Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

Holistic burden of illness in patients with endogenous Cushing's syndrome: A systematic literature review.

OBJECTIVE: The objective of this systematic literature review (SLR) was to summarize the latest studies evaluating the burden of illness in endogenous Cushing's syndrome (CS), including the impact of CS on overall and domain-specific health-related quality of life (HRQoL) and the economic burden of CS to provide a holistic understanding of disease and treatment burden. METHODS: An SLR was conducted in PubMed, MEDLINE and Embase using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist to identify peer-reviewed manuscripts and conference abstracts published in English from 2015 to December 4, 2020. RESULTS: Forty-five publications were eligible for inclusion; data were extracted from 37 primary studies while 8 SLRs were included for reference only. Thirty-one studies reported HRQoL using validated patient reported outcome (PRO) measures in pre- or post-surgery, radiotherapy and pharmacotherapy patients. Overall, this SLR found that patients with CS have worse outcomes relative to healthy populations across specific dimensions, such as depression, despite an improvement in HRQoL post-treatment. These findings reveal that CS symptoms are not fully resolved by the existing care paradigm. Few studies report on the economic burden of CS and currently available data indicate a high direct healthcare system cost burden. CONCLUSIONS: Patients with CS experience a significant, complex and multifactorial HRQoL burden. Symptom-specific burden studies are sparse in the literature and the understanding of long-term CS symptomatic burden and economic burden is limited. This review intends to provide an updated reference for clinicians, payers and other stakeholders on the burden of CS as reported in published literature and to encourage further research in this area.

Trabecular bone score and bone mineral density as indices of skeletal fragility in endogenous Cushing's syndrome.

OBJECTIVE: Endogenous Cushing's syndrome (CS) is a known cause of secondary osteoporosis. Vertebral fractures (VFs) in endogenous CS may occur despite normal bone mineral density (BMD). Trabecular bone score (TBS) is a relatively new, non-invasive technique to assess bone microarchitecture. The objective of our study was to analyse the BMD and bone microarchitecture using TBS in endogenous CS and compare it with a group of age and sex-matched healthy controls, and also analyse the factors predicting BMD and TBS. DESIGN: Cross-sectional study of cases and controls. PATIENTS AND MEASUREMENTS: We included 40 female patients with overt endogenous CS, out of which 32 were adrenocorticotropic hormone (ACTH)-dependent CS and 8 were ACTH-independent. We also included 40 healthy, female controls. Both patients and controls were subjected to an assessment of biochemical parameters and BMD and TBS. RESULTS: Patients with endogenous CS had significantly lower BMD at the lumbar spine, femoral neck, and total hip and significantly lower TBS than healthy controls (all p < .001), while no significant difference was noted in the distal radius BMD (p = .055). In endogenous CS, a large proportion of patients, n = 13 (32.5%) had normal BMD for age (BMD Z-score ≥ -2.0) with low TBS (L1 -L4 TBS ≤ 1.34). TBS correlated negatively with HbA1c (p = .006), and positively with serum T4 (p = .027). CONCLUSION: TBS should be considered an important complementary tool in addition to BMD for the routine assessment of skeletal health in CS.

[Exploration of clinical pathway-oriented optimal management diagnosis and treatment model for rare diseases].

This study takes Cushing's syndrome, a rare disease, as a model, and adopts the path of "Plan, Do, Check, Action" (PDCA) to explore new methods to optimize the clinical path, can improve the quality and efficiency of diagnosis and treatment of rare diseases. After sorting out the problems existing in the previous diagnosis and treatment mode, our team optimizes the path in various ways and establishes a standard operation procedure (SOP) for the new path. In the evaluation of the optimized mode, 55 patients with Cushing's syndrome were admitted to the Department of Endocrinology, Peking Union Medical College Hospital, including 19 males and 36 females, aged (41.8±14.4) years (6-68 years). The pathway group (28 cases) and the control group (27 cases) were divided according to whether they were included in the new path management at the time of admission, and the effect of path optimization was assessed in terms of time, efficacy, safety and cost. The results showed that compared with the control group, the pathway group had a shorter time of hospitalization in the Department of Endocrinology and critical tests, such as blood cortisol rhythm, low-dose dexamethasone inhibition test, and bilateral inferior petrosal sinus sampling (all P<0.05). There was no significant differences in the decrease of total cortisol after operation, the incidence of postoperative complications, and hospitalization expenses (all P>0.05). The optimized path improves the medical efficiency while ensuring medical quality, safety and no increase in cost. This study proposes PDCA path optimization for complex diseases and establishes SOP process, which provides experience in management optimization for the patient-centered and clinical path-oriented diagnosis and treatment mode of rare diseases.

