Glucocorticoid Deficiency Research Articles

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects.

Nicotinamide nucleotide transhydrogenase (NNT), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify NNT mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages. Sanger or massive parallel sequencing of NNT and patient monitoring. Homozygous or compound heterozygous NNT mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G>A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8-18 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed. NNT should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.

The importance of adrenal hypoandrogenism in infertile women with low functional ovarian reserve: a case study of associated adrenal insufficiency.

BackgroundLow testosterone (T), whether due to ovarian and/or adrenal insufficiency, usually results in poor follicle maturation at small growing follicle stages. The consequence is a phenotype of low functional ovarian reserve (LFOR), characterized by poor granulosa cell mass, low anti-Müllerian hormone and estradiol but rising follicle stimulating hormone. Such hypoandrogenism can be of ovarian and/or adrenal origin. Dehydroepiandrosterone sulfate (DHEAS) is exclusively produced by adrenals and, therefore, reflects adrenal androgen production in the zona reticularis. We here determined in a case study of infertile women with LFOR the presence of adrenal hypoandrogenism, its effects on ovarian function, and the possibility of presence of concomitant adrenal insufficiency (AI), thus reflecting insufficiency of all three adrenal cortical zonae.MethodsWe searched our center’s anonymized electronic research database for women with LFOR, who were also characterized by peripheral adrenal hypoandrogenemia (total testosterone < 16.9 ng/dL) and low DHEAS (<76.0 μg/dL). Among 225 women with LFOR, we identified 29 (12.9 %). The adrenal function of so identified women were further investigated with morning cortisol and ACTH levels and/or standard ACTH stimulation tests. We also determined the prevalence of classical AI (insufficiency glucocorticoid production by zona fasciculata) in hypoandrogenic women with LFOR, and impact of adrenal hypoandrogenism on ovaries.ResultsAmong 14/28 women with adrenal hypoandrogenism due to insufficiency of the zona reticularis available for follow up, 4 (28.6 %) also demonstrated previously unrecognized classical primary, secondary or tertiary AI due to insufficiency of the zona fasciculata. An additional patient with presenting diagnosis of seemingly primary ovarian insufficiency (POI), demonstrated extremely low T and DHEAS levels, a diagnosis of Addison’s disease, and was on glucocorticoid but not androgen supplementation. As her dramatic improvement in ovarian function criteria after androgen supplementation confirmed, her correct diagnosis, therefore, was actually secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism.ConclusionsWomen with LFOR, characterized by low T and DHEAS, are also at risk for AI, while women with AI may be at risk for adrenal induced hypoandrogenism and, therefore, SOI. A currently undetermined percentage of POI patients actually are, likely, affected by SOI, a for prognostic reasons highly significant difference in diagnosis.

Diagnosis and management of pediatric adrenal insufficiency.

Adrenal insufficiency (AI) is a wellknown cause of potentially life-threatening disorders. Defects at each level of the hypothalamic-pituitary-adrenal axis can impair adrenal function, leading to varying degrees of glucocorticoid (GC) deficiency. Iatrogenic AI induced by exogenous GCs is the most common cause of AI. The criteria for the diagnosis and management of iatrogenic AI, neonatal AI, and critical illness-related corticosteroid insufficiency (CIRCI) are not clear. We reviewed the recent original publications and classical data from the literature, as well as the clinical, diagnostic and management strategies of pediatric AI. Practical points in the diagnosis and management of AI with an emphasis on iatrogenic AI, neonatal AI, and CIRCI are provided. Given the lack of sensitive and practical biochemical tests for diagnosis of subtle AI, GC treatment has to be tailored to highly suggestive clinical symptoms and signs. Treatment of adrenal crisis is well standardized and patients almost invariably respond well to therapy. It is mainly the delay in treatment that is responsible for mortality in adrenal crisis. Education of patients and health care professionals is mandatory for timely interventions for patients with adrenal crisis.

