Can the DEX/CRH test or markers of oxidative stress distinguish work-related stress from major depressive disorder and normal controls?

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Changes in acromegaly comorbidities, treatment, and outcome over three decades: a nationwide cohort study.

Objective: To study the time-dependent changes in disease features of Danish patients with acromegaly, including treatment modalities, biochemical outcome, and comorbidities, with a particular focus on cancer and mortality. Methods: Pertinent acromegaly-related variables were collected from 739 patients diagnosed since 1990. Data are presented across three decades (1990-1999, 2000-2009, and 2010-2021) based on the year of diagnosis or treatment initiation. Results: Adenoma size and insulin-like growth factor I (IGF-I) levels at diagnosis did not differ significantly between study periods. The risk of being diagnosed with diabetes, heart disease, sleep apnea, joint disease, and osteoporosis increased from the 1990s to the later decades, while the mortality risk declined to nearly half. The risk of cancer did not significantly change. Treatment changed toward the use of more medical therapy, and fewer patients underwent repeat surgeries or pituitary irradiation. A statistically significant increase in the proportion of patients achieving IGF-I normalization within 3-5 years was observed over time (69%, 83%, and 88%). The proportion of patients with three or more deficient pituitary hormones decreased significantly over time. Conclusion: Modern medical treatment regimens of acromegaly as well as increased awareness and improved diagnostics for its comorbidities have led to better disease control, fewer patients with severe hypopituitarism, and declining mortality in the Danish cohort of acromegaly patients. The risk of cancer did not increase over the study period.

Long-term pituitary function and functional and patient-reported outcomes in severe acquired brain injury.

OBJECTIVE: Assessment of posttraumatic hypothalamic-pituitary dysfunctions is expected to be the most relevant assessment to offer patients with severe intracranial affection. In this study, we aim to investigate the prevalence of hypopituitarism in patients with severe acquired traumatic brain injury (TBI) compared with nontraumatic brain injury (NTBI) and to relate pituitary insufficiency to functional and patient-reported outcomes. DESIGN: This is a prospective study. METHODS: We included patients admitted for inpatient neurorehabilitation after severe TBI (N = 42) and NTBI (N = 18). The patients underwent a pituitary function assessment at a mean of 2.4 years after the injury. Functional outcome was assessed by using Functional Independence Measure and Glasgow Outcome Scale-Extended (both 1 year after discharge from neurorehabilitation) and patient-reported outcome was assessed by using Multiple Fatigue Inventory-20 and EQ-5D-3L. RESULTS: Hypopituitarism was reported in 10/42 (24%) patients with TBI and 7/18 (39%) patients with NTBI (P = .23). Insufficiencies affected 1 axis in 14/17 (82%) patients (13 hypogonadotropic hypogonadism and 1 growth hormone [GH] deficiency) and 2 axes in 3/17 (18%) patients (1 hypogonadotropic hypogonadism and GH deficiency, and 2 hypogonadotropic hypogonadism and arginin vasopressin deficiency). None had central hypoadrenalism or central hypothyroidism. In patients with both TBI and NTBI, pituitary status was unrelated to functioning and ability scores at 1 year and to patient-reported outcome scores at a mean of 2.4 years after the injury. CONCLUSION: Patients with severe acquired brain injury may develop long-term hypothalamus-pituitary insufficiency, with an equal occurrence in patients with TBI and NTBI. In both types of patients, mainly isolated deficiencies, most commonly affecting the gonadal axis, were seen. Insufficiencies were unrelated to functional outcomes and patient-reported outcomes, probably reflecting the complexity and heterogeneous manifestations in both patient groups.

Determination of cortisol cut-off limits and steroid dynamics in the ACTH stimulation test: a comparative analysis using Roche Elecsys Cortisol II immunoassay and LC-MS/MS.

