Dexamethasone Suppression Test Cortisol Research Articles

Relationship Between Dexamethasone Suppression Test Cortisol Level >0.9 μg/dL and Depression and Quality of Life in Adrenal Incidentalomas: A Single Center Observational Case-Control Study

ObjectiveThere has been increasing evidence that patients with adrenal incidentalomas (AIs) who have 1-mg dexamethasone suppression test (DST) cortisol levels >0.9 μg/dL may be exposed to the adverse consequences of hypercortisolaemia. We aim to evaluate whether there is a difference in Beck Depression Inventory-II (BDI-II) and quality of life (QoL) score in patients with AI based on the threshold of a DST cortisol level >0.9 μg/dL. MethodsThis case-control study included 42 nonfunctional adrenal incidentaloma (NFAI), 53 mild autonomic cortisol secretion (MACS) and 42 healthy controls (HCs). In addition, patients were categorized as ≤0.9 and >0.9 μg/dL according to their DST cortisol results. ResultsThere was no difference in the QoL and BDI-II scores of MACS compared to NFAI. The BDI-II score was higher and QoL was lower in MACS and NFAI compared to HCs. The difference in QoL and BDI-II scores between MACS and NFAI remained insignificant when the DST cortisol levels threshold was graded upward (5.0 μg/dL). The prevalence of depression was higher in the AI >0.9 μg/dL group than the AI ≤0.9 μg/dL group (respectively, 16.7% and 55.8%, P = .003), BDI-II scores were higher in the AI >0.9 μg/dL group than in the AI ≤0.9 μg/dL group and HCs. The DST was an independent factor affecting the frequency of depression (odds ratio: 1.39, P = .037). ConclusionMACS and patients with NFAI had similar QoL and depression scores according to the 1.8 μg/dL and above, whereas, had lower QoL and higher depression scores according to the 0.9 μg/dL.

Kidney Function in Patients With Adrenal Adenomas: A Single-Center Retrospective Cohort Study.

Patients with nonfunctioning adrenal adenomas (NFA) and mild autonomous cortisol secretion (MACS) demonstrate an increased risk of chronic kidney disease (CKD); however, factors associated with CKD are unknown. We aimed to identify the factors associated with CKD and assess the effect of adrenalectomy on kidney function in patients with NFA or MACS. A single-center cohort study of patients with NFA and MACS, 1999 to 2020, was conducted. MACS was diagnosed based on post dexamethasone suppression test (DST) cortisol greater than or equal to 1.8 mcg/dL. Age, sex, dysglycemia, hypertension, therapy with statin, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker were included in the multivariable analysis. Outcomes included estimated glomerular filtration rate (eGFR) at the time of diagnosis with MACS or NFA and postadrenalectomy delta eGFR. Of 972 patients, 429 (44%) had MACS and 543 (56%) had NFA. At the time of diagnosis, patients with MACS had lower eGFR (median 79.6 vs 83.8 mL/min/1.73 m2; P < .001) than patients with NFA. In a multivariable analysis, factors associated with lower eGFR were older age, hypertension, and higher DST. In 204 patients (MACS: 155, 76% and NFA: 49, 24%) treated with adrenalectomy, postadrenalectomy eGFR improved in both groups starting at 18 months up to 3.5 years of follow-up. Factors associated with increased eGFR were younger age, lower preadrenalectomy eGFR, and longer follow-up period. DST cortisol is an independent risk factor for lower eGFR in patients with adrenal adenomas. Patients with both MACS and NFA demonstrate an increase in eGFR post adrenalectomy, especially younger patients with lower eGFR pre adrenalectomy.

THU606 Cognitive Impairment In Patients With Mild Autonomous Cortisol Secretion: A Cross-sectional Study