Four Cases of Hypovolemic Renin-Aldosterone Axis Deficiency Without Hyperkalemia Following Unilateral Adrenalectomy for Primary Aldosteronism

ABSTRACT Objective: Hyperkalemia can occur following unilateral adrenalectomy for primary aldosteronism due to hypoaldosteronism. We hereby report the cases of 4 male patients exhibiting prolonged failure of the renin-aldosterone (RA) axis in association with normal-to-high kalemia or labile blood pressure and, most significantly, a decrease in extracellular fluid volume (ECFV). Methods: Prior to surgery, all patients exhibited hypokalemic hypertension, with documented primary aldosteronism. Within a few weeks of undergoing unilateral adrenalectomy, the patients developed either mild hyperkalemia or labile blood pressure. Complementary investigations revealed a decrease in measured ECFV with inappropriate normal renal sodium excretion, low supine plasma renin activity, and insufficient orthostatic-related aldosterone production. The adrenocorticotropic hormone (ACTH) stimulation test demonstrated no glucocorticoid deficiency, along with responsive aldosterone secretion. Results: The discrepancy between th...

Increasing Prevalence Of Addison Disease: Results From A Nationwide Study

Primary adrenal insufficiency is a life-threatening endocrine disease unless properly treated. However, few studies on the prevalence, concomitances of the disease, and prescribing of drugs have been published. The goal of the study was to establish the prevalence of primary adrenal insufficiency in Iceland and additionally, to study the most common concomitant diseases in patients with primary adrenal insufficiency, as well as the mode of glucocorticoid replacement therapies. To achieve this, the medical records of all patients in Iceland who had received the International Classification of Diseases and Related Health Problems, 10th Revision, diagnosis code E27, were evaluated for true primary adrenal insufficiency. Additionally, these records were evaluated for concomitant diseases, as well as the mode of glucocorticoid replacement therapy. The study covered the whole population of Iceland over 18 years of age. It was thus a nationwide study. The records were retrieved from large hospitals and clinics and every practicing specialist in endocrinology. Primary adrenal insufficiency was found in 53 individuals, 26 women and 27 men, yielding a prevalence of 22.1 per 100,000 population. Hypothyroidism was by far the most common concomitant disease. Most patients had their glucocorticoid deficiency replaced with short-acting glucocorticoids. The prevalence of primary adrenal insufficiency in Iceland is higher than in earlier reports, with comorbidities being in line with recent studies. Treatment is according to the latest protocols.

Primary Adrenocortical Insufficiency Case Series: Genetic Etiologies More Common than Expected

Background/Aims: Primary adrenal insufficiency (AI) is an important cause of morbidity in children. Our objectives were: (1) to describe the clinical presentation of children with new-onset primary AI, and (2) to identify monogenic causes of primary AI in children. Methods: Chart review and mutation detection in candidate genes were conducted for 11 patients with primary AI. Results: The likely cause of AI was determined in 9 patients. One had a homozygous MC2R mutation associated with familial glucocorticoid deficiency. Two had the same homozygous mutation in the AIRE gene which is associated with type 1 autoimmune polyglandular syndrome. One patient had a heterozygous change in this gene of undetermined significance. Five were homozygous for the previously reported p.R188C STAR mutation causing nonclassic lipoid congenital adrenal hyperplasia, representing the largest cohort of such patients from a single geographic area. In the remaining 2 patients, no clear etiology was identified. Conclusions: We recommend genetic testing for patients who have negative anti-adrenal antibodies or suggestive family history. Diagnosing a genetic etiology can provide information about prognosis and treatment, and is therefore beneficial for patients. Our high proportion of patients with nonclassic lipoid congenital adrenal hyperplasia likely represents a founder effect.

