Adrenal insufficiency in pediatric kidney transplantation recipients.

BACKGROUND: Immunosuppression of pediatric kidney transplant (PKT) recipients often includes corticosteroids. Prolonged corticosteroid exposure has been associated with secondary adrenal insufficiency (AI); however, little is known about its impact on PKT recipients. METHODS: This was a retrospective cohort review of PKT recipients to evaluate AI prevalence, risk factors, and adverse effects. AI risk was assessed using morning cortisol (MC) and diagnosis confirmed by an ACTH stimulation test. Potential risk factors and adverse effects were tested for associations with MC levels and AI diagnosis. RESULTS: Fifty-one patients (60.8% male, age 7.4 (IQR 3.8, 13.1) years; 1 patient counted twice for repeat transplant) were included. Patients at risk for AI (MC < 240 nmol/L) underwent definitive ACTH stimulation testing, confirming AI in 13/51 (25.5%) patients. Identified risk factors for AI included current prednisone dosage (p = .001), 6-month prednisone exposure (p = .02), daily prednisone administration (p = .002), and rejection episodes since transplant (p = .001). MC level (2.5 years (IQR 1.1, 5.1) post-transplant) was associated with current prednisone dosage (p < .001), 6-month prednisone exposure (p = .001), daily prednisone administration (p = .006), rejection episodes since transplant (p = .003), greater number of medications (ß = -16.3, p < .001), 6-month hospitalization days (ß = -3.3, p = .013), creatinine variability (ß = -2.4, p = .025), and occurrence of acute kidney injury (ß = -70.6, p = .01). CONCLUSION: Greater corticosteroid exposure was associated with a lower MC level and confirmatory diagnosis of AI noted with an ACTH stimulation test. Adverse clinical findings with AI included greater medical complexity and kidney function lability. These data support systematic clinical surveillance for AI in PKT recipients treated with corticosteroids.

[A rare cause of hypercorticism: ACTH-secreting pheochromocytoma (a case report)]. / Une cause rare d'hypercorticisme: un phéochromocytome sécrétant l'ACTH (à propos d'un cas).

Ectopic ACTH-secreting pheochromocytoma is a very rare cause of Cushing´s syndrome, posing diagnostic and therapeutic challenges. We here report the case of a female patient with suspected severe Cushing´s syndrome associated with melanoderma, arterial hypertension resistant to triple therapy and unbalanced diabetes treated with insulin therapy. Biologically, urinary ethoxylated, 24-hour urinary free cortisol and ACTH were very high. Imaging showed a 3.5 cm left adrenal mass. The patient underwent left adrenalectomy after medical preparation, with good clinico-biological outcome. Anatomopathological examination confirmed the diagnosis of pheochromocytoma. This case study highlights the importance of measuring methoxylated derivatives in any patient with ACTH-dependent Cushing´s syndrome associated with an adrenal mass. The aim is to ensure early treatment and avoid life-threatening complications.

Hypokalemia Due to Ectopic Adrenocorticotropic Hormone.

Hypokalemia is a common disorder in clinical practice. The underlying pathophysiology can be attributed to 3 main mechanisms: insufficient potassium intake, excessive urinary or gastrointestinal losses, and transcellular shift. Renal loss is the most common cause of hypokalemia. Renal loss of potassium can occur due to diuretics, mineralocorticoid excess or hypercortisolism (Cushing syndrome). Among patients with Cushing syndrome, ectopic adrenocorticotropic hormone (ACTH) is the most frequent cause. We present a case of hypokalemia and hypertension due to ectopic ACTH production leading to Cushing syndrome.

Immune checkpoint inhibitor-induced hypophysitis with transient ACTH-dependent hypercortisolism.

A woman in her 70s with metastatic melanoma presenting with refractory hypokalaemia on combined immune checkpoint inhibitors, nivolumab-ipilimumab, was diagnosed with adrenocorticotropic hormone (ACTH)-dependent hypercortisolism 11 weeks following the initiation of her immunotherapy. Investigations also demonstrated central hypothyroidism and hypogonadotropic hypogonadism. She underwent imaging studies of her abdomen and brain which revealed normal adrenal glands and pituitary, respectively. She was started on levothyroxine replacement and had close pituitary function monitoring. Two weeks later, her cortisol and ACTH levels started to trend down. She finally developed secondary adrenal insufficiency and was started on hydrocortisone replacement 4 weeks thereafter.This report highlights a case of immunotherapy-related hypophysitis with well-documented transient central hypercortisolism followed, within weeks, by profound secondary adrenal insufficiency. Healthcare professionals should remain vigilant in monitoring laboratory progression in these patients. Early recognition of the phase of hypercortisolism and its likely rapid transformation into secondary adrenal insufficiency can facilitate timely hormonal replacement and prevent complications.

