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Congenital adrenal hyperplasia describes a group of inherited autosomal recessive disorders characterized by an enzymatic defect in cortisol biosynthesis, compensatory increases in corticotropin secretion, and adrenocortical hyperplasia. 21-Hydroxylase deficiency is responsible for more than 95% of cases and is one of the most common known autosomal recessive disorders. The classic or severe type presents in the newborn period or early childhood with virilization and adrenal insufficiency, with or without salt loss; the mild or nonclassic form presents in late childhood or early adulthood with mild hyperandrogenism and is an important cause of masculinization and infertility in women. This wide range of phenotypic expression is mostly explained by genetic variation, although genotype-phenotype discrepancies have been described. Reproductive, metabolic, and other comorbid conditions, including risk for tumors, are currently under investigation in both forms of the disease. A high proportion of patients with adrenal incidentalomas may be homozygous or heterozygous for 21-hydroxylase deficiency. Women with congenital adrenal hyperplasia often develop the polycystic ovary syndrome. Ectopic adrenal rest tissue is often found in the testes of men with congenital adrenal hyperplasia; characteristic clinical and radiologic findings help differentiate this tissue from other tumors. Levels of corticotropin-releasing hormone are elevated in patients with depression and anxiety and are expected to be elevated in patients with congenital adrenal hyperplasia; it is unknown whether patients with 21-hydroxylase deficiency have an increased incidence of these psychiatric disorders. Abnormalities in both the structure and function of the adrenal medulla have been shown in patients with classic congenital adrenal hyperplasia, and the degree of adrenomedullary impairment may be a biomarker of disease severity. The 21-hydroxylase-deficient mouse has provided a useful model with which to examine disease mechanisms and test new therapeutic interventions in classic disease, including gene therapy. Treatment of this condition is intended to reduce excessive corticotropin secretion and replace both glucocorticoids and mineralocorticoids. However, clinical management is often complicated by inadequately treated hyperandrogenism, iatrogenic hypercortisolism, or both. New treatment approaches currently under investigation include combination therapy to block androgen action and inhibit estrogen production, and bilateral adrenalectomy in the most severely affected patients. Other approaches, which are in a preclinical stage of investigation, include treatment with a corticotropin-releasing hormone antagonist and gene therapy.

To explore the associations of vitamin D status and obesity with insulin resistance (IR) in children.A sample of 2282 schoolchildren (9-13 years old) in Greece was examined. Sociodemographic, anthropometric (weight, height), biochemical (fasting plasma glucose, serum insulin and 25(OH)D), pubertal status and physical activity data were collected, using standard methods. The "Vitamin D Standardization Program" protocol was applied to standardize serum 25(OH)D values.The prevalence of vitamin D insufficiency (serum 25(OH)D < 50 nmol/L) was higher in obese children compared to their over- and normal-weight counterparts (60.5% vs 51.6% and 51%, P = .017). Furthermore, children with IR (both obese and non-obese) had higher prevalence of vitamin D insufficiency compared to non-obese, non-insulin resistant children (66% and 59.2% vs 49.8%, P < .05), possibly indicating that IR is associated with vitamin D insufficiency, independently of obesity. In line with the above, the results from logistic regression analyses controlled for several potential confounders, showed a 1.48 (95% C.I: 1.2-1.84) higher likelihood for vitamin D insufficiency for insulin resistant children compared to the non-insulin resistant ones, while no significant association was observed with obesity.The present study revealed a high prevalence of vitamin D insufficiency among schoolchildren in Greece, particularly among obese and insulin resistant ones. In addition, it highlighted that the significant association of vitamin D insufficiency with IR is possibly independent of obesity. Further clinical trials are needed to confirm this possible independent association but also explore the potential beneficial effect of vitamin D supplementation on IR and possibly on weight management too.