PURPOSE: Measurement of cortisol concentrations is method dependent. The study aimed to establish assay-specific cut-off limits for cortisol after adrenocorticotropic hormone (ACTH) stimulation, comparing Roche Elecsys Cortisol II immunoassay to liquid chromatography-mass spectrometry (LC-MS/MS), and to assess the impact of patient characteristics, estrogen containing oral contraceptives as well as relation to other adrenocortical steroid hormone dynamics. METHODS: One hundred healthy participants underwent a 250 µg ACTH-test, with plasma samples analyzed using ElecsysCortI, ElecsysCortII, and LC-MS/MS. Cortisone, corticosterone, 17-OH-progesterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone were additionally analyzed with LC-MS/MS. Cut-off limit for a normal cortisol response to the ACTH-test was defined as: 2.5th percentile-1.96 × SE. RESULTS: ElecsysCort II measured cortisol concentrations 21% (95% CI: 19-22%) lower than ElecsysCort I. Cut-off limits for cortisol 30 and 60 min after ACTH were 426 and 485 nmol/L (ElecsysCort II) and 411 and 470 nmol/L (LC-MS/MS). Cut-offs were unaffected by gender, or body-composition. The ACTH-test resulted in significantly increased adrenocortical steroid hormones, except for decreased cortisone concentrations (both sexes), and decreased testosterone in men (1.9 nmol/L, 95% CI: 1.3-2.5). Testosterone was increased in women (0.07 nmol/L, 95% CI: 0.02-0.13). CONCLUSION: ElecsysCort II has high analytical performance and yields significantly lower cortisol concentrations than prior polyclonal immunoassays. This clinically relevant difference underscores the necessity for revised cut-off limits for improved diagnostic precision. Suggested 30-minute cortisol cutoff limits are 411 nmol/L (LC-MS/MS) and 426 nmol/L (ElecsysCort II). Adrenocortical steroids increased upon ACTH stimulation, except for cortisone in both sexes and testosterone in men, both of which decreased.

Dual-release hydrocortisone improves body composition and the glucometabolic profile in patients with secondary adrenal insufficiency.

PURPOSE: Studies have suggested improved metabolic profiles in patients with adrenal insufficiency treated with dual-release hydrocortisone (DR-HC) compared with conventional hydrocortisone (C-HC). This study investigates the effect of DR-HC compared with C-HC treatment on five health variables: diurnal salivary cortisol/cortisone, body composition, bone health, glucose metabolism, lipids, and blood pressure. METHODS: Prospective study of 27 participants (24 men) with secondary adrenal insufficiency with measurements during stable C-HC and 16 weeks after treatment switch to DR-HC. OUTCOMES: Diurnal salivary-cortisol/cortisone, body composition assessed by Dual-Energy X-ray absorptiometry scan, bone status indices (serum type I N-terminal procollagen [PINP], collagen type I cross-linked C-telopeptide [CTX], osteocalcin, receptor activator kappa-B [RANK] ligand, osteoprotegerin, and sclerostin), lipids, haemoglobin A1c (HbA1c), and 24-hour blood pressure. RESULTS: After the switch to DR-HC, the diurnal salivary-cortisol area under the curve (AUC) decreased non-significantly (mean difference: -55.9 nmol/L/day, P = 0.06). The salivary-cortisone-AUC was unchanged. Late-evening salivary-cortisol and cortisone were lower (-1.6 and -1.7 nmol/L, P = 0.002 and 0.004). Total and abdominal fat mass (-1.5 and -0.5 kg, P = 0.003 and 0.02), HbA1c (-1.2 mmol/mol, P = 0.02), and osteocalcin decreased (-7.0 µg/L, P = 0.03) whereas sclerostin increased (+41.1 pg/mL, P = 0.0001). The remaining bone status indices, lipids, and blood pressure were unchanged. CONCLUSION: This study suggests that switching to DR-HC leads to lower late-evening cortisol/cortisone exposure and a more favourable metabolic profile and body composition. In contrast, decreased osteocalcin with increasing sclerostin might indicate a negative impact on bones. CLINICAL TRIAL REGISTRATION: EudraCT201400203932.

Outlook for 615 Small Intestinal Neuroendocrine Tumor Patients: Recurrence Risk after Surgery and Disease-Specific Survival in Advanced Disease.

