Chronic Hypercortisolism Research Articles

Cushing's syndrome and COVID-19.

This review aims to present current data on the course of COVID-19 in patients with Cushing syndrome (CS) and discuss treatment for CS during to the pandemic. Literature review using PubMed (pubmed.ncbi.nlm.nih.gov). The search included the following terms: "COVID19" in combination with "Cushing syndrome", "Hypercortisolism" and "Glucocorticoid". Chronic hypercortisolism has been reported to increase infectious risk and worsens prognostic of patients with COVID-19 potentially due to its direct impact on the immune system: lymphopenia, impairment of monocytes and neutrophils activity, diminution of complement activation. Main metabolic complications of CS - i.e. diabetes, hypertension and obesity - have been recognized as COVID-19 complications risk factors. Patients with CS treated with steroidogenesis inhibitors might experience adrenal insufficiency during COVID-19. Special attention should be paid to patients with CS and COVID-19. The pandemic has impacted - and delayed - care of chronic illnesses including CS. Specific recommendations had been provided during the pandemic: favor telemedicine consultations, limit in-hospital explorations and postpone surgery when feasible. There are enough evidence for an increased prevalence and severity of COVID-19 to recommend a specific attention and caution in patients with CS.

Cushing's disease presenting with recurrent abscesses followed by post-remission hyperthyroidism.

We report a case of a 59-year-old woman with Cushing's disease who developed hyperthyroidism following treatment of hypercortisolaemia. The patient with a history of recurrent hospitalisations caused by multi-sited soft tissue abscesses was admitted with sepsis. Both her medical history and physical examination suggested Cushing's syndrome. The initial hormonal diagnostic process, conducted after sepsis treatment, brought forth conflicting results. However, hormonal assessment repeated 3 months later indicated pituitary hypercortisolaemia, which was confirmed through bilateral inferior petrosal sinus sampling and was successfully treated with transsphenoidal pituitary surgery. Three months after the surgery, the patient was readmitted to our epartment with symptoms of hyperthyroidism, which was confirmed by laboratory tests. Thyroid scintiscans indicated Graves' disease. However, the absence of anti-thyroid stimulating hormone antibodies suggested other etiologies of hyperthyroidism. Eventually, the patient underwent radioiodine therapy. Currently, her condition is improving and she has had no recurrence of abscesses, severe infections, or hyperthyroidism. In conclusion, while clinical manifestation of hypercortisolaemia might be non-specific, its treatment may trigger the development of autoimmune diseases. The presence of recurrent severe infections should prompt physicians to consider the possibility of hypercortisolaemia. Chronic hypercortisolism is debilitating and can lead to significant disability. Dexamethasone suppression testing in patients with active or recent severe inflammatory or infectious illnesses may produce misleading or confusing results. Clinicians should be aware of the potential development of autoimmune diseases following successful treatment of hypercortisolaemia.

Chronic hypercortisolism disrupts the principal functional gradient in Cushing’s disease: A multi-scale connectomics and transcriptomics study

Cushing’s disease (CD) represents a state of cortisol excess, serving as a model to investigate the effects of prolonged hypercortisolism on functional brain. Potential alterations in the functional connectome of the brain may explain frequently reported cognitive deficits and affective disorders in CD patients. This study aims to elucidate the effects of chronic hypercortisolism on the principal functional gradient, which represents a hierarchical architecture with gradual transitions across cognitive processes, by integrating connectomics and transcriptomics approaches. Utilizing resting-state functional magnetic resonance imaging data from 140 participants (86 CD patients, 54 healthy controls) recruited at a single center, we explored the alterations in the principal gradient in CD patients. Further, we thoroughly explored the underlying associative mechanisms of the observed characteristic alterations with cognitive function domains, biological attributes, and neuropsychiatric representations, as well as gene expression profiles. Compared to healthy controls, CD patients demonstrated changes in connectome patterns in both primary and higher-order networks, exhibiting an overall converged trend along the principal gradient axis. The gradient values in CD patients’ right prefrontal cortex and bilateral sensorimotor cortices exhibited a significant correlation with cortisol levels. Moreover, the cortical regions showing gradient alterations were principally associated with sensory information processing and higher-cognitive functions, as well as correlated with the gene expression patterns which involved synaptic components and function. The findings suggest that converged alterations in the principal gradient in CD patients may mediate the relationship between hypercortisolism and cognitive impairments, potentially involving genes regulating synaptic components and function.