Effects of noise exposure on stress hormone changes during task performance in young Korean men: quasi-experimental study.

Numerous studies have suggested that noise exposure might be associated with changes in stress hormone levels. However, quantitative evidence for these effects in humans is rare and remains controversial. This study aimed to investigate the acute effects of exposure to noise and its different levels on stress hormone changes in task performance. Quasi-experimental noise exposure environment was established for 90 male university student volunteers in their twenties, and each was exposed to different noise levels during task performance. The stress hormones tested included cortisol, adrenocorticotropic hormone (ACTH), adrenaline, and noradrenaline. A one-way ANOVA was performed to investigate differences in hormone levels measured in the three groups according to the noise exposure levels (35, 45, or 75 dB). Analysis of covariance (ANCOVA) was used to adjust for confounding factors that might affect hormone levels. After adjusting for confounders, significant exposure-dependent differences were found in hormone levels in salivary cortisol, serum cortisol, serum ACTH, and serum adrenaline. The amount of hormonal increase in 75 dB exposure group compared to 35 or 45 dB groups was detected. Similar results were also seen in the rate of change analysis. Our findings indicate that short-term noise exposure during task performance elevates stress hormone levels. Further, the extent of stress hormone alterations varies with noise exposure levels. Changes in hormone levels are an objective measure that may be used to identify health effects and stress responses in various noise environments.

Partial hypopituitarism with ACTH deficiency as the main manifestation as a complication of hemorrhagic fever with renal syndrome.

Hypopituitarism is a relatively rare complication of hemorrhagic fever with renal syndrome. However, almost all available reported cases were total anterior pituitary hypofunction, isolated growth-hormone deficiency, or isolated gonadotropin deficiency. Here, we firstly describe a patient with partial hypopituitarism with ACTH deficiency as the main manifestation as a complication of hemorrhagic fever with renal syndrome.

The influence of cortisol co-secretion on clinical characteristics and postoperative outcomes in unilateral primary aldosteronism.

Context: The prevalence of unilateral primary aldosteronism (UPA) with cortisol co-secretion varies geographically. Objective: To investigate the prevalence and clinical characteristics of UPA with cortisol co-secretion in a Chinese population. Design: Retrospective cohort study. Methods: We recruited 580 patients with UPA who underwent cosyntropin stimulation test (CST) after the 1-mg dexamethasone suppression test (DST) and retrospectively analyzed the clinical characteristics and postoperative outcomes of UPA with and without cortisol co-secretion. Results: UPA with cortisol co-secretion (1 mg DST>1.8 ug/dL) was identified in 65 of 580 (11.2%) patients. These patients were characterized by older age, longer duration of hypertension, higher concentration of plasma aldosterone and midnight cortisol, lower adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS), larger tumor diameter, and more history of diabetes mellitus. Cortisol and aldosterone levels were higher and DHEAS level was lower in UPA with cortisol co-secretion at 0-120 min after CST. Among 342 UPA patients with KCNJ5 gene sequencing and follow-up results, the complete clinical success rate was lower in UPA with cortisol co-secretion (33.3% vs. 56.4%, P<0.05); the complete biochemical success rate and KCNJ5 mutation did not differ between the two groups. Age, tumor size, and ACTH were independent predictors of UPA with cortisol co-secretion. Sex, BMI, duration of hypertension, KCNJ5 mutation, and cortisol co-secretion were independent predictors for complete clinical success in UPA after surgery. Conclusions: UPA with cortisol co-secretion is not uncommon in China, but the clinical features were distinctly different from those without co-secretion. Cortisol co-secretion is an independent risk factor for incomplete clinical success after surgery in UPA.

Spring and fall blood concentrations of adrenocorticotropic hormone, insulin, and thyroxine in healthy horses in Saskatchewan.