Sugar or salt? The relative roles of the glucocorticoid and mineralocorticoid axes in traumatic shock

Glucocorticoid deficiency (GD) has been proposed as a key contributor to shock states, but the presence and role of acute mineralocorticoid deficiency may be of equal or greater significance. We sought to analyze the incidence and degree of acute mineralocorticoid deficiency and GD in an animal model of severe hemorrhage and shock. Fifty-seven swine underwent 35% volume-controlled hemorrhage followed by aortic cross-clamping for 50 minutes to induce truncal ischemia-reperfusion. Protocol-guided resuscitation was performed. Laboratory analysis included cortisol, aldosterone, and plasma renin activity. The aldosterone-to-renin ratio (ARR) was calculated at each time point, and changes were correlated to markers of perfusion. Mean baseline cortisol levels were 5.8 μg/dL. Following hemorrhage, there was a significant increase in mean cortisol to 9.2 μg/dL (p < 0.001). After 1 hour of reperfusion, there was no change in mean cortisol levels (9.8 μg/dL, p = 0.12). Mean baseline aldosterone was 13.3 pg/mL. Aldosterone levels before cross-clamp removal increased significantly to 115.1 pg/mL (p < 0.001) and then rapidly declined to 49.2 pg/mL (p < 0.001) after 1 hour of reperfusion. Conversely, baseline plasma renin activity was 0.75 ng/mL per hour and increased significantly before cross-clamp removal (1.8) and at 1 hour (8.9, both p < 0.001). The ARR at baseline was 96.1 and increased to 113.5 (p = 0.68) before cross-clamp removal but significantly declined following 1 hour of reperfusion to 7.6 (p < 0.001). Overall, this represented a 93% reduction in mean ARR following reperfusion. The degree of aldosterone deficiency correlated with degree of systemic shock as measured by arterial base deficit (r = 0.47, p = 0.04), while cortisol showed no correlation. Hemorrhagic shock with ischemia-reperfusion injury resulted in only modest impact on the glucocorticoid axis, but major dysfunction of the mineralocorticoid axis and severe hyperreninemic hypoaldosteronism. The degree of aldosterone deficiency may provide prognostic information or offer potential targets for pharmacologic intervention. Diagnostic study, level III.

P1-10: Renin-aldosterone axis deficiency without frank hyperkalemia following unilateral adrenalectomy for primary aldosteronism (PA) : about 4 cases

Background Aldosterone-producing adenoma is classically treated by unilateral adrenalectomy. Severe hyperkalemia, related to adrenal insufficiency, have been already reported after surgery. We describe here 4 male patients who, despite subnormal kalemia, developed a failure of the renin-aldosterone (RA) axis, resulting in a decrease in extracellular fluid volume (ECFV) following surgery Methods PA diagnosis was established according to French recommendations. Unilateral adrenalectomy was performed in all. Postoperative explorations included ECFV measurement using inulin, and RA axis functionally test by orthostatic and ACTH stimulation. Abstract P1-10 – Table Patient 1 2 3 4 ECFV (mL/kg) N:180-210 108 165 166 167 Plasma potassium (mmol/L) 4.9 4.6 4.5 4.2 Plasma renin (mUI/L) N:2.8-39.9 5.5 3.1 19.4 10.5 Plasma aldosterone (ng/L): Supine N:10-105 15 10 21 16 1-hour orthostatism N:34-273 14 31 14 Post ACTH 41 35 48 12 A decrease in ECFV with low renin level, and insufficient orthostatism-induced aldosterone production were depicted. The ACTH test demonstrated no glucocorticoid deficiency, along with responsive aldosterone secretion. The discrepancy in aldosterone response in orthostatic position versus ACTH stimulation test suggested that hypoaldosteronism primarily results from the lack of angiotensin 2 stimulation as a result of hyporeninism. Conclusions Following unilateral adrenalectomy for PA, the occurrence of normal-to-high kalemia prompted an evaluation of the RA system using ortho-static stimulation test rather than simply measuring baseline values and evaluating the glucocorticoid axis. When confirmed, RA axis depression causes latent hypovolemia, meaning that all treatment likely to further decrease plasma volume should be avoided, while this may at times require mineralo-corticoid substitution.

