Search

Introduction: Hepatocyte nuclear factor-1 beta (HNF1B) encodes a homeodomain-containing transcription factor, which is expressed early in embryogenesis and is involved in the development of multiple tissues and organs. HNF1Bmutations cause complex multisystem disorders, with renal developmental disease and maturity onset diabetes of the young (HNF1B MODY), a rare cause of diabetes mellitus, being representative features. Methods: We present two adolescent boys from different socioeconomic backgrounds who were diagnosed with genetically confirmed HNF1B MODY following hospitalization for diabetic ketoacidosis in the first case and after diagnostic work-up due to impaired glucose tolerance in the second case. Multisystem manifestations, including pancreatic hypoplasia and early-onset diabetes mellitus (DM), renal cysts, hypomagnesemia, hyperuricemia, liver and biliary impairment, genital tract malformations, and primary hyperparathyroidism were also present, strongly suggesting HNF1B MODY. Results: The first patient was treated with subcutaneous insulin but was lost to follow-up due to social reasons. Conversely, early diagnosis in the second patient allowed the management of multisystem defects by a multidisciplinary team of experts. Moreover, manifestation of HNF1B MODY in the form of diabetic ketoacidosis was prevented and a structured diabetes training program has proven successful in regulating glycemic control, postponing the necessity for insulin treatment. Conclusion: Early genetic work-up of patients with dysglycemia associated with a specific phenotype suggestive of HNF1B MODY is extremely important in the care of children and adolescents with diabetes since it ensures that early and optimal management is initiated, thereby preventing the onset of life-threatening diabetic ketoacidosis and other multisystem complications and/or comorbidities.

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours that arise not only in adulthood but also in childhood and adolescence. Up to 70–80% of childhood PPGL are hereditary, accounting for a higher incidence of metastatic and/or multifocal PPGL in paediatric patients than in adult patients. Key differences in the tumour biology and management, together with rare disease incidence and therapeutic challenges in paediatric compared with adult patients, mandate close expert cross-disciplinary teamwork. Teams should ideally include adult and paediatric endocrinologists, oncologists, cardiologists, surgeons, geneticists, pathologists, radiologists, clinical psychologists and nuclear medicine physicians. Provision of an international Consensus Statement should improve care and outcomes for children and adolescents with these tumours.

Purpose: This study aimed to present recent trends in the pubertal timing of a Greek female sample. Methods: Data were collected retrospectively from medical records of healthy females aged 6–18 years who attended a tertiary Adolescent Friendly Health Center over a 5-year period (2016–2020) and included gestational age, birth anthropometrics, and age of thelarche and/or pubarche and/or menarche, along with corresponding anthropometric, hormonal, and biochemical measurements. Results: Data from 298 girls’ medical records were included in the analysis. Median age at menarche, thelarche, and pubarche was 12, 9, and 9 years, respectively. The mean interval between pubertal onset and menarche was 1.99 years. The mean body mass index (BMI) at menarche and thelarche was 20.99 kg/m2and 18.90 kg/m2, respectively. The mean weight at menarche was 49.6 kg, whereas the mean height difference between thelarche and menarche was 19.17 cm. Among participants, 6.3% had premature menarche, while 24.0% had premature thelarche. Birth weight was moderately correlated with BMI at thelarche/pubarche (rs=0.334, p= 0.005). Birth weight and BMI at thelarche/pubarche were not predictive of premature menarche or premature thelarche. Median (interquartile range, IQR) levels at menarche vs. thelarche were significantly higher for insulin-like growth factor-1 [358.00 (140.50) vs. 176.00 (55.00) ng/ml], follicle stimulation hormone [5.65 (3.14) vs. 3.10 (4.23) mIU/ml], testosterone [25.50 (31.00) vs. 13.00 (21.00) ng/dl], dehydroepiandrosterone sulfate [117.00 (112.50) vs. 46.40 (51.90) µg/dl], and insulin [17.40 (15.05) vs. 8.47 (4.97) µIU/ml]. Conclusion: The timing of pubertal stages in the Greek female sample studied followed the recent international downward trends. Younger age at menarche was not related to BMI.