Objective: To characterize concentrations of adrenocorticotropic hormone (ACTH), insulin, and thyroxine (T4) at 2 times of the year in healthy horses in Saskatchewan. Animals and procedure: A prospective, observational study was carried out in 52 healthy, client-owned horses. Inclusion criteria were no recent travel outside of Saskatchewan, normal physical examination findings, and no history or evidence of ongoing illness. Blood concentrations of ACTH, insulin and T4 were determined by chemiluminescence. Samples were collected in spring and fall and compared using the paired Student's t-test or Wilcoxon signed-rank test. Generalized estimating equations were used to assess the associations between ACTH, T4, and insulin concentrations and gender, age, season, body condition score, glucose concentration, and breed. Results: There were increases in both ACTH and insulin concentrations in the fall compared to spring (P < 0.001 and P = 0.001, respectively). Other than season, insulin concentration was associated with breed, whereas ACTH concentration was associated with age. Finally, T4 concentration was associated with breed and glucose concentration, but not with season. Conclusion and clinical relevance: These results highlighted the differences between spring and fall concentrations of both ACTH and insulin in healthy horses residing in the Canadian prairie provinces, which are known for extreme differences in summer and winter temperatures as well as day length. Geographically adjusted reference values are necessary to account for these variations, to improve diagnostic accuracy. This is the first published Canadian study evaluating these factors and their associations with hormone concentrations in clinically healthy animals.

Concentrations sanguines printanières et automnales d'hormone adrénocorticotrope, d'insuline et de thyroxine chez des chevaux en bonne santé en Saskatchewan. Objectif: Caractériser les concentrations d'hormone adrénocorticotrope (ACTH), d'insuline et de thyroxine (T4) à 2 moments de l'année chez des chevaux en bonne santé en Saskatchewan. Animaux et procédure: Une étude observationnelle prospective a été réalisée auprès de 52 chevaux en bonne santé appartenant à des clients. Les critères d'inclusion étaient l'absence de voyage récent à l'extérieur de la Saskatchewan, les résultats normaux de l'examen physique et l'absence d'antécédents ou de signes de maladie persistante. Les concentrations sanguines d'ACTH, d'insuline et de T4 ont été déterminées par chimiluminescence. Des échantillons ont été collectés au printemps et à l'automne et comparés à l'aide du test de Student apparié ou du test du rang de signe de Wilcoxon. Des équations d'estimation généralisées ont été utilisées pour évaluer les associations entre les concentrations d'ACTH, de T4 et d'insuline et le sexe, l'âge, la saison, l'état corporel, la concentration de glucose et la race. Résultats: Il y avait une augmentation des concentrations d'ACTH et d'insuline à l'automne par rapport au printemps (P < 0,001 et P = 0,001, respectivement). Hormis la saison, la concentration d'insuline était associée à la race, alors que la concentration d'ACTH était associée à l'âge. Enfin, la concentration de T4 était associée à la race et à la concentration en glucose, mais pas à la saison. Conclusion et pertinence clinique: Ces résultats ont mis en évidence les différences entre les concentrations printanières et automnales d'ACTH et d'insuline chez les chevaux en bonne santé résidant dans les provinces des Prairies canadiennes, reconnues pour leurs différences extrêmes de températures estivales et hivernales ainsi que de durée du jour. Des valeurs de référence géographiquement ajustées sont nécessaires pour tenir compte de ces variations et améliorer la précision du diagnostic. Il s'agit de la première étude canadienne publiée évaluant ces facteurs et leurs associations avec les concentrations d'hormones chez des animaux cliniquement sains.(Traduit par Dr Serge Messier).

The diagnostic yield of inferior petrosal sinus sampling in Cushing syndrome in the era of ovine CRH shortage.

PURPOSE: The ovine corticotropin-releasing hormone (oCRH) stimulation test has been routinely used in the diagnostic work-up of ACTH-dependent Cushing syndrome (CS). With oCRH currently being out-of-stock in Europe, we aimed at evaluating the diagnostic performance of inferior petrosal sinus sampling (IPSS) without oCRH stimulation. METHODS: We compared the values of 40 patients with ACTH-dependent CS and negative MRI findings in whom ACTH was measured before and after oCRH stimulation. RESULTS: The ratio of central-to-peripheral ACTH measurement (IPS:P) before the combined 3, 5, and 10 min of oCRH stimulation yielded diminished sensitivity (85% vs. 97%), alongside markedly decreased specificity (57% vs. 71%), as well as reduced positive and negative predictive values (90% vs. 94% and 44% vs. 83%), respectively. CONCLUSIONS: With the current drug shortages in Europe, ACTH measurements without oCRH stimulation in IPSS cannot be recommended. Thus, we call for desmopressin or the commercially available human CRH as a potential alternative in the confirmation of ACTH excess by IPSS in equivocal MRI findings.