Altered thalamic volume in patients with mild autonomous cortisol secretion: a structural brain MRI study.

PURPOSE: To compare thalamic volume and cognitive functions of patients with mild autonomous cortisol secretion (MACS) with control subjects and patients with overt Cushing's syndrome (CS). METHODS: In this cross-sectional study, volumes of regions of interest were assessed using 3 T magnetic resonance imaging and a voxel-based morphometry approach in 23 patients with MACS, 21 patients with active CS, 27 patients with CS in remission, and 21 control subjects. Cognitive functions were assessed using validated questionnaires. RESULTS: Patients with MACS had smaller left thalamic (F = 3.8, p = 0.023), left posterior thalamic (F = 4.9, p = 0.01), left medial thalamic (F = 4.7, p = 0.028), and right lateral thalamic (F = 4.1, p = 0.025) volumes than control subjects. Patients with active CS also had smaller left thalamic (F = 3.8, p = 0.044), left posterior thalamic (F = 4.9, p = 0.007), left medial thalamic (F = 4.7, p = 0.006), and right lateral thalamic (F = 4.1, p = 0.042) volumes compared to controls. Patients with CS in remission had smaller left medial (F = 4.7, p = 0.030) and right lateral thalamic (F = 4.1, p = 0.028) volumes than controls. Neuropsychological tests showed no difference between the groups. CONCLUSION: MACS may decrease thalamic volume.

Eleven-Year Experience with Selective Adrenal Vein Sampling in Management of Primary Adrenal Hormonal Hypersecretion.

Introduction: Nearly half of the adult population in the United States has been diagnosed with hypertension. Adrenal hormonal hypersecretion is a leading cause of secondary hypertension. Adrenal vein sampling (AVS) may assist in differentiating between unilateral and bilateral adrenal hormonal hypersecretion to identify patients who are candidates for adrenalectomy. We reviewed the use of AVS at our institution along with associated outcomes after adrenalectomy. Materials and Methods: A retrospective chart review was conducted of patients with a diagnosis of primary hyperaldosteronism (PA) or adrenocorticotropic hormone-independent Cushing syndrome (AICS) and who underwent adrenalectomy between January 1, 2010, and December 1, 2021. Patient data of baseline characteristics, preoperative workup, including AVS, and postoperative outcomes were collected and analyzed. Results: Seventy-one patients were identified in the study period (48 PA and 23 AICS). Computed tomography scan identified unilateral adrenal nodules in 52 patients (29 left; and 23 right), bilateral nodules in 13 patients, and no nodules in 6 patients. AVS was performed in 45 patients with PA (93%) and 5 patients with AICS (21%). After surgery, the number of PA patients with hypokalemia or requiring potassium supplementation significantly decreased after adrenalectomy (before surgery: 33 [68.7%]; and after surgery: 5 [10.4%], P < .01). The number of medications required for hypertension in AICS patients also significantly decreased. No major adverse events were noted. Conclusions: Our long-term experience demonstrates the ongoing use of AVS during workup of patients with primary hyperaldosteronism and for select patients with adrenocorticotropic hormone-independent Cushing syndrome. However, a low level of discordance between imaging and AVS findings in PA patients suggests that there may be a subset of patients in whom preoperative AVS is not necessary.

Patient reported outcomes and treatment satisfaction in patients with cushing syndrome.

PURPOSE: Cushing Syndrome (CS) is a rare endocrine disorder associated with physical and mental symptoms that can drastically affect quality of life (QoL). This study characterizes QoL in patients with CS, describes their treatment experiences, and identifies patient subsets associated with decreased QoL or shared impressions of treatment. METHODS: A 136-question survey addressing QoL factors and treatment experiences was completed by adult patients with CS from the Cushing Support and Research Foundation. Patient demographics, tumor characteristics, and treatment information were collected. Bivariate analyses were conducted to determine if patients' symptoms or treatment experiences were significantly associated with demographics or other variables. RESULTS: A total of 178 patients, predominantly female (94%) with mean age 53 years, completed the survey. Anxiety and/or depression (n = 163, 94%), loss of physical strength (n = 164, 93%), loneliness (n = 156, 90%), fatigue from treatment (n = 142, 89%), memory loss (n = 153, 88%), insomnia (n = 144, 83%), and pain (n = 141, 83%) were symptoms most commonly experienced by respondents. Patients experiencing delay of diagnosis >10 years were more likely to have suicidal thoughts (p = 0.002). Younger patients were more likely to express concerns about hair loss (p = 0.007), loneliness (p = 0.025), pain (p = 0.004), or the impact of CS on their marriage (p = 0.039) or children (p = 0.024). CONCLUSION: This survey demonstrates CS impacts patients across many dimensions, emphasizing the need for holistic support. We identified patient subsets in which QoL may be improved with additional patient resources or provider attention.