The effects of hypercortisolism on the frequency and magnitude of sleep EEG waves in patients with Cushing syndrome: A spectral analysis study

ObjectivesOur aim was to investigate the effects of endogenous chronic hypercortisolism on sleep electroencephalogram (EEG) and differences between the adrenocorticotropic hormone (ACTH)-dependent and independent Cushing Syndrome (CS) patients through a sleep spectral analysis program. MethodsA total of 32 patients diagnosed as having endogenous CS (12 ACTH-dependent and 20 ACTH-independent) and a control group comprising 16 healthy individuals were included in the study. Polysomnographic analysis was performed. Blood samples were collected at 08:00 AM for analysis of ACTH and basal cortisol, and at 00:00 AM for midnight cortisol levels. The frequency and power of the slow wave activity (SWA), theta, alpha, and beta waves of the first and last non-rapid eye movement (NREM) cycles were measured with a spectral analysis program. ResultsThe CS patient group had higher SWA power, especially in the first NREM cycle. In the ACTH-dependent group, SWA maximum and mean power values were higher in the frontal channels in the first NREM, compared to the last NREM sleep stage (p<0.05). ConclusionCortisol has been found to be associated with SWA waves, making these waves higher in power, especially in the first NREM phase. This difference was much less pronounced in the final NREM sleep stage. The difference between the first and last NREM sleep stages with respect to the power of SWA in the frontal channel in the ACTH-dependent group suggests that not only cortisol but also high levels of ACTH affect the power of slow waves during sleep.

Cushing’s disease and bipolar disorder: study of medicopsychiatric intricacies from a clinical vignette

IntroductionCushing’s syndrome is a relatively rare condition that results from chronic hypercortisolism. This syndrome is characterized by the presence of various psychiatric manifestations that can accompany it at all its stages of evolution. They can either inaugurate the clinical picture, or appear during the course of the disease, as they can persist even after the resolution of the syndrome. of Cushing. Through a clinical vignette, we report a case of Cushing’s syndrome in a 52-year-old patient who presented with a picture of melancholic depression as part of a bipolar disorder and who had preceded the discovery of Cushing’s disease.Objectivesestablish the relationship between Cushing’s syndrome and bipolar disorder and identify the main pillars of care.MethodsIt was proposed to present the clinical case of a 52-year-old patient in whom psychiatric manifestations of the psychotic and thymic types preceded the discovery of Cushing’s disease, to recall the main psychiatric symptoms that can be encountered during such endocrine disorders and their possible entanglement with psychiatric pathologies.ResultsMrs. F. is 52 years old. married and mother of 3 children, without social security coverage for medullary carcinoma of the thyroid, having benefited from thyroidectomy with radiotherapy, admitted for treatment of paraneoplastic Cushing’s syndrome. The beginning of his troubles goes back to 6 months before his consultation with psychiatry. The initial symptoms were typical of a progressive weight gain noticed by the entourage. There was the installation of thymic symptoms such as an elation of mood, self-esteem, multiple projects. One month before admission to the internal medicine department, the patient presented with a depressed mood, anhedonia , a disgust for life, and dark thoughts. She had stopped all drug treatment.Cushing’s disease is the most common cause of endogenous hypercortisolism (&gt;85%). Corticotropic micro-adenomas , are the most frequently observed, i.e., in 90% of cases, and are sometimes not visible on magnetic resonance imaging . Its first-line treatment is neurosurgical with trans-sphenoidal excision. In its second intention, it uses drugs whose targets are pituitary or adrenal, as well as radiotherapy.Conclusionswe present the case of a patient with a picture of bipolar mood disorder and Cushing’s disease. Thymic and psychotic psychiatric symptoms preceded the discovery of endocrine disease whose symptoms were not apparent at first. The hypotheses of comorbidity or rather of the inauguration of the endocrine disease by a psychiatric picture, in particular bipolar mood disorder, remain advanced and the limits betweenDisclosure of InterestNone Declared