BACKGROUND: Small intestinal neuroendocrine tumors (siNET) are one of the most common neuroendocrine neoplasms. Radical surgery is the only curative treatment. METHOD: We utilized a single-center study including consecutive patients diagnosed from 2000 to 2020 and followed them until death or the end of study. Disease-specific survival and recurrence-free survival (RFS) were investigated by Cox regression analyses with the inclusion of prognostic factors. Aims/primary outcomes: We identified three groups: (1) disease specific-survival in the total cohort (group1), (2) RFS and disease-specific survival after intended radical surgery (group2), (3) disease specific-survival in patients with unresectable disease or residual tumor after primary resection (group3). RESULTS: In total, 615 patients, with a mean age (SD) 65 ± 11 years were included. Median (IQR) Ki-67 index was 4 (2-7)%. Median disease-specific survival in group1 was 130 months. Median RFS in group2 was 138 months with 5- and 10-year RFS rates of 72% and 59% with age, plasma chromogranin A (p-CgA) and Ki-67 index as prognostic factors. The ten year disease-specific survival rate in group2 was 86%. The median disease-specific survival in group3 was 85 months with age, Ki-67 index, p-CgA and primary tumor resection as prognostic factors. When proliferation was expressed by WHO grade, no difference was observed between G1 vs. G2 for any of the primary outcomes. CONCLUSIONS: Recurrence rates remained high 5-10 years after surgery (group2) supporting long-term follow-up. Median disease-specific survival in patient with unresectable disease (group3) was 7 years, with a favorable impact of primary tumor resection. Our data does not support the current grading system since no significant prognostic information was detected in G1 vs. G2 tumors.

Imaging surveillance in multiple endocrine neoplasia type 1: Ten years of experience with somatostatin receptor positron emission tomography.

Guidelines for multiple endocrine neoplasia type 1 (MEN1) recommend intensive imaging surveillance without specifying a superior regimen, including the role of somatostatin receptor imaging (SRI) with positron emission tomography (PET). The primary outcomes were to: (1) Assess change in treatment of duodenal-pancreatic neuroendocrine neoplasms (DP-NENs), bronchopulmonary NENs, and thymic tumors attributed to use of SRI PET/computed tomography (CT) and (2) estimate radiation from imaging and risk of cancer death attributed to imaging radiation. This was a retrospective single center study, including all MEN1 patients, who had had at least one SRI PET/CT. A total of 60 patients, median age 42 (range 21-54) years, median follow-up 6 (range 1-10) years were included. Of 470 cross sectional scans (MRI, CT, SRI PET/CT), 209 were SRI PET/CT. The additional information from SRI PET had implications in 1/14 surgical interventions and 2/12 medical interventions. The estimated median radiation dose per patient was 104 (range 51-468) mSv of which PET contributed with 13 (range 5-55) mSv and CT with 91 mSv (range 46-413 mSv), corresponding to an estimated increased median risk of cancer death of 0.5% during 6 years follow-up. SRI PET had a significant impact on 3/26 decisions to intervene in 60 MEN1 patients followed for a median of 6 years with SRI PET/CT as the most frequently used modality. The surveillance program showed a high radiation dose. Multi-modality imaging strategies designed to minimize radiation exposure should be considered. Based on our findings, SRI-PET combined with CT cannot be recommended for routine surveillance in MEN1 patients.

Consequences of undertreatment of hypothyroidism.

PURPOSE: To provide an overview of consequences of undertreatment with levothyroxine (LT4) in the common non-communicable disease, hypothyroidism. METHODS: Narrative review of the literature. RESULTS: Hypothyroidism is globally very prevalent at all age groups and represents a non-communicable disease in which the risks and consequences are preventable. In children and adolescents, the most devastating consequences of undertreatment are poor growth and development. Lack of early treatment in congenital hypothyroidism can lead to permanent damage of brain function. In young to middle-aged adults, consequences are often overlooked, and treatment delayed by many years. The resulting consequences are also at this age group compromised brain and physical functioning but less severe and partly reversible with treatment. The undertreated condition often results in a higher risk of several secondary devastating diseases such as increased cardiovascular disease burden, obesity, hypertension, poor physical capacity, poor quality of life. In young women of fertile age the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, preeclampsia, compromised fetal growth and neurocognitive development. There is a further risk of 30-50% of developing postpartum thyroiditis. In the elderly population care must be given to avoid confusing a slightly high serum TSH as result of physiological age adaptation with a requirement for LT4 treatment in a truly hypothyroid patient. CONCLUSION: Undertreatment of the preventable non-communicable disease hypothyroidism requires more focus both from caretakers in the healthcare system, but also from the global political systems in order to prevent the personally devastating and socioeconomically challenging consequences.