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups.To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < −2.5 SDS at age 2 years or < −2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Purpose: Although ACTH is considered a secondary regulator of aldosterone production, patients with apparent essential hypertension have been treated with mineralocorticoid receptor antagonists (MRAs). In this study, we aimed to identify potentially damaging variants that might be implicated in the phenotype of a well-characterized cohort of 21 hypertensive patients without PA but with stress-induced aldosterone hypersecretion. The patients’ blood pressure was normalized though MRA administration. Methods: Genetic screening was performed through whole-exome sequencing (WES), and variants in PA-associated or in ion-channels of aldosterone-regulating genes were prioritized. Variants with population frequency &lt; 0.01, predicted to alter protein structure and classified as likely pathogenic by in silico tools, were retained. Results: Qualifying variants were identified in nine of the 21 patients screened. Seven patients were carriers of six potentially damaging variants in six genes associated with PA (KCNK9, KCNK5, ATP13A3, SLC26A2, CACNA1H,and CACNA1D). A novel variant in the KCNK9gene (p.V221M) is reported. Our analysis revealed two variants in two novel susceptibility genes for aldosterone hypersecretion, namely, KCNK16(p.P255H) and CACNA2D3(p.V557I). Conclusion: WES revealed potentially damaging germline variants in genes participating in aldosterone synthesis/regulating pathways in 9/21 patients of our cohort. The variants identified might play a role in aldosterone hypersecretion under conditions of stress. The potential pathogenicity of these variants should be examined in future functional studies.

Background: Giant prolactinomas are rare in childhood and adolescence and represent a challenge in diagnosis and management. Case presentation: A 15.7-year-old male adolescent presented with short stature and delayed puberty. On clinical examination, mild right central VII paresis, gait instability, decreased visual acuity, and impaired visual fields were noted. Investigations showed hyperprolactinemia (2209 ng/mL), secondary hypothyroidism, hypogonadotropic hypogonadism, and growth hormone deficiency. Imaging studies showed an enormous invasive skull base mass. Craniotomy was undertaken to debulk the tumor and perform biopsies. Histology revealed a very large atypical, prolactin-secreting pituitary macroadenoma, i.e., a giant prolactinoma. After commencing cabergoline treatment, prolactin concentrations decreased in 5 months and normalized 18 months later, while significant shrinkage of the tumor was observed. The diagnostic work-up for genetic syndromes often associated with sporadic macroadenomas was negative. Conclusion: Giant prolactinomas presenting with multiple pituitary hormone deficiencies in childhood or adolescence are rare and require prompt diagnosis and multidisciplinary management.

This article aims to provide guidance on prevention and treatment of COVID-19 in patients with genetic obesity. Key principals of the management of patients with genetic obesity during COVID-19 pandemic for patients that have contracted COVID-19 are to be aware of: possible adrenal insufficiency (e.g., POMC deficiency, PWS); a more severe course in patients with concomitant immunodeficiency (e.g., LEP and LEPR deficiency), although defective leptin signalling could also be protective against the pro-inflammatory phenotype of COVID-19; disease severity being masked by insufficient awareness of symptoms in syndromic obesity patients with intellectual deficit (in particular PWS); to adjust medication dose to increased body size, preferably use dosing in m2; the high risk of malnutrition in patients with Sars-Cov2 infection, even in case of obesity. Key principals of the obesity management during the pandemic are to strive for optimal obesity management and a healthy lifestyle within the possibilities of the regulations to prevent weight (re)gain and to address anxiety within consultations, since prevalence of anxiety for COVID-19 is underestimated.