The Role of Serum Inflammation-Based Scores in Diagnosis and Assessing Remission in Cushing's Disease.

Chronic hypercortisolism causes diverse alterations in the immune system and inflammatory disruptions. Serum inflammation-based scores (SIBS) are indicators of systemic inflammatory status. This study aims to determine the role of SIBS in the diagnosis and evaluation of remission in patients with Cushing's disease (CD). This retrospective cross-sectional study was conducted on 195 participants; 52 patients diagnosed and followed up after treatment with CD, 65 patients with subclinical Cushing's syndrome (SCS), and 78 healthy individuals whose complete blood counts (CBC) were obtained for analysis. Participants with additional diseases or drug use that could affect CBC were excluded from the study. SIBS of the three groups were compared. Scores considered were neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). The correlations between SIBS and initial diagnostic tests for hypercortisolism were analyzed. The SIBS of patients with CD at the diagnosis were compared with those after remission. In addition, receiver operator characteristic curve analyses were used to determine the diagnostic accuracy, specificity, and sensitivity of the scores significantly high in the CD group. MLR and SII values were significantly higher in CD patients than in the healthy group (p<0.01). NLR and SII were significantly higher in patients with CD than those with SCS (p<0.05). There were no significant differences between the SCS and the control groups in all SIBS. We determine significant, positive, and moderately correlated findings between SIBS and initial diagnostic tests for hypercortisolism in the CD group (0.30<r<0.70; p<0.05). All of the scores evaluated were significantly lower in the remission of the disease compared to the active period (p<0.001). An optimal cut-off MLR value of 0.20 showed the best diagnostic value (p=0.003; sensitivity, 78.4%; specificity, 51.4%), and an optimal cut-off SII value of 776.20 showed the best diagnostic value (p=0.017; sensitivity, 54.9%; specificity, 70.0%). The SIBS, which can be easily calculated with the data obtained from CBC and do not have additional costs, can contribute to the diagnosis and assessment of remission in patients with CD.

HSD108 Physician Perceptions on the Treatment and Health-Related Quality of Life Burden of Endogenous Cushing's Syndrome

Endogenous Cushing’s syndrome (CS) results from chronic hypercortisolism and is associated with symptoms and complications that adversely impact morbidity. Research indicates that a health-related quality of life (HRQoL) burden persists despite treatment. This study evaluated physician perceptions on treatments and their rationale behind treatment decisions.

PMON160 Improvements in Clinical Signs of Hypercortisolism and Quality of Life According to Urinary and Late-Night Salivary Cortisol Levels in Patients with Cushing's Disease Treated with Osilodrostat