Autoantibodies against Cytochrome P450 Side-Chain Cleavage Enzyme in Dogs (Canis lupus familiaris) Affected with Hypoadrenocorticism (Addison’s Disease)

Canine hypoadrenocorticism likely arises from immune-mediated destruction of adrenocortical tissue, leading to glucocorticoid and mineralocorticoid deficiency. In humans with autoimmune Addison’s disease (AAD) or autoimmune polyendocrine syndrome (APS), circulating autoantibodies have been demonstrated against enzymes associated with adrenal steroid synthesis. The current study investigates autoantibodies against steroid synthesis enzymes in dogs with spontaneous hypoadrenocorticism. Coding regions of canine CYP21A2 (21-hydroxylase; 21-OH), CYP17A1 (17-hydroxylase; 17-OH), CYP11A1 (P450 side-chain cleavage enzyme; P450scc) and HSD3B2 (3β hydroxysteroid dehydrogenase; 3βHSD) were amplified, cloned and expressed as 35S-methionine radiolabelled recombinant protein. In a pilot study, serum samples from 20 dogs with hypoadrenocorticism and four unaffected control dogs were screened by radio-immunoprecipitation assay. There was no evidence of reactivity against 21-OH, 17-OH or 3βHSD, but five dogs with hypoadrenocorticism showed immunoreactivity to P450scc compared with controls. Serum samples were subsequently obtained from 213 dogs diagnosed with hypoadrenocorticism and 110 dogs from a hospital control population. Thirty control dogs were randomly selected to establish a threshold for antibody positivity (mean + 3 × standard deviation). Dogs with hypoadrenocorticism were more likely to be P450scc autoantibody positive than hospital controls (24% vs. 1.2%, respectively; p = 0.0016). Sex was significantly associated with the presence of P450scc autoantibodies in the case population, with 30% of females testing positive compared with 17% of males (p = 0.037). Significant associations with breed (p = 0.015) and DLA-type (DQA1*006:01 allele; p = 0.017) were also found. This cross-sectional study indicates that P450scc autoantibodies are present in a proportion of dogs affected with hypoadrenocorticism.

Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life.

To evaluate adrenal crises after the start of treatment up to the age of 6 years in children with classic congenital adrenal hyperplasia (CAH). Analysis of data extracted from a population-based prospective long-term follow-up study of children detected in neonatal screening. Data of 102 Bavarian children with classic CAH due to 21-hydroxylase deficiency were analyzed, using parental questionnaires and medical reports. Parent-reported hospital admissions of children diagnosed with acute health impairment were included in the analysis if salt loss (hyponatremia) or hypoglycemia was documented in the discharge summary. A total of 74 children (72.5%) had no report of hospital admissions with salt loss or hypoglycemia during the observational period. However, in 27.5% of the children, 22 salt-wasting crises (seven of these also with low blood glucose) and 16 hypoglycemic episodes without salt loss were reported. Furthermore, the cumulative incidence for seizures was elevated; 13 children experienced seizures during hyponatremia or hypoglycemia. Most adrenal crises were triggered by infections, often with inappropriate emergency management, but in 11 cases hypoglycemia occurred unexpectedly, without evidence of severe illness and without any management errors. Frequency of adrenal crises was 6.5 per 100 patient years (95% CI: 4.6-8.8). Crisis prevention remains a permanent challenge for families and physicians caring for children with classic CAH. Expert care and compliance with emergency recommendations are crucial. Further research on the interactions among glucocorticoid deficiency, adrenomedullary dysfunction, and glucose metabolism is necessary for the prevention of hypoglycemia, especially in young CAH patients.

A novel homozygous insertion and review of published mutations in the NNT gene causing familial glucocorticoid deficiency (FGD)

Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by low levels of cortisol despite high adrenocorticotropin (ACTH) levels, due to the reduced ability of the adrenal cortex to produce cortisol in response to stimulation by ACTH. FGD is a heterogeneous disorder for which causal mutations have been identified in MC2R, MRAP, MCM4 and TXNRD2. Also mutations in STAR and CYP11A1 can sometimes present with a phenotype resembling FGD. Recently, it has been indicated that FGD can also be caused by mutations in NNT (nicotinamide nucleotide transhydrogenase).We identified a 6.67 Mb homozygous region harboring the NNT gene by SNP haplotyping in a 1-year old Dutch boy presenting with FGD, but without mutations in MC2R and MRAP. Exome-sequencing revealed a novel homozygous mutation (NM_012343.3: c.1259dupG) in NNT that was predicted to be disease-causing. The mutation is located in exon 9 and creates a frameshift leading to a premature stop-codon (p.His421Serfs*4) that is known to result in FGD. Both parents were shown to be heterozygous carriers. We reviewed the literature for all the reported NNT mutations and their clinical presentation. The median age of disease onset in 23 reported patients, including the present patient, was 12 months (range 3 days–39 months). There was no difference in age of disease onset between truncating and non-truncating NNT mutations. Based on recent literature, we advise to monitor patients with FGD due to NNT mutations for possible combined mineralocorticoid insufficiency and extra-adrenal manifestations.

Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptin.

Leptin administration restores euglycemia in rodents with severe insulin-deficient diabetes, and recent studies to explain this phenomenon have focused on the ability of leptin to normalize excessive hypothalamic-pituitary-adrenal (HPA) axis activity. Here, we employed a streptozotocin-induced rat model (STZ-DM) of uncontrolled insulin-deficient diabetes mellitus (uDM) to investigate the contribution of HPA axis suppression to leptin-mediated glucose lowering. Specifically, we asked if HPA axis activation is required for diabetic hyperglycemia, whether HPA axis normalization can be achieved using a dose of leptin below that needed to normalize glycemia, and if the ability of leptin to lower plasma glucocorticoid levels is required for its antidiabetic action. In STZ-DM rats, neither adrenalectomy-induced (ADX-induced) glucocorticoid deficiency nor pharmacological glucocorticoid receptor blockade lowered elevated blood glucose levels. Although elevated plasma levels of corticosterone were normalized by i.v. leptin infusion at a dose that raises low plasma levels into the physiological range, diabetic hyperglycemia was not altered. Lastly, the potent glucose-lowering effect of continuous intracerebroventricular leptin infusion was not impacted by systemic administration of corticosterone at a dose that maintained elevated plasma levels characteristic of STZ-DM. We conclude that, although restoring low plasma leptin levels into the physiological range effectively normalizes increased HPA axis activity in rats with uDM, this effect is neither necessary nor sufficient to explain leptin's antidiabetic action.

Whole-Exome Sequencing in the Differential Diagnosis of Primary Adrenal Insufficiency in Children.

Adrenal insufficiency is a rare, but potentially fatal medical condition. In children, the cause is most commonly congenital and in recent years a growing number of causative gene mutations have been identified resulting in a myriad of syndromes that share adrenal insufficiency as one of the main characteristics. The evolution of adrenal insufficiency is dependent on the variant and the particular gene affected, meaning that rapid and accurate diagnosis is imperative for effective treatment of the patient. Common practice is for candidate genes to be sequenced individually, which is a time-consuming process and complicated by overlapping clinical phenotypes. However, with the availability, and increasing cost effectiveness of whole-exome sequencing, there is the potential for this to become a powerful diagnostic tool. Here, we report the results of whole-exome sequencing of 43 patients referred to us with a diagnosis of familial glucocorticoid deficiency (FGD) who were mutation negative for MC2R, MRAP, and STAR the most commonly mutated genes in FGD. WES provided a rapid genetic diagnosis in 17/43 sequenced patients, for the remaining 60% the gene defect may be within intronic/regulatory regions not covered by WES or may be in gene(s) representing novel etiologies. The diagnosis of isolated or familial glucocorticoid deficiency was only confirmed in 3 of the 17 patients, other genetic diagnoses were adrenal hypo- and hyperplasia, Triple A, and autoimmune polyendocrinopathy syndrome type I, emphasizing both the difficulty of phenotypically distinguishing between disorders of PAI and the utility of WES as a tool to achieve this.

An ex vivo RT-qPCR-based assay for human peripheral leukocyte responsiveness to glucocorticoids in surgically induced inflammation.