Hyperthyroidism in pregnancy: design and methodology of a Danish multicenter study.

BACKGROUND: Graves' disease (GD) is the main cause of hyperthyroidism in women of the fertile age. In pregnant women, the disease should be carefully managed and controlled to prevent maternal and fetal complications. Observational studies provide evidence of the adverse effects of untreated hyperthyroidism in pregnancy and have in more recent years substantiated a risk of teratogenic side effects with the use of antithyroid drugs (ATDs). These findings have challenged the clinical recommendations regarding the choice of treatment when patients become pregnant. To extend observational findings and support future clinical practice, a systematic collection of detailed clinical data in and around pregnancy is needed. METHODS: With the aim of collecting clinical and biochemical data, a Danish multicenter study entitled 'Pregnancy Investigations on Thyroid Disease' (PRETHYR) was initiated in 2021. We here describe the design and methodology of the first study part of PRETHYR. This part focuses on maternal hyperthyroidism and recruits female patients in Denmark with a past or present diagnosis of GD, who become pregnant, as well as women who are treated with ATDs in the pregnancy, irrespective of the underlying etiology. The women are included during clinical management from endocrine hospital departments in Denmark, and study participation includes patient questionnaires in pregnancy and postpartum as well as review of medical records from the mother and the child. RESULTS: Data collection was initiated on November 1, 2021 and covered all five Danish Regions from March 1, 2022. Consecutive study inclusion will continue, and we here report the first status of inclusion. As of November 1, 2022, a total of 62 women have been included in median pregnancy week 19 (interquartile range (IQR): 10-27) with a median maternal age of 31.4 years (IQR: 28.5-35.1). At inclusion, 26 women (41.9%) reported current use of thyroid medication; ATDs (n = 14), Levothyroxine (n = 12). CONCLUSION: This report describes a newly established systematic and nationwide collection of detailed clinical data on pregnant women with hyperthyroidism and their offspring. Considering the course and relatively low prevalence of GD in pregnant women, such nationwide design is essential to establish a sufficiently large cohort.

Glucose metabolism, gut-brain hormones, and acromegaly treatment: an explorative single centre descriptive analysis.

PURPOSE: Active acromegaly is associated with impaired glucose metabolism, which improves upon treatment. Treatment options include surgery, medical therapy with somatostatin analogues (SSA) and Pegvisomant (PEG), and irradiation. The objective of the study was to describe the differential effect of various treatment regimens on the secretion of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) in patients with acromegaly. METHODS: 23 surgically treated, non-diabetic patients with acromegaly and 12 healthy controls underwent an oral glucose tolerance test (OGTT) and subsequently isoglycaemic intravenous glucose infusion on a separate day. Baseline hormone concentrations, time-to-peak and area under the curve (AUC) on the OGTT-day and incretin effect were compared according to treatment regimens. RESULTS: The patients treated with SSA (N = 15) had impaired GIP-response (AUC, P = 0.001), and numerical impairment of all other hormone responses (P > 0.3). Patients co-treated with PEG (SSA + PEG, N = 4) had increased secretion of insulin and glucagon compared to patients only treated with SSA (SSA ÷ PEG, N = 11) (insulinAUC mean ± SEM, SSA + PEG 49 ± 8.3 nmol/l*min vs SSA ÷ PEG 25 ± 3.4, P = 0.007; glucagonAUC, SSA + PEG 823 ± 194 pmol/l*min vs SSA ÷ PEG 332 ± 69, P = 0.009). GIP secretion remained significantly impaired, whereas GLP-1 secretion was numerically increased with PEG (SSA + PEG 3088 ± 366 pmol/l*min vs SSA ÷ PEG 2401 ± 239, P = 0.3). No difference was found in patients treated with/without radiotherapy nor substituted or not with hydrocortisone. CONCLUSION: SSA impaired the insulin, glucagon, and incretin hormone secretions. Co-treatment with PEG seemed to counteract the somatostatinergic inhibition of the glucagon and insulin response to OGTT. We speculate that PEG may exert its action through GH-receptors on pancreatic δ-cells. Clinical trial registration NCT02005978.