Our study aimed to evaluate the effectiveness of an 8-week stress management intervention program that included progressive muscle relaxation, diaphragmatic breathing, guided imagery, and cognitive restructuring in obese Greek children and adolescents. Thirty-six patients were prospectively recruited to participate in this randomized controlled study. Of these, 16 participants formed the intervention group and 20 participants the control group. Anthropometric measurements and salivary cortisol, determined serially 3 times a day, were assessed at the beginning and at the end of the study. Participants also completed the state–trait anxiety in children questionnaire (STAIC), the stress in children questionnaire (SiC), and the child behavior checklist (CBCL). The intervention resulted in a significant reduction of waist-hip ratio (p= 0.008) in the intervention group compared with the control group. Moreover, school performance was improved in the intervention group (p= 0.025), while both the intervention and the control group adopted healthier daily habits (p= 0.020 and 0.011, respectively). However, there was no statistically significant difference between body mass index (BMI) z-score, stress, anxiety, and diurnal patterns in salivary cortisol. The present study supports the effectiveness of stress management intervention programs on waist-hip ratio reduction. Further research is required to investigate biomarkers able to predict and evaluate the effectiveness of stress management intervention programs.

Glucocorticoids play a fundamental role in many physiologic functions and contribute substantially to the achievement of homeostasis. These pleiotropic glucocorticoid actions are mediated by a ubiquitously expressed transcription factor, the human glucocorticoid receptor (hGR), which may influence the transcription rate of numerous target genes, interact with other transcription factors, trigger the activation of several kinase pathways or modulate mitochondrial DNA expression. Any genetic defects in the NR3C1gene that encodes the hGR may cause Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes, two rare allostatic endocrinologic conditions characterized by partial impaired tissue sensitivity to glucocorticoids. However, there are patients who present with clinical manifestations suggestive of the above syndromes and do not harbor an inactivating or activating point mutation, insertion or deletion in the NR3C1gene. In these cases, several other factors might influence the glucocorticoid signal transduction. In this review, we discuss the numerous glucocorticoid functions and the multiple hGR isoforms, we present the genomic, nongenomic and mitochondrial glucocorticoid signaling cascade and we summarize the clinical manifestations and pathogenesis of Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes. Finally, we speculate that the next generation sequencing technologies will undoubtedly enable us to gain a deeper understanding of the GR “interactome”.

Carriers of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) demonstrate increased secretion of Cortisol precursors following ACTH stimulation, suggestive of impaired Cortisol production and compensatory increases in hypothalamic corticotropin-releasing hormone (CRH) secretion. Both Cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression. We performed an endocrinologic and psychological evaluation in carriers of 21-OHD and matched control subjects. We recruited 29 parents of children with classic CAH (14 males, 15 females; age (mean±SD): 41.8±5.7 yr), and hence 21-OHD carriers, and 13 normal subjects (5 males, 8 females; age: 43.8±6.1 yr). All subjects underwent a formal ovine (o) CRH stimulation test with measurement of ACTH, Cortisol, 17-hydroxyprogesterone (17-OHP) and androstenedione concentrations, which was preceded by determination of 24-hour urinary free Cortisol (UFC) excretion. Psychometric assessment was performed by administering the State-Anxiety (STAI 1) and Trait-Anxiety (STAI 2) Inventory, Beck Depression Inventory, Symptom Checklist-90R and Temperament and Character Inventory. Carriers of 21-OHD had significantly higher 17-OHP concentrations following oCRH stimulation and higher STAI 1 (47.6±5.6 vs. 43.3±5.4, P=0.023) scores than control subjects. Mean 24-hour UFC concentrations were positively correlated with paranoid ideation (r=0.435; P=0.023) and psychoticism (r=0.454; P=0.017). Stepwise multiple linear regression analysis revealed that the single independent predictor of STAI 1 was peak stimulated 17-OHP concentrations (β: 0.055, SE: 0.023, R2: 0.290, P=0.031). Carriers of 21-OHD may be predisposed to the development of anxiety disorders.