["Herbalist" supplements maliciously expanding from Mexico to the world. Artriking and company]. / Complementos "herbolarios" expandiéndose maliciosamente de México para el mundo. Artriking y compañíal.

This letter aims to inform the medical community about herbal supplements that have steroidal and non-steroidal drugs hidden in their formulation, entailing risks to the health of consumers, in addition to the fact that they are not regulated at the local level and the producers of these supplements try to sell them internationally, which would bring serious consequences, since it would become a serious global health problem; these supplements have provoked Cushing's syndrome, diabetes mellitus, sepsis, pneumonitis and invasive helminthiasis.

La presente carta pretende informar a la comunidad médica sobre los complementos herbolarios que tienen de manera oculta en su formulación fármacos esteroideos y no esteroideos, lo cual conlleva riesgos a la salud de los consumidores, además de que no hay una regulación de los mismos a nivel local y quienes los producen buscan que se diseminen en forma global, lo cual traería consecuencias graves, dado que se convertiría en un problema de salud pública mundial; estos complementos han condicionado síndrome de Cushing, diabetes mellitus, sepsis, neumonitis y helmintiasis invasivas.

Hypocalcemia Is a Common Risk Factor for Osteoporosis in Taiwanese Patients with Cushing's Syndrome.

Background: Osteoporosis is a cardinal manifestation of Cushing's syndrome. There is a lack of relevant research on risk factors for osteoporosis among patients with Cushing's syndrome (CS) in Taiwan. Thus, this study was designed to explore the possible risk factors of osteoporosis. Methods: We gathered patients with a diagnosis of CS between 2001 and 2017 in the Chang Gung Research Database (CGRD). We extracted data including diagnoses and biochemistry from hospital records. The diagnosis of CS was based on ICD-9-CM codes (255.0). Osteoporosis was defined by a T value equal to or less than −2.5 in BMD examination and hypocalcemia was defined as serum calcium concentrations < 8.0 mg/dL. Results: A total of 356 patients with CS who made regular visits to the outpatient department were enrolled in this study. The mean age was 68.6 years, and 74.9% of the patients were female. Of them, 207 patients (58.1%) were diagnosed with osteoporosis. Multivariable logistic regression models indicated that serum calcium level was negatively associated with osteoporosis (OR 0.70, CI 0.54−0.91, p < 0.001) after adjustment for age, sex, and other confounding risk factors. In addition, hypocalcemia was associated with heart failure (HF) (OR 2.14, CI 1.02−4.47, p < 0.05), stroke (OR 2.58, CI 1.21−5.46, p < 0.05) and osteoporosis (OR 3.04, CI 1.24−7.41, p < 0.05) in multivariate analysis. Conclusions: Our study found that lower serum calcium levels were common among patients with CS and osteoporosis. Furthermore, CS patients with HF or stroke had high proportion of hypocalcemia. Therefore, these patients must pay more attention to adequate calcium supplementation and undergo the appropriate osteoporosis drug treatment to reduce the risk of subsequent fracture and disability.

Excess dietary zinc drives a Cushing's-like syndrome in ovariectomized mice - Implications for postmenopausal obesity.

Postmenopausal women have an increased risk of obesity, but the underlying cause is not clear. We unexpectedly found that excess dietary zinc induced severe obesity and a Cushing's-like syndrome without increased food intake in ovariectomized (Ovx) but not in sham-operated mice. Zinc accumulated in the adrenal glands and inhibited adrenal 17,20-lyase activity and steroid synthesis. As adrenal steroids are the only source of estrogen in Ovx mice, estrogen deficiency induced adrenal hyperplasia, glucocorticoid overproduction, and consequent development of a Cushing's-like syndrome. Adrenal steroid supplementation prevented the effects of zinc. Plasma zinc was positively correlated with cortisol level and negatively correlated with the levels of adrenal steroids and estrogen in obese postmenopausal women. The finding of a link between dietary zinc, estrogen deficiency, and postmenopausal obesity, implies that postmenopausal obesity might be prevented by supplementation with a adrenal steroid and avoiding excess dietary zinc.