Abstract Objective Cushing's disease (CD) is a debilitating disorder of chronic hypercortisolism. Assessment of 24h mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC) is recommended for screening and monitoring treatment response. In the published core period of the Phase III, LINC 3 study (NCT02180217), osilodrostat therapy (a potent oral 11β-hydroxylase inhibitor) produced rapid, sustained reductions in both mUFC and LNSC alongside improvements in clinical signs of hypercortisolism and health-related quality of life (HRQoL) in patients with CD. Here we explored cardiovascular/metabolic-related parameters, physical features and HRQoL according to mUFC and/or LNSC control. Methods LINC 3 (core period) enrolled 137 adults with CD and mUFC &amp;gt;1.5x upper limit of normal (ULN), who received open-label osilodrostat up to 48-week (W) (starting dose: 2 mg twice daily [bid]; maximum: 30 mg bid); eligible patients were randomized in an 8W placebo-controlled, withdrawal period (W26–34). mUFC (three sample average; normal 11–138 nmol/24h [4–‍50 µg/24h]) and LNSC (single sample; normal ≤2.5 nmol/L) were assessed centrally by liquid chromatography-tandem mass spectrometry. Cardiovascular/metabolic-related parameters, physical features (rating: 0=absent;1=mild;2=moderate;3=severe), CushingQoL and Beck Depression Inventory-II (BDI-II) scores were also evaluated. Data were recorded at baseline, regularly throughout, and at W48. Analyses are presented for patients with both mUFC and LNSC assessments, defined as: both mUFC+LNSC controlled (mUFC≤ULN+LNSC≤ULN), only mUFC controlled (mUFC≤ULN+LNSC&amp;gt;ULN), only LNSC controlled (mUFC&amp;gt;ULN+LNSC≤ULN) and both mUFC+LNSC uncontrolled (mUFC&amp;gt;ULN+LNSC&amp;gt;ULN). Results Of evaluable patients at baseline (n=87), 74 (85.1%) had both mUFC+LNSC uncontrolled. At W48, 38 patients (54.3%) had both mUFC+LNSC controlled, 21 (30.0%) had only mUFC controlled, 3 (4.3%) had only LNSC controlled, and 8 (11.4%) had both mUFC+LNSC uncontrolled. Patients with both mUFC+LNSC controlled had generally greater mean improvements from baseline to W48 in cardiovascular/metabolic-related parameters than those with only mUFC or LNSC controlled or both mUFC+LNSC uncontrolled, respectively: weight, –5.9, –3.3, –2.2 and –‍3.8 kg; systolic blood pressure, –14.4, –8.0, –7.4, –3.0 mmHg; diastolic blood pressure, –‍8.6, –4.8, –8.2, –4.0 mmHg; fasting plasma glucose, –16.9, –4.8, –15.0, –11.0 mg/dL; and HbA1c, –0.4, –0.3, –0.9, –0.0%. CushingQoL/BDI-II scores improved from baseline to W48 irrespective of mUFC and/or LNSC control. The proportion of patients with improved physical manifestations of hypercortisolism (facial rubor, striae, fat pads, bruising, hirsutism [females], muscle atrophy) was greatest in patients with both mUFC+LNSC controlled or only mUFC controlled. Discussion At W48, over half the evaluable patients had both mUFC+LNSC controlled following osilodrostat treatment. Improvements in clinical signs of hypercortisolism and HRQoL occurred irrespective of mUFC and/or LNSC control; however, for some clinical outcomes, improvements were greater in patients with both mUFC+LNSC controlled. Findings are limited by small patient numbers in some groups. mUFC and LNSC are complementary parameters used to assess disease control and patients with both mUFC+LNSC controlled have better outcomes. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP349 Risk of Coronavirus Disease 2019 (COVID-19) in patients with Cushing's Disease (CD) is increased and independently associated with both obesity and disease activity