Glucocorticoid receptor (GR) gene mutations may cause familial or sporadic generalized glucocorticoid resistance syndrome. Most of the missense forms distribute in the ligand-binding domain and impair its ligand-binding activity and formation of the activation function (AF)-2 that binds LXXLL motif-containing coactivators. We performed molecular dynamics simulations to ligand-binding domain of pathologic GR mutants to reveal their structural defects. Several calculated parameters including interaction energy for dexamethasone or the LXXLL peptide indicate that destruction of ligand-binding pocket (LBP) is a primary character. Their LBP defects are driven primarily by loss/reduction of the electrostatic interaction formed by R611 and T739 of the receptor to dexamethasone and a subsequent conformational mismatch, which deacylcortivazol resolves with its large phenylpyrazole moiety and efficiently stimulates transcriptional activity of the mutant receptors with LBP defect. Reduced affinity of the LXXLL peptide to AF-2 is caused mainly by disruption of the electrostatic bonds to the noncore leucine residues of this peptide that determine the peptide's specificity to GR, as well as by reduced noncovalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent. The results reveal molecular defects of pathologic mutant receptors and provide important insights to the actions of wild-type GR.

Primary Generalized Glucocorticoid Resistance is a rare condition characterized by generalized, partial, target tissue insensitivity to glucocorticoids owing to inactivating mutations, insertions or deletions in the human glucocorticoid receptor (hGR) gene (NR3C1). Recent advances in molecular and structural biology have enabled us to elucidate the molecular mechanisms of action of the mutant receptors and to understand how certain conformational alterations of the defective hGRs result in generalized glucocorticoid resistance. Furthermore, our ever-increasing understanding of the molecular mechanisms of glucocorticoid action indicates that the glucocorticoid signaling pathway is a stochastic system that plays a fundamental role in maintaining both basal and stress-related homeostasis. In this review, we summarize the clinical manifestations and molecular pathogenesis of Primary Generalized Glucocorticoid Resistance, we present our recent findings from the functional characterization of three novel heterozygous point mutations in the NR3C1gene, and we discuss the diagnostic approach and therapeutic management of the condition. When the condition is suspected, we recommend sequencing analysis of the NR3C1gene as well as of other genes encoding proteins involved in the glucocorticoid signal transduction. The tremendous progress of next-generation sequencing will undoubtedly uncover novel hGR partners or cofactors.

Context:Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K+, and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA).Objective:We tested whether chronic stress–related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT).Patients and Methods:One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-μg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2chimeric gene and KCNJ5gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs.Results:Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5mutations were detected in the HYPER group.Conclusions:A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.

Adrenal insufficiency is the clinical manifestation of deficient production or action of glucocorticoids, with or without deficiency also in mineralocorticoids and adrenal androgens. It is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease due to impairment of the hypothalamic–pituitary axis. Prompt diagnosis and management are essential. The clinical manifestations of primary adrenal insufficiency result from deficiency of all adrenocortical hormones, but they can also include signs of other concurrent autoimmune conditions. In secondary or tertiary adrenal insufficiency, the clinical picture results from glucocorticoid deficiency only, but manifestations of the primary pathological disorder can also be present. The diagnostic investigation, although well established, can be challenging, especially in patients with secondary or tertiary adrenal insufficiency. We summarise knowledge at this time on the epidemiology, causal mechanisms, pathophysiology, clinical manifestations, diagnosis, and management of this disorder.

Natural mutations of the human glucocorticoid receptor (GR) isoform α cause the glucocorticoid resistance syndrome. Mutant receptors may have abnormal interactions with the ligand, target DNA sequences, and/or multiple intracellular proteins, as well as aberrant nucleocytoplasmic trafficking. Using fluorescence recovery after photobleaching (FRAP) analysis, all GR pathologic mutant receptors examined, as well as 2 synthetic GR mutants lacking the activation function (AF)-1 or the ligand-binding domain (and hence the AF-2), had defective transcriptional activity and dynamic motility defects inside the nucleus of living cells. In the presence of dexamethasone, these mutants displayed a curtailed 50% recovery time (t1/2) after photobleaching and, hence, significantly increased intranuclear motility and decreased “chromatin retention.” The t1/2values of the mutants correlated positively with their transcriptional activities and depended on the GR domain affected. GRβ, a natural splice variant of the GR gene, also demonstrated a shorter t1/2than GRa. The motility responsiveness of the natural and artificial mutant receptors examined, and of GRβ, to the proteasomal inhibitor MG-132 also depended on the mutant domain. Thus, mutant glucocorticoid receptors possess dynamic motility defects in the nucleus, possibly caused by their inability to properly interact with all key partner nuclear molecules necessary for full activation of glucocorticoid-responsive genes.