Survival and long-term socioeconomic consequences of childhood and adolescent onset of brain tumours.

AIM: To evaluate survival distributions, long-term socioeconomic consequences, and health care costs in patients with childhood and adolescent onset of brain tumours in a Danish nationwide prospective cohort study. METHOD: A search of national registries identified 2283 patients (1198 males, 1085 females; mean age 9 years 6 months [SD 5 years 7 months]) diagnosed with a brain tumour between 1980 and 2015 and aged no older than 18 years at diagnosis. These were compared with sex-, age-, and residency-matched comparison individuals. Patients with malignant tumours were compared with those with benign tumours. Survival distributions were estimated by the Kaplan-Meier method and hazard ratio by the Cox proportional hazard model. Socioeconomic data at age 20 and 30 years were assessed. RESULTS: The probability of mortality was highest during the first year after tumour diagnosis. In young adulthood, the patients were generally less likely to be married, had lower grade-point averages, educational levels, and income, were less likely to be in employment, and had higher health care costs than comparison individuals. Patients with malignant tumours had worse outcomes with respect to education, employment, and health care costs than those with benign tumours. INTERPRETATION: A diagnosis of brain tumour in childhood and adolescence adversely affects survival and has negative long-term socioeconomic consequences, especially in patients with malignant tumours. These patients require continuous social support.

Sex difference in patients with controlled acromegaly-A multicentre survey.

OBJECTIVE: Active acromegaly is subject to sex differences in growth hormone (GH) and Insulin like growth factor 1 (IGF-I) patterns as well as clinical features but whether this also pertains to controlled disease is unclear. DESIGN: In a cross-sectional, multi-centre study, 84 patients with acromegaly (F = 43, M = 41), who were considered controlled after surgery alone (n = 23) or during continued somatostatin receptor ligand (SRL) treatment (n = 61), were examined. METHODS: Serum concentrations of GH, insulin, glucose and free fatty acid (FFA) were measured during an oral glucose tolerance test (OGTT) together with baseline serum IGF-I and completion of two HR-Qol questionnaires (acromegaly quality of life questionnaire [AcroQol] and Patient-assessed Acromegaly Symptom Questionnaire [PASQ]). RESULTS: The mean age at the time of the study was 57 (±1.1) years and the majority of females (were postmenopausal. Females had significantly higher fasting GH but comparable IGF-I standard deviation scores (SDS). Using fasting GH < 1.0 µg/L as cut off, disease control was less prevalent in females (F: 56% vs. M: 83%, p = .007) whereas a comparable figure was observed using IGF-I SDS < 2 (F:79% vs. M:76%, p = .71). Compared with males, female patients showed impaired AcroQol physical score (p = .05), higher fasting FFA (p = .03) and insulin concentrations during the OGTT (p = .04). CONCLUSION: In patients with acromegaly considered controlled, postmenopausal females exhibited higher GH levels than males despite comparable IGF-I levels, which also translated into impaired metabolic health and well-being. Our findings point to the relevance of including GH measurements in the assessment of disease control and suggest that disease-specific sex differences prevail after treatment.

Recurrence-Free Survival and Disease-Specific Survival in Patients with Pancreatic Neuroendocrine Neoplasms: A Single-Center Retrospective Study of 413 Patients.