Journal Article Corticotropin-Releasing Hormone Is not the Sole Factor Mediating Exercise-Induced Adrenocorticotropin Release in Humans Get access BONNIE SMOAK, BONNIE SMOAK 1Department of Military Medicine, Uniformed Services University of the Health Sciences Bethesda, Maryland 20814; The Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health Bethesda, Maryland 20892 Search for other works by this author on: Oxford Academic Google Scholar PATRICIA DEUSTER, PATRICIA DEUSTER 1Department of Military Medicine, Uniformed Services University of the Health Sciences Bethesda, Maryland 20814; The Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health Bethesda, Maryland 20892 Search for other works by this author on: Oxford Academic Google Scholar DOUGLAS RABIN, DOUGLAS RABIN 1Department of Military Medicine, Uniformed Services University of the Health Sciences Bethesda, Maryland 20814; The Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health Bethesda, Maryland 20892 Search for other works by this author on: Oxford Academic Google Scholar GEORGE CHROUSOS GEORGE CHROUSOS 1Department of Military Medicine, Uniformed Services University of the Health Sciences Bethesda, Maryland 20814; The Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health Bethesda, Maryland 20892 Search for other works by this author on: Oxford Academic Google Scholar The Journal of Clinical Endocrinology & Metabolism, Volume 73, Issue 2, 1 August 1991, Pages 302–306, https://doi.org/10.1210/jcem-73-2-302 Published: 01 August 1991 Article history Received: 22 October 1990 Published: 01 August 1991

Abstract Introduction A major diagnostic enigma regarding ACTH-dependent Cushing syndrome is the distinction between the source of ACTH, which may have either a pituitary or ectopic origin. We present the first described patient with cyclic Cushing syndrome caused by an intestinal neuroendocrine tumour (NET) detected by 68GA-DOTATATE PET-CT, despite functional tests that were indicative of pituitary Cushing disease. Clinical Case A 53-year old man was admitted to outpatient clinic because of muscle weakness. His phenotype and clinical findings (progressively worsening upper and lower limb weakness, emotional disturbances, easy bruising, a Buffalo hump, prediabetes and leucocytosis) led to the diagnosis of Cushing syndrome. Initial laboratory tests established the diagnosis with an abnormal diurnal cortisol and ACTH secretion (night cortisol F: 22.1μg / dl), absence of suppression with dexamethasone 1mg and increased free urinary free cortisol 24h (243.5μg /24h). Abdominal CT scanning revealed a left-sided adrenal adrenocortical adenoma 1.5 mm in max diameter. Pituitary MRI and somatostatin scintigraphy were normal. Low dexamethasone suppression test was indicative of Cushing (F: 14μg / dl) followed by a combined CRH stimulation test during bilateral inferior petrosal sinus sampling. Pituitary / peripheral ACTH ratio pre-infusion of CRH and 3 min after CRH infusion was compatible with right-sided pituitary origin of ACTH hypersecretion. Pending the results of the laboratory, the patient showed a remission of his symptoms along with a laboratory-confirmed recession of active hypercortisolaemia (LDDST test), and this led to the suspicion of periodic Cushing syndrome. The patient was followed with clinical and laboratory examinations weekly, with recurrence of symptoms 2 months later followed by a new remission 3 months later. A PETGA CT SCAN with 68GA-HA-DOTATATE was performed, which showed an increased uptake of the radioisotope in the small intestine. A surgical excision of the affected small bowel region was performed according to the guidelines for intestinal NETs. Histology confirmed the existence of a well-differentiated neuroendocrine neoplasm of the small intestine of 1.1 cm diameter, grade 1 (WHO 2010). Immunophenotype was positive for serotonin and ACTH. Postoperatively, the patient showed a complete remission of symptomatology and regression of hypercortisolaemia over a 18-month period. Follow-up abdominal MRI and 68GA-HA-DOTATATE revealed no pathological findings. Conclusion: Our patient is the first case of ectopic Cushing disease caused by intestinal NET. The differential diagnosis between pituitary and ectopic Cushing syndrome due to ACTH or CRH hypersecretion is not easy and frequently complicated by the periodicity of the disease. In patients with no visible pituitary lesions on MRI we suggest further investigation for ectopic ACTH- driven Cushing syndrome.