An Unusual Presentation of Adrenocortical Carcinoma (ACC): Panic Attacks and Psychosis.

BACKGROUND Adrenocortical carcinoma (ACC) is a very rare disease, with an incidence of 1.02 per million population per year. The most commonly secreted hormone in ACC is cortisol, often presenting as a rapidly progressive Cushing syndrome (CS). We describe a case of ACC with an unusual presentation, mainly with psychiatric manifestations, including panic attacks and hallucinations. CASE REPORT A 52-year-old woman presented with episodes of acute anxiety, hallucinations, palpitations, hot flashes, gastrointestinal upset associated with paroxysmal hypertension, tachycardia, and flushing for 1 week. The initial workup was aimed at ruling out causes of acute psychosis and/or anxiety such as substance use, and organic diseases such as pheochromocytoma (PCC). Our initial suspicion of PCC was ruled out based on the negative serum and urinary metanephrines (MN) and normetanephrines (NMN). Recurrent metabolic alkalosis and hypokalemia despite fluid and potassium supplementation prompted us to work up for hyperaldosteronism. Her renin level was elevated and the aldosterone level was appropriately suppressed. Elevated cortisol, positive dexamethasone (DXM) suppression test, low adrenocorticotropic hormone (ACTH), imaging revealing an adrenal mass, and postoperative histology confirmed the diagnosis of cortisol-producing ACC. CONCLUSIONS It is essential to recognize psychiatric presentations of CS to achieve early diagnosis and prevent mortality and morbidity. Panic attacks, a common presentation of CS, can present with features mimicking pheochromocytoma (PCC), including palpitations, sweating, tachycardia, and paroxysmal hypertension. A comprehensive workup is warranted to reach a diagnosis, with a combination of hormonal levels, imaging, and histology.

Ectopic Cushing's Syndrome due to Thymic Neuroendocrine Tumor Treated with Surgery and Radiotherapy.

The most common cause of ectopic Cushing's syndrome is small cell lung cancer; less common causes include pancreatic and thymic neuroendocrine tumors. A 35-year male was investigated after detecting low potassium in the tests performed for weakness. The patient was admitted for exclusion of Cushing's syndrome because of high cortisol (108 µg/dl) and ACTH (827ng/L) levels. There was no suppression in the high-dose dexamethasone test, and the patient was thought to have ectopic Cushing's syndrome. A mass in the thymus was detected in thorax tomography. Postoperative ACTH and cortisol levels decreased rapidly. Postoperatively, ACTH did not drop to normal, suggesting the possibility of residual tumor. Radiotherapy was given to the patient because the surgical margin was positive in the pathology report. No functional focus was detected in Ga 68 DOTATATE PET CT after radiotherapy. This case is presented because of the rare association of a thymic neuroendocrine tumor with ectopic Cushing's syndrome, which was revealed during the investigation of the etiology of hypokalemia. Key Words: Hypokalemia, Cushing syndrome, Thymic neuroendocrine tumor.

A Rapidly Progressive Case of Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome.

BACKGROUND Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) secondary to an ectopic source is an uncommon condition, accounting for 4-5% of all cases of CS. Refractory hypokalemia can be the presenting feature in patients with ectopic ACTH syndrome (EAS), and is seen in up to 80% of cases. EAS can be rapidly progressive and life-threatening without timely diagnosis and intervention. CASE REPORT We present a case of a 74-year-old White woman who first presented with hypokalemia, refractory to treatment with potassium supplementation and spironolactone. She progressively developed generalized weakness, recurrent falls, bleeding peptic ulcer disease, worsening congestive heart failure, and osteoporotic fracture. A laboratory workup showed hypokalemia, hypernatremia, and primary metabolic alkalosis with respiratory acidosis. Hormonal evaluation showed elevated ACTH, DHEA-S, 24-h urinary free cortisol, and unsuppressed cortisol following an 8 mg dexamethasone suppression test, suggestive of ACTH-dependent CS. CT chest, abdomen, and pelvis, and FDG/PET CT scan showed a 1.4 cm right lung nodule and bilateral adrenal enlargement, confirming the diagnosis of EAS, with a 1.4-cm lung nodule being the likely source of ectopic ACTH secretion. Due to the patient's advanced age, comorbid conditions, and inability to attend to further evaluation and treatment, her family decided to pursue palliative and hospice care. CONCLUSIONS This case illustrates that EAS is a challenging condition and requires a multidisciplinary approach in diagnosis and management, which can be very difficult in resource-limited areas. In addition, a delay in diagnosis and management often results in rapid deterioration of clinical status.