IntroductionAn assay to determine glucocorticoid (GC) responsiveness in humans could be used to monitor GC non-responsiveness in states of GC insufficiency and could provide a tool to adapt GC treatment to individual patients. We propose an ex vivo assay to test GC responsiveness in peripheral leukocytes. The assay was evaluated in a human experimental model of surgery-induced inflammation.Patients and methodsChanges in expression of the GC-regulated genes GILZ, IL1R2, FKBP5, and HLA-DR and glucocorticoid receptor alpha (GRα) were determined by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in peripheral leukocytes from surgical patients and healthy blood donors (total n=60) in response to low (1 nM) and high (1 µM) dexamethasone (DEX). The final selection of a suitable endogenous control gene was based on the studies of stability during DEX treatment and inflammation. Correlations between pre- and postoperative GC-induced gene expression, the postoperative systemic inflammatory and metabolic response (CRP, IL-6, white blood cell count, cytokines, resistin, free fatty acids, glucose, insulin, and adiponectin), and the clinical outcome were analyzed. The length of stay in the intensive care unit (ICU-LOS), the length of stay in the hospital, and postoperative complications were used to measure clinical outcome.ResultsWhen the blood donors were compared to the patients, there were no significant differences in the regulation of the genes in response to DEX, except for GRα. Preoperative, but not postoperative, gene regulation of GILZ and GRα was negatively correlated to ICU-LOS (P<0.05 and P<0.01, respectively). Preoperative GILZ and FKBP5 gene regulation was negatively correlated to postoperative systemic TNFα and MIP-1α levels.ConclusionWe suggest that this assay could be used to determine GC responsiveness. An alteration in preoperative GC responsiveness may be related to a patient’s ability to recover from surgically induced inflammatory stress.

Allgrove’s Syndrome: Two Case Reports and Review of Literature

Introduction: Allgrove’s syndrome (AS) is a rare cause of adrenal insufficiency inherited in an autosomal recessive pattern. Usually the disease is manifested during the first decade of life with severe hypoglycaemia, which can lead to sudden death. Case Presentation: Here we described two cases of Allgrove’s syndrome; the first case was an 8-year-old male admitted to hospital for evaluation of seizure and gait abnormality and the second case was a 4-year-old boy admitted for evaluation of hyperpigmentation of his skin and buccal mucosa for eight months, also we made a review of literature. Conclusions: Alacrima is considered to be the earliest clinical manifestation of Triple A syndrome and early recognition of glucocorticoid deficiency would prevent hypoglycaemic convulsions, neurological sequelae and death. A carful replacement of glucocorticoids is critical to avoid adrenal crisis and allow normal growth and development.

Melanocortin receptor accessory proteins in adrenal disease and obesity.

Melanocortin receptor accessory proteins (MRAPs) are regulators of the melanocortin receptor family. MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency type 2. The role of its paralog melanocortin-2-receptor accessory protein 2 (MRAP2), which is predominantly expressed in the hypothalamus including the paraventricular nucleus, has recently been linked to mammalian obesity. Whole body deletion and targeted brain specific deletion of the Mrap2 gene result in severe obesity in mice. Interestingly, Mrap2 complete knockout (KO) mice have increased body weight without detectable changes to food intake or energy expenditure. Rare heterozygous variants of MRAP2 have been found in humans with severe, early-onset obesity. In vitro data have shown that Mrap2 interaction with the melanocortin-4-receptor (Mc4r) affects receptor signaling. However, the mechanism by which Mrap2 regulates body weight in vivo is not fully understood and differences between the phenotypes of Mrap2 and Mc4r KO mice may point toward Mc4r independent mechanisms.

Diagnosis and management of rare forms of CAH

Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders. It comprises a group of autosomal recessive disorders caused by the mutations in the genes encoding for steroidogenic enzymes that are involved in cortisol synthesis [1]. More than 90% of cases are caused by a defect in the enzyme 21-hydroxylase. Four other enzyme deficiencies (P450scc, P450c17, P450c11β, 3βHSD) in the steroid biosynthesis pathway [2-4], along with one cholesterol transport protein defect (StAR) [5], and one electron-transfer protein (P450 oxidoreductase) [6] account for the remaining cases. In these rare forms of CAH, so-called “atypical CAH”, the clinical and hormonal phenotypes can be complicated, and are not well characterized. The clinical symptoms of the different forms of CAH result from the particular hormones that are deficient and those that are produced in excess. A characteristic feature of CAH is genital ambiguity or disordered sex development (DSD), and most variants are associated with glucocorticoid deficiency. This talk will focus on the diagnosis and management of the variant forms of CAH other than 21-hydroxylase so-called “atypical CAH”, including the genetic analyses, and phenotypic correlates.