It has been demonstrated that Brain-Derived Neurotrophic Factor (BDNF) is a mediator of neuroprotective and neuroplastic processes, and that serum BDNF is representative of central concentrations as well. Interestingly, there is evidence that BDNF levels are elevated in response to exercise. PURPOSE: This study aimed at investigating the acute and chronic effects of a full season swimming training on serum BDNF, both at rest and after a maximal exercise bout in young athletes. METHODS: Twelve well-trained male swimmers (14.08±1.0 yrs) participated in the study. Measurements were carried out at the beginning of the training season (T1) as well as pre- and post- taper of each of the two competitive periods (i.e., T2, T3 for the first macrocycle, and T4, T5 for the second macrocycle, respectively). At each of the above time points, blood samples were collected pre- and 1 hour post a maximal, 400m swimming testing. Serum BDNF levels were measured by ELISA. Adjustment for exercise-induced plasma volume changes was performed before data analysis. Two-way ANOVA with repeated measures was used for statistics. RESULTS: A significant pre-post testing difference was observed at T2 (p=0.048). In addition, a main effect of time was found among the 5 time points (T1-T5; p=0.000). Moreover, both pre- and post- testing responses had a similar profile exhibiting a decline from T1 to T3 (pre: 23,412±2,504 pg/ml vs 3,433±669 pg/ml, post: 23,004±3,410 pg/ml vs 2,743±550 pg/ml) and from T4 to T5 (pre: 19,428±1,097 pg/ml vs 11,993±969 pg/ml, post: 22,111±1,455 pg/ml vs 12,838±1,763 pg/ml), and an increase from T3 to T4 (pre: 3,433±669 pg/ml vs 19,428±1,097 pg/ml, post: 2,743±550 pg/ml vs 22,111±1,455 pg/ml). CONCLUSIONS: To the authors’ best knowledge this is the first study examining the acute and chronic BDNF responses during one season training in young athletes. These findings indicate that long-term swimming training can affect the resting and acute (pre-post testing) circulating BDNF in young swimmers.

The aim of the present study was to investigate the associations of iron depletion (ID) with menstrual blood losses, lifestyle, and dietary habits, in pubertal girls. The study sample comprised 1222 girls aged 9–13 years old. Biochemical, anthropometrical, dietary, clinical, and physical activity data were collected. Out of 274 adolescent girls with menses, 33.5% were found to be iron depleted (defined as serum ferritin &lt; 12 μ g/L) compared to 15.9% out of 948 girls without menses. Iron-depleted girls without menses were found to have lower consumption of poultry (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.017</mml:mn></mml:math>) and higher consumption of fruits (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.044</mml:mn></mml:math>) and fast food (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.041</mml:mn></mml:math>) compared to their peers having normal iron status. Multivariate logistic regression analysis showed that girls with menses were 2.57 (95% CI: 1.37, 4.81) times more likely of being iron depleted compared to girls with no menses. Iron depletion was found to be associated with high calcium intake, high consumption of fast foods, and low consumption of poultry and fruits. Menses was the only factor that was found to significantly increase the likelihood of ID in these girls. More future research is probably needed in order to better understand the role of diet and menses in iron depletion.

The dramatic fluctuations in energy demands by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for biological temporal organization across phylogeny. The intrinsic circadian timing system (CS), represents a highly conserved and sophisticated internal "clock", adjusted to the 24-hour rotation period of the earth, enabling a nyctohemeral coordination of numerous physiologic processes, from gene expression to behavior. The human CS is tightly and bidirectionally interconnected to the stress system (SS). Both systems are fundamental for survival and regulate each other's activity in order to prepare the organism for the anticipated cyclic challenges. Thereby, the understanding of the temporal relationship between stressors and stress responses is critical for the comprehension of the molecular-basis of physiology and pathogenesis of disease. A critical loss of the harmonious timed order at different organizational levels may affect the fundamental properties of neuroendocrine, immune and autonomic systems, leading to a breakdown of biobehavioral adaptative mechanisms with increased stress sensitivity and vulnerability. In this review, following an overview of the functional components of the SS and CS, we present their multilevel interactions and discuss how traumatic stress can alter the interplay between the two systems. Circadian dysregulation after traumatic stress exposure may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of trauma through maladaptive stress regulation. Understanding the mechanisms susceptible to circadian dysregulation and their role in stress-related disorders could provide new insights into disease mechanisms, advancing psychochronobiological treatment possibilities and preventive strategies in stress-exposed populations.

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).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).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/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs.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 KCNJ5 mutations were detected in the HYPER group.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.