Abstract Patients with Cushing's disease (CD) are usually immunosuppressed due to chronic hypercortisolism, therefore more susceptible to COVID-19. Comorbidities like obesity, hypertension and diabetes mellitus (DM), highly prevalent in CD, have been shown to increase severity of COVID-19 in the general population. The aim of this study was to evaluate the incidence, risk factors, and outcome of COVID-19 in a cohort of CD patients from February/15 2020 to November/15 2021 (before the arrival of the Omicron variant in Brazil). Sixty out of 66 CD patients were included (54F). From October/1 to November/30/2021, patients or family members answered a questionnaire about the diagnosis and time of COVID-19 infection (PCR-confirmed), its outcome and vaccination status through phone interview. Clinical and biochemical data, obtained from our electronic medical records, showed that 15 patients were in hypercortisolism (25%) and 45 were in remission (75%). A similar proportion was found among those 6 patients that did not participate in the study. The cumulative incidence of COVID-19 in the cohort during the entire observation period (22 months) was 32% (19/60), much higher than reported in the general reference population within the same area during the same period (9.5%). Since vaccination only started in February/2021, 55 patients were considered as not fully vaccinated (less than two doses) up to July/2021 (observation period: 17 months). In those patients, the cumulative incidence of COVID-19 during that period of time was also higher (27%) than in the reference population (8.4%). When CD patients were stratified according to comorbidities, the cumulative incidence of COVID-19 was shown to be significantly higher in patients with active disease (hypercortisolism) [57%vs 17%,P= 0. 012] and in those with obesity [54%vs 9%,P&amp;lt;0. 001], but not with hypertension or DM. In multivariate analysis, both hypercortisolism and obesity were independent risk factors for COVID-19 in CD patients [RR=2.1 (CI: 1-4.4),P=0. 05 andRR=4.8 (CI: 1.5-15.5),P=0. 009, respectively]. One single patient (5.2%) died from COVID-19 (she had hypercortisolism, obesity, hypertension and DM). During the next 5 months, when all 60 patients had been fully vaccinated, there were four (4/41) new infections and no (0/19) reinfection. The incidence of COVID-19 is higher in CD patients and is associated with hypercortisolism, as expected, and more strongly with obesity, which is a novel and unexpected finding that has only recently been reported in the general population (1). Thus, correction of hypercortisolism, obesity, and preventive measures should be more aggressively implemented in CD patients during the current COVID-19 pandemia. Reference: (1) Recalde et al., J Clin Endocrinol Metab. 2021 Nov 19;106(2): e5030-e5042. Presentation: No date and time listed

Dexamethasone-Induced Adipose Tissue Redistribution and Metabolic Changes: Is Gene Expression the Main Factor? An Animal Model of Chronic Hypercortisolism.

Chronic hypercortisolism has been associated with the development of several metabolic alterations, mostly caused by the effects of chronic glucocorticoid (GC) exposure over gene expression. The metabolic changes can be partially explained by the GC actions on different adipose tissues (ATs), leading to central obesity. In this regard, we aimed to characterize an experimental model of iatrogenic hypercortisolism in rats with significant AT redistribution. Male Wistar rats were distributed into control (CT) and GC-treated, which received dexamethasone sodium phosphate (0.5 mg/kg/day) by an osmotic minipump, for 4 weeks. GC-treated rats reproduced several characteristics observed in human hypercortisolism/Cushing’s syndrome, such as HPA axis inhibition, glucose intolerance, insulin resistance, dyslipidemia, hepatic lipid accumulation, and AT redistribution. There was an increase in the mesenteric (meWAT), perirenal (prWAT), and interscapular brown (BAT) ATs mass, but a reduction of the retroperitoneal (rpWAT) mass compared to CT rats. Overexpressed lipolytic and lipogenic gene profiles were observed in white adipose tissue (WAT) of GC rats as BAT dysfunction and whitening. The AT remodeling in response to GC excess showed more importance than the increase of AT mass per se, and it cannot be explained just by GC regulation of gene transcription.

Effects of Fibroblast factor 21 to adrenal renewal after chronic hypercortisolism

Effects of Fibroblast factor 21 to adrenal renewal after chronic hypercortisolism

Effects of ACTH-Induced Long-Term Hypercortisolism on the Transcriptome of Canine Visceral Adipose Tissue.