Ectopic ACTH secretion from a metastatic gastric carcinoma with neuroendocrine component.

An elderly gentleman was admitted to hospital with severe hypokalaemia of 1.75mmol/L. A background of a recently diagnosed metastatic gastric carcinoma with a neuroendocrine component pointed towards the diagnosis of ectopic ACTH secretion causing this dangerous electrolyte imbalance. He was treated with aggressive potassium supplementation and the adrenal steroid synthesis blocker metyrapone to acutely control his Cushing's syndrome. Chemotherapy consisting of carboplatin/etoposide combination was initiated but unfortunately the patients' health deteriorated, and he died three months after his initial diagnosis. This case highlights the accelerated presentation of hypercortisolism due to ectopic ACTH secretion. It discusses the classification of neuroendocrine tumours and their varied prognosis depending on the underlying tumour grade. It emphasises the importance of having a multidisciplinary team to be able to care for two underlying pathologies simultaneously: both the severe hypercortisolism and his metastatic gastric tumour.

Dysfunction in Sertoli cells participates in glucocorticoid-induced impairment of spermatogenesis.

The effect of stress on male fertility is a widespread public health issue, but less is known about the related signaling pathway. To investigate this, we established a hypercortisolism mouse model by supplementing the drinking water with corticosterone for four weeks. In the hypercortisolism mice, the serum corticosterone was much higher than in the control, and serum testosterone was significantly decreased. Moreover, corticosterone treatment induced decrease of sperm counts and increase of teratozoospermia. Increased numbers of multinucleated giant cells and apoptotic germ cells as well as downregulated meiotic markers suggested that corticosterone induced impaired spermatogenesis. Further, upregulation of macrophage-specific marker antigen F4/80 as well as inflammation-related genes suggested that corticosterone induced inflammation in the testis. Lactate content was found to be decreased in the testis and Sertoli cells after corticosterone treatment, and lactate metabolism-related genes were downregulated. In vitro phagocytosis assays showed that the phagocytic activity in corticosterone-treated Sertoli cells was downregulated and accompanied by decreased mitochondrial membrane potential, while pyruvate dehydrogenase kinase-4 inhibitor supplementation restored this process. Taken together, our results demonstrated that dysfunctional phagocytosis capacity and lactate metabolism in Sertoli cells participates in corticosterone-induced impairment of spermatogenesis.

Manifestaciones clínicas predictivas del diagnóstico del hipercortisolismo endógeno / Clinical Manifestations Predicting Endogenous Hypercortisolism

Introducción: El diagnóstico clínico del hipercortisolismo endógeno puede ser complejo si las manifestaciones clínicas no son patognomónicas. Es importante conocer cuáles son las distintivas en nuestros pacientes, que permitan diagnosticar la enfermedad de forma precoz. Objetivo: Determinar sensibilidad, especificidad y valor predictivo positivo de las manifestaciones clínicas para diagnosticar el hipercortisolismo endógeno. Métodos: Estudio descriptivo transversal. Grupo I: 65 pacientes con hipercortisolismo endógeno y grupo II (comparación): 75 con sospecha clínica de hipercortisolismo endógeno a los que se les descartó la enfermedad. Se estudiaron pacientes con diagnóstico de hipercortisolismo endógeno (2004-2017), atendidos en el Instituto de Endocrinología. Se determinaron los valores de sensibilidad, especificidad y valor predictivo positivo para el diagnóstico de hipercortisolismo endógeno de cada síntoma y signo por separado, así como para las combinaciones de tres manifestaciones clínicas; además se realizó una regresión logística binaria para identificar las combinaciones de sintomatologías que mejor predicen la presencia de hipercortisolismo endógeno. Se consideró diferencia estadística significativa con p ≤ 0,05. Resultados: La mayoría de los síntomas presentó una sensibilidad inferior al 45 por ciento. La circunferencia de la cintura fue el único signo que mostró alta sensibilidad (76,9 por ciento), baja especificidad (28,6 por ciento) con valor predictivo positivo de 42,0 por ciento. Cuando se presentan dos o tres de estos signos: rubicundez, cara de "luna llena" e hirsutismo la posibilidad de tener hipercortisolismo endógeno es 75,4 por ciento, con valor predictivo positivo de 71 por ciento y, cuando no están presentes la probabilidad de no tenerlo es de 77,5 por ciento. Conclusiones: La combinación de sensibilidad, especificidad y valor predictivo positivo de los síntomas y signos de forma aislada no predice el diagnóstico de la enfermedad; sin embargo, la presencia de dos o tres de los síntomas y/o signos tiene una elevada sensibilidad y valor predictivo positivo para el diagnóstico del hipercortisolismo endógeno. Las combinaciones que mejor predicen la posibilidad de tener un hipercortisolismo endógeno son: piel fina, edema y acné; cara de "luna llena", hirsutismo y rubicundez, así como "giba de búfalo", hematomas y estrías(AU)

