an earlier attainment of ATO and APHV, whereas a more intensive adrenarchal process may precipitate a shorter pubertal growth spurt and a notably earlier onset of breast and genital development in girls and boys, respectively.