Cushing’s syndrome, or hypercortisolism (HC), a common endocrinopathy in adult dogs, is caused by chronic hypercortisolemia. Among different metabolic disorders, this syndrome is associated with enhanced subcutaneous lipolysis and visceral adiposity. However, effects of HC in adipose tissue, especially regarding visceral adipose tissue (VAT), are still poorly understood. Herein, the transcriptomic effects of chronic HC on VAT of dogs were evaluated. For this, subcutaneously implanted ACTH-releasing pumps were used, followed by deep RNA sequencing of the canine VAT. Prolonged HC seems to affect a plethora of regulatory mechanisms in VAT of treated dogs, with 1190 differentially expressed genes (DEGs, p and FDR < 0.01) being found. The 691 downregulated DEGs were mostly associated with functional terms like cell adhesion and migration, intracellular signaling, immune response, extracellular matrix and angiogenesis. Treatment also appeared to modulate local glucocorticoid and insulin signaling and hormonal sensitivity, and several factors, e.g., TIMP4, FGF1, CCR2, CXCR4 and HSD11B1/2, were identified as possible important players in the glucocorticoid-related expansion of VAT. Modulation of their function during chronic HC might present interesting targets for further clinical studies. Similarities in the effects of chronic HC on VAT of dogs and humans are highlighted.

Cushing’s Disease of Unknown Etiology: A Clinical Case Report

Cushing’s disease (CD) remains a diagnostic and therapeutic challenge. Different subtypes may be recognized that will offer insight in this complex situation. We describe an atypical case that we assume is a common variation albeit with no previous formal description. A young female patient presented with minimal clinical features of CD, but increased adrenocorticotropic hormone (ACTH) and cortisol levels, with maintained circadian rhythm that was not suppressed either after the rapid dexamethasone or the prolonged low-dose dexamethasone tests, but suppressed with the prolonged high-dose dexamethasone test and presented a flat ACTH and cortisol response after the corticotropin-releasing hormone (CRH) test. A diffuse enlarged pituitary gland with thickened pituitary stalk was present and a mixed corticotroph adenoma was removed. CD persisted despite now normal pituitary morphology, except for pituitary stalk widening. Plasma levels of CRH were low and no abnormalities were found in the coding region or flanking introns of glucocorticoid receptor (GCR) gene ( NR3C1 ). Somatostatin receptors were not present in the octreoscan, and treatment with cabergoline or somatostatin analogs was ineffective. Morbidity and mortality are increased in CD even in patients successfully treated and in remission. Despite early success in over 80% of the patients, in the long term CD recurs in almost 50% of the patients. Defining subtypes of CD may help elucidate mechanisms of the disease. We propose a new variant that we assume is common. Furthermore adaptation to chronic hypercortisolism is present. J Endocrinol Metab. 2022;12(1):40-48 doi: https://doi.org/10.14740/jem784

Glucocorticoid-induced Fingerprints on Visceral Adipose Tissue Transcriptome and Epigenome.

Chronic glucocorticoid (GC) overexposure, resulting from endogenous Cushing's syndrome (CS) or exogenous GC therapy, causes several adverse outcomes, including persistent central fat accumulation associated with a low-grade inflammation. However, no previous multiomics studies in visceral adipose tissue (VAT) from patients exposed to high levels of unsuppressed GC during active CS or after remission are available yet. To determine the persistent VAT transcriptomic alterations and epigenetic fingerprints induced by chronic hypercortisolism. We employed a translational approach combining high-throughput data on endogenous CS patients and a reversible CS mouse model. We performed RNA sequencing and chromatin immunoprecipitation sequencing on histone modifications (H3K4me3, H3K27ac, and H3K27me3) to identify persistent transcriptional and epigenetic signatures in VAT produced during active CS and maintained after remission. VAT dysfunction was associated with low-grade proinflammatory status, macrophage infiltration, and extracellular matrix remodeling. Most notably, chronic hypercortisolism caused a persistent circadian rhythm disruption in VAT through core clock genes modulation. Importantly, changes in the levels of 2 histone modifications associated to gene transcriptional activation (H3K4me3 and H3K27ac) correlated with the observed differences in gene expression during active CS and after CS remission. We identified for the first time the persistent transcriptional and epigenetic signatures induced by hypercortisolism in VAT, providing a novel integrated view of molecular components driving the long-term VAT impairment associated with CS.