[Acute heart failure in a neonate]. / æ–°ç”Ÿå„¿æ€¥æ€§å¿ƒåŠŸèƒ½ä¸å ¨1例.

The male patient, one day old, was admitted to the hospital due to hypoglycemia accompanied by apnea appearing six hours after birth. The patient had transient hypoglycemia early after birth, and acute heart failure suddenly occurred on the eighth day after birth. Laboratory tests showed significantly reduced levels of adrenocorticotropic hormone and cortisol, and pituitary magnetic resonance imaging was normal. Genetic testing results showed that the patient had probably pathogenic compound heterozygous mutations of the TBX19 gene (c.917-2A>G+c.608C>T), inherited respectively from the parents. The patient was conclusively diagnosed with congenital isolated adrenocorticotropic hormone deficiency caused by mutation of the TBX19 gene. Upon initiating hydrocortisone replacement therapy, cardiac function rapidly returned to normal. After being discharged, the patient continued with the hydrocortisone replacement therapy. By the 18-month follow-up, the patient was growing and developing well. In neonates, unexplained acute heart failure requires caution for possible endocrine hereditary metabolic diseases, and timely cortisol testing and genetic testing should be conducted.

Effects of antidepressant on FKBP51 mRNA expression and neuroendocrine hormones in patients with panic disorder.

OBJECTIVE: The purpose of this study was to investigate the effects of escitalopram on the peripheral expression of hypothalamic-pituitary-adrenal (HPA) axis-related genes (FKBP51, HSP90, NR3C1 and POMC) and HPA-axis hormones in patients with panic disorder (PD). METHODS: Seventy-seven patients with PD were treated with escitalopram for 12 weeks. All participants were assessed for the severity of panic symptoms using the Panic Disorder Severity Scale (PDSS). The expression of HPA-axis genes was measured using real-time quantitative fluorescent PCR, and ACTH and cortisol levels were measured using chemiluminescence at baseline and after 12 weeks of treatment. RESULTS: At baseline, patients with PD had elevated levels of ACTH and cortisol, and FKBP51 expression in comparison to healthy controls (all p < 0.01). Correlation analysis revealed that FKBP51 expression levels were significantly positively related to cortisol levels and the severity of PD (all p < 0.01). Furthermore, baseline ACTH and cortisol levels, and FKBP51 expression levels were significantly reduced after 12 weeks of treatment, and the change in the PDSS score from baseline to post-treatment was significantly and positively related to the change in cortisol (p < 0.01). CONCLUSIONS: The results suggest that PD may be associated with elevated levels of ACTH and cortisol, and FKBP51 expression, and that all three biomarkers are substantially decreased in patients who have received escitalopram treatment.

The predictive value of cortisol in psychodynamic psychotherapy for social anxiety disorder: Extended results of the SOPHONET-Study.

Psychotherapy is an effective treatment for anxiety disorders (AD), yet a vast majority of patients do not respond to therapy, necessitating the identification of predictors to enhance outcomes. Several studies have explored the relationship between stress response and treatment outcome, as a potential treatment mechanism. However, the latter remains under-researched in patients with social anxiety disorder (SAD). We studied N = 29 patients undergoing psychodynamic psychotherapy (PDT) within the SOPHONET-Study. Stress reactivity (i.e., area under the curve with respect to the increase; AUCi) was induced by a standardized psychosocial stressor (Trier Social Stress Test; TSST) and assessed by means of adrenocorticotropic hormone (ACTH), blood and salivary cortisol samples before (t1) treatment. Samples of these biomarkers were taken -1 min prior stress exposure and six more blood samples were collected post-TSST ( + 1, + 10, + 20, + 30, + 45, + 60 min.). The participants were diagnosed with SAD based on the Structured Clinical Interview for DSM-IV (SCID) and completed the Liebowitz Social Anxiety Scale as well as the Beck Depression Inventory before (t1) and after psychotherapy (t2). Pre-treatment stress reactivity significantly predicted changes in depression (salivary p < 0.001 and blood cortisol p = 0.001), as well as in avoidance behavior (blood cortisol p = 0.001). None of the biomarkers revealed significant results in fear or in the total LSAS-scores, except for ACTH with a trend finding (p = 0.06). Regarding therapy success, symptoms of social anxiety (p = 0.005) and depression (p < 0.001) were significantly reduced from pre (t1) to post-treatment (t2). Our study showed that stress reactivity pre-treatment may serve as a predictor of psychotherapy outcome. In this regard, alterations in stress response relate to changes in symptoms of social anxiety and depression after PDT. This implies that patients with chronic stress might benefit from a targeted interventions during psychotherapy, especially to manage fear in social contexts.