INTRODUCTION: The prognosis and impact of different prognostic factors in pancreatic neuroendocrine neoplasms (pNEN) remain controversial. AIM: To investigate prognostic factors for recurrence-free survival and disease-specific survival in patients with pNEN, divided into three groups: patients undergoing surveillance (tumor size < 2 cm, group 1), patients followed after curative-intended surgery (group 2), and patients with unresectable disease or residual tumors after resection (group 3). METHOD: A single-center retrospective study including consecutive patients over a 20-year period. Multivariate Cox regression analyses were performed to identify risk factors. RESULTS: 413 patients were included, with a mean (SD) age of 62 ± 14 years. In group 1 (n = 51), median (IQR) follow-up was 29 (21-34) months, and tumor size was 1.0 (0.8-1.4) cm. One progressed and had a tumor resection. In group 2 (n = 165), follow-up 59 (31-102) months, median tumor size 2 (1.2-3.4) cm, median Ki-67 index 5 (3-10)%, the 5-year recurrence rate was 21%. Tumor size (p < 0.001), Ki-67 index (p = 0.02), and location in the pancreatic head (p < 0.001) were independent risk factors. In group 3 (n = 197), follow-up 19 (6-46) months, median tumor size 4.2 (2.6-7.0) cm, Ki-67 index 17 (9-64)%, the median disease-specific survival was 22 (6-75) months-99 in NET G1; 54 in NET G2; 14 in NET G3; and 6 months in neuroendocrine carcinomas (NEC). Age (p = 0.029), plasma chromogranin A (p = 0.014), and proliferation, expressed by grade (p = 0.001) and Ki-67 index (p < 0.001), were risk factors. CONCLUSION: Growth in pNET < 2 cm requiring surgery was observed in 1/51. Tumor size, Ki-67 index, and location in the head were prognostic factors for disease recurrence, while age, plasma chromogranin A, and proliferation predicted mortality in patients with unresectable disease or residual tumors after resection.

[Hyperpigmentation reveals Addison's disease in a pregnant woman].

A 31-year-old woman was admitted to the local department of endocrinology for control of known anti-TPO positive hypothyroidism during pregnancy. The clinician noticed a remarkable hyperpigmentation. Primary adrenal insufficiency was diagnosed and treatment with cortico- and mineralosteroids commenced. Diagnosis of primary adrenal insufficiency during pregnancy is challenging as many symptoms overlap with normal symptoms of pregnancy. The usual diagnostic criteria cannot be used due to the altered hormone concentrations during pregnancy.

Case Report: Giant Paraganglioma of the Skull Base With Two Somatic Mutations in SDHB and PTEN Genes.

Head and neck paragangliomas (HNPGLs) are neuroendocrine tumors. They arise from the parasympathetic ganglia and can be either sporadic or due to hereditary syndromes (up to 40%). Most HNPGLs do not produce significant amounts of catecholamines. We report a case of a giant paraganglioma of the skull base with an unusually severe presentation secondary to excessive release of norepinephrine, with a good outcome considering the severity of disease. A 39-year-old Caucasian woman with no prior medical history was found unconscious and emaciated in her home. In the intensive care unit (ICU) the patient was treated for multi-organ failure with multiple complications and difficulties in stabilizing her blood pressure with values up to 246/146 mmHg. She was hospitalized in the ICU for 72 days and on the 31st day clinical assessment revealed jugular foramen syndrome and paralysis of the right n. facialis. A brain MRI confirmed a right-sided tumor of the skull base of 93.553 cm3. Blood tests showed high amounts of normetanephrine (35.1-45.4 nmol/L, ref <1.09 nmol/L) and a tumor biopsy confirmed the diagnosis of a paraganglioma. Phenoxybenzamine and Labetalol were used in high doses ((Dibenyline®, 90 mg x 3 daily) and labetalol (Trandate®, 200 + 300 + 300 mg daily) to stabilize blood pressure. The patient underwent two tumor embolization procedures before total tumor resection on day 243. Normetanephrine and blood pressure normalized after surgery (0.77 nmol/L, ref: < 1.09 nmol/L). The damage to the cranial nerve was permanent. Our patient was comprehensively examined for germline predisposition to PPGLs, however we did not identify any causal aberrations. A somatic deletion and loss of heterozygosity (LOH) of the short arm (p) of chromosome 1 (including SDHB) and p of chromosome 11 was found. Analysis showed an SDHB (c.565T>G, p.C189G) and PTEN (c.834C>G, p.F278L) missense mutation in tumor DNA. The patient made a remarkable recovery except for neurological deficits after intensive multidisciplinary treatment and rehabilitation. This case demonstrates the necessity for an early tertiary center approach with a multidisciplinary expert team and highlights the efficacy of the correct treatment with alpha-blockade.

Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity.