ABSTRACT Introduction: The clinical diagnosis of endogenous hypercortisolism can be complex if clinical manifestations are not pathognomonic. It is important to know what are distinctive in our patients, which allows to diagnose the disease early. Objective: To determine the sensitivity, specificity and positive predictive value of clinical manifestations for diagnosis. of endogenous hypercortisolism. Methods: Descriptive and cross-sectional study. Group I was made up of 65 patients with endogenous hypercortisolism; group II (comparison) was made up of 75 patients with clinical suspicion of endogenous hypercortisolism, finally ruled out. We studied patients diagnosed of endogenous hypercortisolism from 2004 to 2017, treated at the Endocrinology Institute. Sensitivity, specificity and positive predictive values were determined for the diagnosis of endogenous hypercortisolism for each symptom and sign separately, as well as for the combinations of three clinical manifestations; in addition, binary logistic regression was performed to identify the combinations of symptoms that best predict the presence of endogenous hypercortisolism. A statistically significant difference was considered with p ≤ 0.05. Results: Most of the symptoms presented a sensitivity lower than 45 percent. Waist circumference was the only sign that showed high sensitivity (76.9 percent), low specificity (28.6 percent), and positive predictive value of 42.0 percent. When two or three of these signs (redness, "full-moon" face, and hirsutism) are present, the possibility of having endogenous hypercortisolism is 75.4 percent, with positive predictive value of 71 percent; and, when they are not present, the probability of not having it is 77,5 percent. Conclusions: The combination of sensitivity, specificity and positive predictive value of the symptoms and signs in isolation does not predict the diagnosis of the disease; however, the presence of two or three of the symptoms and/or signs has a high sensitivity and positive predictive value for the diagnosis of endogenous hypercortisolism. The combinations that best predict the possibility of having an endogenous hypercortisolism are thin skin, edema and acne; "full-moon" face, hirsutism and redness; as well as "buffalo hump," bruises and stretch marks(AU)

Rationale and design of the cardiovascular status in patients with endogenous cortisol excess study (CV-CORT-EX): a prospective non-interventional follow-up study.

BACKGROUND: Endogenous Cushing's syndrome (CS) results in increased cardiovascular (CV) morbidity and mortality. So far, most studies focussed on distinct disease entities rather than the integrity of the CV system. We here describe the design of the Cardiovascular Status in Endogenous Cortisol Excess Study (CV-CORT-EX), a study aiming to comprehensively investigate the health status of patients with endogenous CS (with a particular focus on CV phenotypes, biochemical aspects, quality of life, and psychosocial status). METHOD: A prospective non-interventional cohort study performed at a German tertiary referral centre. At the time of enrolment, patients will be categorised as: (1) newly diagnosed overt CS, (2) recurrent overt CS, (3) CS in remission, (4) presence of mild autonomous cortisol excess (MACE). The target cohorts will be n = 40 (groups 1 + 2), n = 80 (group 3), and n = 20 (group 4). Patients with overt CS at the time of enrolment will be followed for 12 months after remission (with re-evaluations after 6 and 12 months). At each visit, patients will undergo transthoracic echocardiography, cardiac magnetic resonance imaging, 24-h electrocardiogram, 24-h blood pressure measurement, and indirect evaluation of endothelial function. Furthermore, a standardised clinical investigation, an extensive biochemical workup, and a detailed assessment of quality of life and psychosocial status will be applied. Study results (e.g. cardiac morphology and function according to transthoracic echocardiography and cardiac magnetic resonance imaging; e.g. prevalence of CV risk factors) from patients with CS will be compared with matched controls without CS derived from two German population-based studies. DISCUSSION: CV-CORT-EX is designed to provide a comprehensive overview of the health status of patients with endogenous CS, mainly focussing on CV aspects, and the holistic changes following remission. TRAIL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ) NCT03880513, registration date: 19 March 2019 (retrospectively registered). Protocol Date: 28 March 2014, Version 2.