Glucagon does not directly stimulate pituitary secretion of ACTH, GH or copeptin.

Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon's impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2 mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.

Impact of systemic treatments for advanced thyroid cancer on the adrenal cortex.

Background: Fatigue is a frequent adverse event during systemic treatments for advanced thyroid cancer, often leading to reduction, interruption, or discontinuation. We were the first group to demonstrate a correlation between fatigue and primary adrenal insufficiency (PAI). Aim: The objective was to assess the entire adrenal function in patients on systemic treatments. Methods: ACTH, cortisol and all the hormones produced by the adrenal gland were evaluated monthly in 36 patients (25 on lenvatinib, six on vandetanib, and five on selpercatinib). ACTH stimulation tests were performed in 26 cases. Results: After a median treatment period of 7 months, we observed an increase in ACTH values in 80-100% of patients and an impaired cortisol response to the ACTH test in 19% of cases. Additionally, dehydroepiandrosterone sulphate, ∆-4-androstenedione and 17-OH progesterone levels were below the median of normal values in the majority of patients regardless of the drug used. Testosterone in females and oestradiol in males were below the median of normal values in the majority of patients on lenvatinib and vandetanib. Finally, aldosterone was below the median of the normal values in most cases, whilst renin levels were normal. Metanephrines and normetanephrines were always within the normal range. Replacement therapy with cortisone acetate improved fatigue in 14/17 (82%) patients with PAI. Conclusion: Our data confirm that systemic treatments for advanced thyroid cancer can lead to impaired cortisol secretion. A reduction in the other hormones secreted by the adrenal cortex has been first reported and should be considered in the more appropriate management of these fragile patients.

Neurobehavioral and molecular changes in a rodent model of ACTH-induced HPA axis dysfunction.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is linked to the pathophysiology of depression. Although exogenous adrenocorticotropic hormone (ACTH) is associated with a depressive-like phenotype in rodents, comprehensive neurobehavioral and mechanistic evidence to support these findings are limited. Sprague-Dawley rats (male, n = 30; female, n = 10) were randomly assigned to the control (male, n = 10) or ACTH (male, n = 20; female n = 10) groups that received saline (0.1 ml, sc.) or ACTH (100 µg/day, sc.), respectively, for two weeks. Thereafter, rats in the ACTH group were subdivided to receive ACTH plus saline (ACTH_S; male, n = 10; female, n = 5; 0.2 ml, ip.) or ACTH plus imipramine (ACTH_I; male, n = 10; female, n = 5;10 mg/kg, ip.) for a further four weeks. Neurobehavioral changes were assessed using the forced swim test (FST), the sucrose preference test (SPT), and the open field test (OFT). Following termination, the brain regional mRNA expression of BDNF and CREB was determined using RT-PCR. After two-weeks, ACTH administration significantly increased immobility in the FST (p = 0.03), decreased interaction with the center of the OFT (p < 0.01), and increased sucrose consumption (p = 0.03) in male, but not female rats. ACTH administration significantly increased the expression of BDNF in the hippocampus and CREB in all brain regions in males (p < 0.05), but not in female rats. Imipramine treatment did not ameliorate these ACTH-induced neurobehavioral or molecular changes. In conclusion, ACTH administration resulted in a sex-specific onset of depressive-like symptoms and changes in brain regional expression of neurotrophic factors. These results suggest sex-specific mechanisms underlying the development of depressive-like behavior in a model of ACTH-induced HPA axis dysregulation.

Strongyle egg shedding and egg reappearance periods in horses with pituitary pars intermedia dysfunction.