Context: Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective. Objective: To investigate the safety and efficacy of Tesomet (0.5 mg tesofensine/50 mg metoprolol) in adults with hypothalamic obesity. Methods: Twenty-one adults with hypothalamic obesity (16 females) were randomized to Tesomet (0.5 mg/50 mg) or placebo for 24 weeks. Patients also received diet/lifestyle counselling. The primary endpoint was safety; secondary endpoints included measures of body weight, appetite scores, quality of life, and metabolic profile. Results: Eighteen patients completed 24 weeks. Consent withdrawal, eligibility, and serious adverse events (SAE) unrelated to treatment resulted in dropouts. One patient experienced a Tesomet-related SAE of exacerbated pre-existing anxiety leading to treatment discontinuation. Tesomet-related adverse events were otherwise mostly mild and included sleep disturbances (Tesomet 50%, placebo 13%), dry mouth (Tesomet 43%, placebo 0%), and headache (Tesomet 36%, placebo 0%). No significant differences in heart rate or blood pressure were observed between groups. Compared to placebo, Tesomet resulted in additional mean (95% CI) weight change of -6.3% ((-11.3; -1.3); P = 0.017), increased the number of patients achieving ≥5% weight loss (Tesomet 8/13, placebo 1/8; P = 0.046), and tended to augment the reduction in waist circumference by 5.7 cm ((-0.1; 11.5); P = 0.054). Conclusion: Tesomet was welltolerated, did not affect heart rate or blood pressure, and resulted in significant reductions in body weight compared to placebo in adults with hypothalamic obesity.

Approach to the Patient With Glucocorticoid-induced Adrenal Insufficiency.

Glucocorticoid-induced adrenal insufficiency is caused by exogenous glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis and is the most prevalent form of adrenal insufficiency. The condition is important to diagnose given the risk of life-threatening adrenal crisis and impact on patients' quality of life. The diagnosis is made with a stimulation test such as the ACTH test. Until now, testing for glucocorticoid-induced adrenal insufficiency has often been based on clinical suspicion rather than routinely but accumulating evidence indicates that a significant number of cases will remain unrecognized. During ongoing oral glucocorticoid treatment or initially after withdrawal, ~50% of patients have adrenal insufficiency, but, outside clinical studies, ≤ 1% of patients have adrenal testing recorded. More than 70% of cases are identified during acute hospital admission, where the diagnosis can easily be missed because symptoms of adrenal insufficiency are nonspecific and overlap those of the underlying and intercurrent conditions. Treatment of severe glucocorticoid-induced adrenal insufficiency should follow the principles for treatment of central adrenal insufficiency. The clinical implications and thus indication to treat mild-moderate adrenal deficiency after glucocorticoid withdrawal has not been established. Also, the indication of adding stress dosages of glucocorticoid during ongoing glucocorticoid treatment remains unclear. In patients with established glucocorticoid-induced adrenal insufficiency, high rates of poor confidence in self-management and delayed glucocorticoid administration in the acute setting with an imminent adrenal crisis call for improved awareness and education of clinicians and patients. This article reviews different facets of glucocorticoid-induced adrenal insufficiency and discusses approaches to the condition in common clinical situations.

Adrenal suppression in patients with chronic obstructive pulmonary disease treated with glucocorticoids: Role of specific glucocorticoid receptor polymorphisms.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids, and thus may alter the therapeutic effects of glucocorticoids. We investigated the prevalence of adrenal suppression after treatment with glucocorticoids and evaluated whether GR SNPs were associated with altered risks of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD). METHODS: In an observational prospective cohort study, we recruited 78 patients with severe COPD receiving 5 days glucocorticoid treatment for an exacerbation of COPD. In total, 55% of these patients were also receiving regular inhaled corticosteroids (ICS). Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK, and 9ß SNPs. RESULTS: The prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 30 days after glucocorticoid treatment was 4/78 (5%). There was no difference between carriers and non-carriers of the polymorphisms (Bcl1, 9ß, ER22/23K, and N363S) in corticotropin stimulated plasma-cortisol concentrations. In the haplotype analyses, we included the 50 patients who had a high-sensitivity (76%), a low-sensitivity (4%), or a wild-type (20%) GR haplotype. There was no difference in the frequency of adrenal suppression or metabolic disorders between the two stratified groups: (a) high-sensitivity (Bcl1 and/or N363S) haplotypes vs. (b) low-sensitivity (9ß and/or ER22/23K) plus wild-type haplotypes (p > 0.05). Carriers of the high-sensitivity GR gene haplotype exhibited a steeper decline in stimulated P-cortisol with increased ICS dose (slope, -1.35 vs. 0.94; p = 0.17), compared to the group with low-sensitivity or wild-type haplotypes, respectively. CONCLUSIONS: In total, 5% of patients exhibited insufficient adrenal function. The Bcl1 and N363S polymorphisms did not seem to increase the risk of glucocorticoid suppression or metabolic disorders in adults treated with glucocorticoids for COPD exacerbations.