The Stress Axis in Obesity and Diabetes Mellitus: An Update

The hypothalamic–pituitary–adrenal axis is a tightly regulated system that represents one of the body’s mechanisms for responding to acute and chronic stress. Prolonged stress and/or inadequate regulation of the stress system can lead to a condition of chronic hypercortisolism or, in some cases, a blunted cortisol response to stress, contributing to insulin resistance, increased adiposity and type 2 diabetes mellitus. Moreover, acute and chronic stress can exacerbate or worsen metabolic conditions by supporting an inflammatory state and a tight relationship between stress, inflammation and adipose tissue has been reported and has been a growing subject of interest in recent years. We reviewed and summarized the evidence supporting hypothalamic–pituitary–adrenal axis dysregulation as an important biological link between stress, obesity, inflammation and type 2 diabetes mellitus. Furthermore, we emphasized the possible role of infectious-related stress such as SarsCov2 infection in adrenal axis dysregulation, insulin resistance and diabetes in a bidirectional link. Understanding and better defining the links between stress and obesity or diabetes could contribute to further definition of the pathogenesis and the management of stress-related complications, in which the HPA axis dysregulation has a primary role.

A novel nonsense mutation in ARMC5 causes primary bilateral macronodular adrenocortical hyperplasia

BackgroundPrimary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare form of adrenal Cushing’s syndrome. The slowly progressing expansion of bilateral adrenal tissues usually persists for dozens of years, leading to delayed onset with severe conditions due to chronic mild hypercortisolism. About 20–50% cases were found to be caused by inactivating mutation of armadillo repeat-containing protein 5 (ARMC5) gene.Case presentationA 51-year-old man was admitted for severe diabetes mellitus, resistant hypertension, centripedal obesity and edema. PBMAH was diagnosed after determination of adrenocorticotropic hormone and cortisol levels, dexamethasone suppression tests and abdominal contrast-enhanced CT scanning. The metabolic disorders of the patient remarkably improved after sequentially bilateral laparoscopic adrenalectomy combined with hormone replacement. Sanger sequencing showed germline nonsense mutation of ARMC5 c.967C>T (p.Gln323Ter). The second somatic missense mutation of ARMC5 was detected in one out of two resected nodules, reflecting the second-hit model of tumorigenesis. Routine genetic testing in his apparently healthy offspring showed one of two daughters and one son harbored the germline mutation.ConclusionsIn conclusion, our case report highlight the importance of genetic testing in the molecular diagnosis of PBMAH. Genetic screening in related family members will find out asymptomatic variant carriers to guide life-long follow-up.

Treatment of Cushing’s disease with macroadenoma through transsphenoidal surgery

Cushing’s disease (CD) is a rare illness characterized by chronic hypercortisolism secondary to the overproduction of adrenocorticotropic hormone by a pituitary adenoma, which is associated with a high risk of developing serious complications, such as diabetes mellitus, cardiovascular disease, and emotional disorders. Endoscopic transsphenoidal surgery is performed for the treatment of CD, and was initially preferred over other types of treatments. However, the recurrence after pituitary surgery for CD is a common problem after an initial successful surgery. In microadenomas, the remission rates were higher than those of macroadenoma. This patient had a giant tumor that was greater than 4 cm in length on sella magnetic resonance imaging, and panhypopituitarism was detected using a combined pituitary stimulation test. After transsphenoidal surgery, the patient required temporary hormone replacement for a short period of time. After 1 year, he showed a normal cortisol response on the overnight dexamethasone suppression test and low morning cortisol levels. Therefore, we indicated that the patient was cured of giant macroadenoma with panhypopituitarism before surgery, and thus, reported this case. Key words: Cushing disease, Theasinensin A, Adenoma, Pituitary

Plasma Cortisol and Risk of Atrial Fibrillation: A Mendelian Randomization Study.