Pituitary pars intermedia dysfunction (PPID) is the most common endocrine disorder of older horses. Immune dysfunction in horses with PPID could increase susceptibility to infectious diseases, including strongyle infections; however, few data are available. The aim of this study was to determine if horses with PPID had increased strongyle faecal egg counts (FEC) compared with control horses, over a fourteen-week period in Victoria, Australia. Clinical signs and plasma adrenocorticotropic hormone (ACTH) concentrations were used to categorise horses into PPID (n=14) or control (n=31) groups. Faecal samples were collected for FEC determination prior to anthelmintic treatment, and fortnightly post-treatment for each horse. Generalised linear mixed modelling, using a gamma distribution, was used to compare differences between groups in the repeated measures study. The confounding variable of age was controlled for as a fixed effect. Following anthelmintic treatment, mean FEC was greater for the PPID group compared to the control group on day 56 (405 ± 756 eggs per gram [EPG] vs 40 ± 85 EPG, p=0.05) and day 70 (753 ±1598 EPG vs 82 ±141 EPG, p=0.04). There were no differences in mean FEC between groups on days 84 and 98. Cumulative FEC (day 14 to day 98) was significantly greater for the PPID horses than control horses (2118 ± 4016 EPG vs 798 ± 768 EPG, p<0.0001). Group egg reappearance period was shorter for PPID horses (day 56 post-anthelmintic treatment) compared to control horses (day 70) and 30% of the PPID horses reached a FEC threshold of >200 EPG on day 42, compared to 0% of control horses (p=0.02). These results suggest that the rate of a re-established patent infection between groups could be different due to a comprised immune response in PPID horses or differences in the host-parasite relationship regarding encysted stage larvae. However, despite differences between groups, some horses with PPID consistently had no detectable or low FEC (<200 EPG) during the study period. These findings highlight the importance of individual FEC monitoring to determine if anthelmintic treatment is required, in line with sustainable parasite management practices.

A novel mutation in the NR3C1 gene associated with reversible glucocorticoid resistance.

OBJECTIVE: Glucocorticoid resistance is a rare endocrine disease caused by variants of the NR3C1 gene encoding the glucocorticoid receptor (GR). We identified a novel heterozygous variant (GRR569Q) in a patient with uncommon reversible glucocorticoid resistance syndrome. METHODS: We performed ex vivo functional characterization of the variant in patient fibroblasts and in vitro through transient transfection in undifferentiated HEK 293T cells to assess transcriptional activity, affinity, and nuclear translocation. We studied the impact of the variant on the tertiary structure of the ligand-binding domain through 3D modeling. RESULTS: The patient presented initially with an adrenal adenoma with mild autonomous cortisol secretion and undetectable adrenocorticotropin hormone (ACTH) levels. Six months after surgery, biological investigations showed elevated cortisol and ACTH (urinary free cortisol 114 µg/24 h, ACTH 10.9 pmol/L) without clinical symptoms, evoking glucocorticoid resistance syndrome. Functional characterization of the GRR569Q showed decreased expression of target genes (in response to 100 nM cortisol: SGK1 control +97% vs patient +20%, P < .0001) and impaired nuclear translocation in patient fibroblasts compared to control. Similar observations were made in transiently transfected cells, but higher cortisol concentrations overcame glucocorticoid resistance. GRR569Q showed lower ligand affinity (Kd GRWT: 1.73 nM vs GRR569Q: 4.61 nM). Tertiary structure modeling suggested a loss of hydrogen bonds between H3 and the H1-H3 loop. CONCLUSION: This is the first description of a reversible glucocorticoid resistance syndrome with effective negative feedback on corticotroph cells regarding increased plasma cortisol concentrations due to the development of mild autonomous cortisol secretion.

Fulminant ectopic Cushing's syndrome caused by metastatic small intestine neuroendocrine tumour - a case report and review of the literature.

Cushing's syndrome (CS) secondary to adrenocorticotropic hormone (ACTH) producing tumours is a severe condition with a challenging diagnosis. Ectopic ACTH-secretion often involves neuroendocrine tumours (NET) in the respiratory tract. ACTH-secreting small intestine neuro-endocrine tumours (siNET) are extremely rare entities barely reported in literature. This review is illustrated by the case of a 75-year old woman with fulminant ectopic CS caused by a ACTH-secreting metastatic siNET. Severe hypokalemia, fluid retention and refractory hypertension were the presenting symptoms. Basal and dynamic laboratory studies were diagnostic for ACTH-dependent CS. Extensive imaging studies of the pituitary and thorax-abdomen areas were normal, while [68Ga]Ga-DOTATATE PET-CT revealed increased small intestine uptake in the left iliac fossa. The hypercortisolism was well controlled with somatostatin analogues, after which a debulking resection of the tumour was performed. Pathological investigation confirmed a well-differentiated NET with sporadic ACTH immunostaining and post-operative treatment with somatostatin analogues was continued with favourable disease control.