Incidence, Clinical Presentation and Trends in Indication for Diagnostic Work-Up of Small Intestinal and Pancreatic Neuroendocrine Tumors.

BACKGROUND: The incidence of small intestinal (SI) and pancreatic neuroendocrine tumors (siNETs and pNETs) seems to have increased. The increased frequency of incidental findings might be a possible explanation. The study aimed to examine (1) changes in incidence and the stage at diagnosis (2010-2011 vs. 2019-2020), (2) changes in the initial indication for diagnostic workup and 3) the differences in stage between incidentally discovered vs. symptomatic disease during the entire study period. METHODS: We performed a retrospective study, that includes consecutive siNET and pNET patients referred to the Copenhagen ENETS center of excellence in 2010-2011 and 2019-2020. RESULTS: The annual incidence of siNET per 100,000 increased from 1.39 to 1.84, (p = 0.05). There was no change in the stage at diagnosis, and in both periods approximately 30% of patients were incidentally diagnosed (p = 0.62). Dissemination was found in 72/121 (60%) of symptomatic vs. 22/50 (44%) of incidentally discovered SI tumors in the entire cohort, (p = 0.06). The annual incidence of pNET increased from 0.42 to 1.39 per 100,000, (p < 0.001). The proportion of patients with disseminated disease decreased from 8/21 (38%) to 12/75 (16%), (p = 0.02) and the number of incidental findings increased from 4/21 (19%) to 43/75 (57%), (p = 0.002). More symptomatic patients had disseminated disease compared to patients with incidentally discovered tumors (15/49 (31%) vs. 5/47 (11%), (p = 0.01)). CONCLUSION: The incidence of siNET and pNETs increased over the past decade. For siNETs, the stage of disease and the distribution of symptomatic vs. incidentally discovered tumors were unchanged between the two periods. Patients with pNETs presented with more local and incidentally discovered tumors in the latter period. Patients with incidentally discovered siNETs had disseminated disease in 44% of the overall cases. The vast majority of incidentally found pNETs were localized.

Brain tumours result in sleep disorders in children and adolescents.

BACKGROUND AND OBJECTIVES: Sleep disturbances are frequently reported in children with brain tumours. The objective of our cross-sectional study was to systematically examine sleep in these children. We hypothesised that children with tumours involving the sleep-wake-regulatory areas have an altered sleep-wake-regulation. METHODS: Sixty-one patients aged 0-18 years and with a diagnosis of a primary brain or cervical medullary tumour were included. They were categorised based upon tumour location into two groups - those affecting the sleep-wake regulatory regions, i.e. brain stem, basal forebrain, hypothalamus, thalamus, and posterior fossa compressing the brain stem and those that did not. Sleep history, questionnaire surveys, polysomnography, and multiple sleep latency test were used, as indicated clinically. Surveys included Pediatric Daytime Sleepiness Scale, Children's Sleep Habits Questionnaire, Strengths and Difficulties Questionnaire, and Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale. RESULTS: Patients with tumours involving the sleep-wake regulatory areas were sleepier/more fatigued (p = 0.03). Sleep apnoea was observed in 86% of all the patients and comorbid narcolepsy in 8%, without group differences (p ≥ 0.12). Patients with tumours involving the sleep-wake-regulatory areas had more emotional problems (p = 0.04), were more affected by mental health problems (p < 0.001), and had poorer quality of life (p ≤ 0.03). CONCLUSIONS: Many children with brain tumours suffer from disturbed sleep, poor mental health, and low quality of life. We recommend that systematic sleep evaluation is included in their routine care along with psychological and social support.