AbstractStress activates the central and peripheral components of the stress system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis and the arousal/sympathetic system. The principal effectors of the stress system are corticotropin-releasing hormone (CRH), arginine vasopressin, the proopiomelanocortin-derived peptides α-melanocyte-stimulating hormone and β-endorphin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development, and may account for a number of endocrine, metabolic, autoimmune and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors and the timing of the stressful event(s), given that prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors. The developing brain undergoes rapid growth and is characterized by high turnover of neuronal connections during the prenatal and early postnatal life. These processes and, hence, brain plasticity, slow down during childhood and puberty, and plateau in young adulthood. Hormonal actions in early life, and to a much lesser extent later, can be organizational, i.e., can have effects that last for long periods of time, often for the entire life of the individual. Hormones of the stress system and sex steroids have such effects, which influence the behavior and certain physiologic functions of individuals for life. Exposure of the developing brain to severe and/or prolonged stress may result in hyperactivity/hyperreactivity of the stress system, with resultant amygdala hyperfunction (fear reaction), decreased activity of the hippocampus (defective glucocorticoid-negative feedback, cognition), and the mesocorticolimbic dopaminergic system (dysthymia, novelty-seeking, addictive behaviors), hyperactivation of the HPA axis (hypercortisolism), suppression of reproductive, growth, thyroid and immune functions, and changes in pain perception. These changes may be accompanied by abnormal childhood, adolescent and adult behaviors, including excessive fear (‘inhibited child syndrome’) and addictive behaviors, dysthymia and/or depression, and gradual development of components of the metabolic syndrome X, including visceral obesity and essential hypertension. Prenatal stress exerted during the period of sexual differentiation may be accompanied by impairment of this process with behavioral and/or somatic sequelae. The vulnerability of individuals to develop varying degrees and/or components of the above life-long syndrome is defined by as yet unidentified genetic factors, which account for up to 60% of the variance. CRH has marked kindling and glucocorticoids have strong consolidating properties, hence both of these hormones are crucial in development and can alone produce the above syndrome. CRH and glucocorticoids may act in synergy, as in acoustic startle, while glucocorticoids may suppress or stimulate CRH, as in the hypothalamus and amygdala, respectively. A CRH type 1 receptor antagonist, antalarmin, inhibits both the development and expression of conditioned fear in rats, and has anxiolytic properties in monkeys. Profound stressors, such as those from sexual abuse, may elicit the syndrome in older children, adolescents and adults. Most frequently, chronic dysthymia and/or depression may develop in association with gastrointestinal complaints and/or the premenstrual tension syndrome. A lesser proportion of individuals may develop the classic posttraumatic stress disorder, which is characterized by hypocortisolism and intrusive and avoidance symptoms; in younger individuals it may present as dissociative personality disorder.Copyright © 2003 S. Karger AG, Basel

Glucocorticoids regulate diverse functions important for the maintenance of central nervous system, cardiovascular, metabolic, and immune homeostasis. The actions of these hormones are mediated by the specific intracellular glucocorticoid receptors (GRs). Pathologic conditions associated with changes of tissue sensitivity to these hormones have been described. The syndrome of familialsporadic glucocorticoid resistance is characterized by hypercortisolism without Cushing syndrome stigmata. Many of the patients present with hypertension, with or without hypokalemic alkalosis, as a result of elevated concentrations of cortisol and other salt-retaining steroids. The molecular defects of 4 kindreds and one sporadic case have been elucidated as inactivating mutations in the ligand-binding domain of the GR. In two patients in whom the GR was mutated at amino acid isoleucine 559 to aspartic acid (GR?I559N) and isoleucine 747 to methionine (GR?I747M), respectively, glucocorticoid resistance developed at the heterozygous state, with transdominant negative activity of each of the mutant receptors upon the wild-type protein. Retention of the wild-type receptor in the cytoplasm by the mutant receptor was found in the former, while inappropriate accumulation of p160-type coactivators on the promoter region of glucocorticoid-responsive genes, because of a defective interaction between the AF2 region of the mutant receptor and the LXXLL motif of the coactivators, was determined in the latter. These results suggest that the pathologic mechanisms of glucocorticoid resistance is quite broad, and this is reflected in the wide variability of the clinical picture in patients with the syndrome.