The hypothalamic-pituitary-adrenal and -thyroid axes activation lasting one year after an earthquake swarm: results from a big data analysis.

PURPOSE: To cope physical and/or psychological threats, the human body activates multiple processes, mediated by a close interconnection among brain, endocrine and inflammatory systems. The aim of the study was to assess the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes involvement after an acute stressful event (Emilia Romagna earthquake swarm) with a big data approach. METHODS: A retrospective, observational trial was performed, collecting all biochemical examinations regarding HPA and HPT axes performed in the same laboratory the year before and the year after the earthquake swarm (20-29 May 2012). RESULTS: Comparing 2576 pre-earthquake to 3021 post-earthquake measurements, a cortisol serum level increase was observed (p < 0.001). Similar increase was evident for urinary free cortisol (p = 0.016), but not for adrenocorticotropic hormone (p = 0.222). The biochemical hypercortisolism incidence increased from 7.6 to 10.3% after earthquakes (p = 0.001). Comparing 68,456 pre-earthquake to 116,521 post-earthquake measurements, a reduction in thyroid-stimulating hormone (TSH) levels was evident (p = 0.018), together with an increase in free triiodothyronine and free thyroxine levels (p < 0.001 and p < 0.001). Moreover, a significant increase in altered TSH after earthquakes was registered considering the epicenter-nearest measurements (p < 0.001). No clinically relevant alterations were observed considering thyroid-specific autoantibodies. CONCLUSION: A long-term HPA axis activation in the inhabitants of the earthquake-affected areas was highlighted for the first time. Moreover, an increased incidence of biochemical hypercortisolism emerged after earthquakes. We confirmed a recruitment of HPT axis after stressful events, together with increased incidence of altered TSH in the. Our big data study allowed to increase knowledge about the connection between external stressors and endocrine regulation.

Ectopic ACTH syndrome of different origin-Diagnostic approach and clinical outcome. Experience of one Clinical Centre.

PURPOSE: Ectopic Cushing Syndrome (EAS) is a rare condition responsible for about 5-20% of all Cushing syndrome cases. It increases the mortality of affected patients thus finding and removal of the ACTH-producing source allows for curing or reduction of symptoms and serum cortisol levels. The aim of this study is to present a 20-year experience in the diagnosis and clinical course of patients with EAS in a single Clinical Centre in Southern Poland as well as a comparison of clinical course and outcomes depending on the source of ectopic ACTH production-especially neuroendocrine tumors with other neoplasms. METHODS: Twenty-four patients were involved in the clinical study with EAS diagnosed at the Department of Endocrinology between years 2000 and 2018. The diagnosis of EAS was based on the clinical presentation, hypercortisolemia with high ACTH levels, high dose dexamethasone suppression test and/or corticotropin-releasing hormone tests. To find the source of ACTH various imaging studies were performed. RESULTS: Half of the patients were diagnosed with neuroendocrine tumors, whereby muscle weakness was the leading symptom. Typical cushingoid appearance was seen in merely a few patients, and weight loss was more common than weight gain. Patients with neuroendocrine tumors had significantly higher midnight cortisol levels than the rest of the group. Among patients with infections, we observed a significantly higher concentrations of cortisol 2400 levels in gastroenteropancreatic neuroendocrine tumors. Chromogranin A correlated significantly with potassium in patients with neuroendocrine tumors and there was a significant correlation between ACTH level and severity of hypokalemia. CONCLUSION: EAS is not common, but if it occurs it increases the mortality of patients; therefore, it should be taken into consideration in the case of coexistence of severe hypokalemia with hypertension and muscle weakness, especially when weight loss occurs. Because the diagnosis of gastroenteropancreatic neuroendocrine tumor worsens the prognosis-special attention should be paid to these patients.