Etiology, diagnosis and management of adrenal insufficiency in children

Adrenal insufficiency(AI) is a disorder that can result from primary adrenal failure(primary type) or secondary adrenal disease due to impairment of the hypothalamic–pituitary axis(central type). It is characterized by glucocorticoid deficiency, with or without inappropriate mineralocorticoid or androgen production.The diagnosis and management of children with AI remain challenging as clinical characteristics of AI in children maybe non-specific and acute adrenal crisis is life-threatening, needing life-long glucocorticoid replacement treatment and education of the patient and the family.New formulations of hydrocortisone which should be able to simulate the circadian rhythm of steroid secretion are supposed to improve outcome in patients with adrenal insufficiency in the near future. Key words: Adrenal insufficiency; Adrenal crisis; Glucocorticoid; Mineralocorticoid

Transforming Non‐Ulcerogenic Stress Stimuli into Gastric Ulcerogenic Ones under the Circumstances of Inhibition of the Hypothalamic‐Pituitary‐Adrenocortical Axis

To investigate contribution of glucocorticoids to the maintenance of gastric mucosal integrity during stress we predominantly used ulcerogenic stress models. Using these models we demonstrated that glucocorticoids released in response to the ulcerogenic stimuli attenuated their harmful action on the gastric mucosa.In the present study we hypothesized that mild stressors does not damage the gastric mucosa due to gastroprotective action of glucocorticoids released in response to these stimuli. To verify the hypothesis the effects of normally non‐ulcerogenic mild stimuli (15‐30 min cold‐restraint) on the gastric mucosa have been studied under the circumstances of inhibition ofthe hypothalamic‐pituitary‐adrenocortical (HPA) axis in rats. The HPA axis was inhibited by: 1) fast inhibitory action of NBI 27914, the selective antagonist of cortricotropin‐releasing factor receptor type 1; 2) fast inhibitory action of metyrapone, inhibitor glucocoricoid synthesis; 3) delayed inhibitory action of a single pharmacological dose of cortisol injected one week before the onset of stress stimulus. Each of these pretreatments decreased 15‐30 min cold‐restraint‐produced corticosterone levels and resulted in an appearance of gastric lesions after the onset of this mild stress. The results suggest that in rats with glucocorticoid deficiency non‐ulcerogenic stimuli are transformed into ulcerogenic ones and confirm the hypothesis. The findings further support for the point of view that glucocorticoids released during acute stress are gastroprotective factors. Supported by the Russian Scientific Foundation (grant N 14‐15‐00790).

Authors' response to letter by Adam Morton regarding: "Managing severe peripartum hyponatraemia: A case report".

We thank Dr Morton for his interest in our case report. He queries whether acute glucocorticoid deficiency could have been responsible for our patient’s symptoms. We agree with him that it is important to exclude adrenal insufficiency early in the investigation of patients with hyponatraemia to avoid the risks of missed diagnosis. However, physicians should take care in the interpretation of a normal cortisol result as this may not exclude the disease, particularly in the third trimester. A number of factors in our case lead us to exclude glucocorticoid deficiency. Firstly, she remained normotensive following fluid resuscitation for her haemorrhage-induced hypovolaemia. Secondly, whilst not shown in the case report, her potassium and blood glucose concentrations were within normal limits. Our patient’s sodium also initially responded to a saline infusion prior to her first discharge from the Intensive Care Unit. Had adrenal insufficiency been the cause this would not have been expected. Finally, her 09:00 serum cortisol concentration measured the morning after her stroke (when her hyponatraemia was first noted) was 403 nmol/l (range at 09:00, 171–536 nmol/ l). With these four factors, we felt glucocorticoid deficiency was unlikely. Dr Morton also highlights a case report of a presentation of Sheehan’s syndrome with acute secondary adrenal insufficiency characterised by hyponatraemia and hypoglycaemia. Whilst we concede that early presentation of secondary adrenal deficiency is possible, clearly this is unusual with a later presentation more typical.