ContextAtrial fibrillation (AF), cardiac arrhythmias, and related risk factors are common in patients with Cushing’s syndrome, or clinical chronic hypercortisolism. While hypercortisolism may be associated with AF, this association has not yet been ascertained causally.ObjectiveTo determine whether plasma cortisol is causally associated with AF using a 2-sample Mendelian randomization (MR) design.MethodsThree genetic variants in the SERPINA1/SERPINA6 locus and functionally associated with plasma cortisol were identified in the CORtisol NETwork consortium (12 597 participants). Summary-level genome-wide association study (GWAS) data for the associations between the cortisol-associated variants and AF were obtained from a GWAS meta-analysis of 6 studies (60 620 AF cases and 970 216 noncases) and the FinnGen consortium (17 325 AF cases and 97 214 noncases). The fixed-effects inverse-variance weighted approach accounting for genetic correlations between variants was used for analysis. Multivariable MR analyses were conducted to assess potential mediating effects of systolic blood pressure (SBP) and waist circumference (WC). Summary-level GWAS data for SBP and WC were obtained respectively from the International Consortium of Blood Pressure (757 601 participants) and the Genetic Investigation of ANthropometric Traits consortium (232 101 participants).ResultsOne standard deviation increase in genetically predicted plasma cortisol was associated with greater risk of AF (odds ratio [OR] 1.20, 95% CI 1.06-1.35). The association attenuated when adjusting for genetically predicted SBP and WC (OR 0.99, 95% CI 0.72-1.38).ConclusionEvidence derived from the MR study suggests a positive association between plasma cortisol and risk of AF, likely mediated through SBP and WC.

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials.

Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

OR03-05 Novel Lipidome Signature in Active Cushing Syndrome Revealed by UHPLC-MS Metabolomics

Background: Alterations in circulating amino acids, polyamines and acylcarnitines have been reported in patients with endogenous chronic hypercortisolism. However, lipid metabolites profiling and its interplay with the serum metabolome and degree of hypercortisolism in patients with active Cushing syndrome (CS) has not been previously assessed. Objective: To identify new metabolomic biomarkers associated with active CS. Methodology: Multiple UHPLC-MS platforms were used to analyze the metabolome of serum samples obtained from 25 patients with active endogenous CS and 25 controls subjects matched by propensity score (sex, BMI, T2D, DLP, HBP). Results: Metabolome of CS patients was deeply disrupted with 122 (27%) of the assessed metabolites significantly altered (p adj. <0.05) out of which 5 bile acids resulted with the highest perturbation (> 2-fold decrease). From the altered metabolites, 3 amino acids (AA), 2 acylcarnitines (ACs), 2 ceramides (CER) and 5 glycerophospholipids showed direction of effect independently associated with 24-h urinary free cortisol (MS) levels. A highly discriminant (AUC 96%) metabolome signature (n=59) characterized by lower levels of AA, ACs, polyunsaturated fatty acids (PUFA) and monoglycerophosphocolines (MGPC) together with increased levels of triacyclglycerols (TG), CER, diacylglycerophosphocholines (DGPC) and cholesteryl esters was identified and cross-validated (R2Y= 0.92, Q2Y= 0.68) using PLS-DA VIP scores >1.5. PUFA omega-6, and alanine, aspartate and glutamate metabolism resulted the most impacted canonical pathways (q-stat 19.7, 10.8 (p<0.001). Finally, topological network analysis detected 158 pairwise differential correlations (p <0.005, 10,000-fold permutation) between 141 metabolites due to CS where the acylPC (P-18:1/0:0) resulted a key metabolite in the network (betweenness =0.117 & closeness centrality =0.467). Conclusion: Active Cushing syndrome leads to a global proatherogenic shift in the circulating ceramides, glycerophospholipids and sphingolipids metabolites which are independently associated to the levels of urinary free cortisol being potential biomarkers of patients’ cardiovascular risk.