Background:Percutaneous administration of dihydrotestosterone (DHT) has been successful in promoting phallic growth in infants and children with 5α-reductase deficiency raised as males. We investigated whether percutaneous administration of DHT is similarly effective in patients with micropenis due to alternative diagnoses. Methods:Six patients (age range 1.9–8.3 years) with micropenis of variable etiology were studied prospectively. 2.5% DHT gel was applied to the phallus once daily at a dose of 0.15–0.33 mg/kg body weight. Serum DHT concentrations were measured at 0, 2, 4, 8, 12 and 24 h following application of DHT gel. Results:Peak DHT concentrations were attained within 2–8 h after application of the gel and subsequently remained within the normal adult range in all but 1 patient, who had received the lowest dose of 0.15 mg/kg. An increase in phallic growth, ranging from 0.5–2.0 cm, was achieved after 3–4 months of treatment in all patients whose DHT concentrations were maintained within adult range. Conclusion:Percutaneous administration of DHT in a dose of 0.2–0.3 mg/kg once daily for a period of 3–4 months may be useful in the management of patients with testosterone biosynthetic defects, who have sufficient masculinization to warrant male sex assignment, or in patients with micropenis prior to reconstructive surgery.

In patients with intact renal function and low dietary nitrate intake, plasma nitrate concentrations reflect endogenous nitric oxide production and are shown to be increased during inflammatory processes. The aim of this study was to compare plasma nitrate concentrations and hence endogenous nitric oxide production in children with infectious and noninfectious diarrhea and to determine whether plasma nitrate concentrations could serve as a discriminant test between acute and chronic diarrhea in children.

In patients with intact renal function and low dietary nitrate intake, plasma nitrate concentrations reflect endogenous nitric oxide production and are shown to be increased during inflammatory processes. The aim of this study was to compare plasma nitrate concentrations and hence endogenous nitric oxide production in children with infectious and noninfectious diarrhea and to determine whether plasma nitrate concentrations could serve as a discriminant test between acute and chronic diarrhea in children. Three groups of patients were identified: 14 patients with acute gastroenteritis, 13 patients with chronic noninfectious diarrhea, and 14 patients with no evidence of gastrointestinal pathology and no underlying infectious process, who served as control subjects. Plasma nitrate concentrations were determined spectrophotometrically using the Greiss reaction before reduction to nitrite with a copper-coated cadmium column. Mean plasma nitrate concentrations were 405.3 µmol/L ± 281.6 µmol/L (standard deviation) in patients with infectious diarrhea, 134.7 µmol/L ± 77.0 µmol/L in patients with chronic diarrhea, and 54.1 µmol/L ± 20.1 µmol/L in control subjects (F = 42.6, P< 0.0001; analysis of variance). Plasma nitrate concentrations were significantly higher in the infectious diarrhea group compared with the noninfectious diarrhea and control groups (Student–Newman–Keuls test, P< 0.5). Although an optimal cutoff concentration cannot be defined, plasma nitrate concentrations in excess of 300 µmol/L are suggestive of an infectious process whereas values less than 100 µmol/L are indicative of noninfectious diarrhea.

Endocrine and inflammatory responses to stress affect many aspects of development, physiology, and cognition.

Distinct activities of glucocorticoid receptor variants and isoforms should be considered in the management of pathologic conditions treated with glucocorticoids.