Abstract Disclosure: J. Saini: None. R. Nathani: None. S. Singh: None. K. Thangamuthu: None. M. Suresh: None. C. Zhang: None. A.L. Ebbehøj: None. M. Thomas: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. N. Stricker: None. I. Bancos: None. Introduction: While patients with overt Cushing syndrome are reported to have impaired cognition, the impact of milder, long-standing hypercortisolism on cognition is incompletely characterized. Objective: To determine the impact of MACS on cognition as compared to age, sex, and education-matched referent subjects. Methods: We conducted a single-center cross-sectional study of adults with MACS and referent subjects. MACS was defined as serum cortisol&amp;gt;1.8 mcg/dL after 1 mg dexamethasone suppression test (DST) in patients with adrenal incidentalomas. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. Exclusion criteria were malignancy and exogenous glucocorticoid use within 1 year. All participants underwent a cognitive evaluation using the NIH Toolbox Cognition Battery between 1/2019 to 7/2022. NIH Toolbox assesses 8 cognitive domains using 7 tests and yields 3 composite scores: fluid cognition (executive function, episodic memory, cognitive flexibility, working memory, and processing speed), crystallized cognition (language and vocabulary), and total composite cognition (composite of all). Results are given in fully corrected T scores (adjusted for age, sex, race, and education) with an average of 50 and a standard deviation (SD) of 10. A subgroup analysis was performed based on DST cortisol. The Kruskal-Wallis test was used to compare scores between groups. Results: A total of 94 patients with MACS (median age 57.2 years, IQR 47.8-66.5, 70% women) and 94 referent subjects (median age 58 years, IQR 49.1-66.4, 70% women) were included. The median post-DST cortisol in patients with MACS was 3.3 mcg/dL (IQR, 2.4-6.2). The mean (SD) total composite T-score was lower in patients with MACS vs referent subjects (51 (9.1) vs 56.3 (9.3), P&amp;lt;0.001). Patients with MACS demonstrated lower mean fluid composite T-score when compared to referent subjects (49.5 (10.4) vs 56.9 (9.7), P&amp;lt;0.001). However, mean crystallized composite T-scores were similar in patients with MACS and referent subjects (52.3 (8.1) vs 53.9 (9.6), P=0.342). A subgroup analysis of patients with post-DST cortisol &amp;lt;3 mcg/dL (n=40) vs patients with post-DST cortisol &amp;gt;3 mcg/dL (n=54) did not show any differences in the total, fluid, or crystalized composite scores. Conclusion: Patients with MACS demonstrate lower cognitive performances than a referent group suggesting MACS has a subtle impact on cognitive functioning. The pattern of cognitive impairment in patients with MACS is similar to that seen with normal cognitive aging: impaired fluid cognitions and unaffected crystallized cognition). Cognitive performance did not differ based on the degree of MACS suggesting that in the absence of overt features of hypercortisolism, the degree of MACS is less important than the presence of MACS. Presentation: Thursday, June 15, 2023

Abstract #1413755: Subclinical Cushing’s Syndrome in an ACTH-secreting Pituitary Macroadenoma

Subclinical Cushing’s syndrome (SCS) is characterized by subtle cortisol hypersecretion, which does not result in the typical signs and symptoms of Cushing’s syndrome (CS). While many of the signs and symptoms of CS are common in the general population, there are some that are discriminatory and specific for CS: supraclavicular fat pads, proximal muscle weakness, facial plethora, and violaceous striae. SCS manifests mostly as obesity, type 2 diabetes, and hypertension. Diagnosing SCS is challenging; however, the best screening test to uncover the subtle hypercortisolism is the dexamethasone suppression test (DST). We report a case of SCS in a 62 years old Caucasian postmenopausal patient with a medical history of total thyroidectomy for Graves’ disease, post-surgical hypothyroidism, 7.4cm right pheochromocytoma status post partial right adrenalectomy, incidentally discovered pituitary macroadenoma (during imaging to look for subarachnoid hemorrhage), untreated type 2 diabetes mellitus (A1c 6.6% and stable for 1 year before treatment), hypertension, atrial fibrillation, cerebrovascular accident, and worsening migraines. Patient’s physical exam was mostly unremarkable; she had central obesity and bilateral lower extremity swelling. Pituitary work-up showed evidence of secondary hypogonadism and secondary hypothyroidism with elevated adrenocorticotropic hormone (ACTH) of 130 (AM range: 7.2-63) and cortisol of 12.6, at 11:52AM. Further work-up for hypercortisolism revealed non-suppressed cortisol (5.83mcg/dL) on the low dose DST and 49% suppression of cortisol and ACTH on the high dose DST. 24-hour urinary cortisol was normal. Patient did not perform the midnight salivary cortisol. Patient subsequently underwent trans-sphenoidal resection of the pituitary macroadenoma. Pathology analysis of the pituitary mass showed weak to moderate immunoreactivity for ACTH. Our patient had abnormal DST but normal 24hour urine cortisol. We may have missed her SCS if we screened her only with a 24hour urine cortisol. This confirms the fact that dexamethasone suppression test should be the first test in the evaluation of subclinical Cushing’s syndrome.

Hypothalamo-Pituitary-Adrenal Axis in Depressive Disorders and Treatment Resistance

Background: hypothalamo-pituitary-adrenal (HPA) axis plays an important role in the pathogenesis of depression. Patterns of HPA functioning depend on both biologic factors and psychological background, which, taken together, may increase the risk of depression later on. Objective: to analyze scientific publications on pathophysiology of depression, linked to HPA disruption, assess causal relationship between hypercorticism and depression, role of hypercorticism in clinical symptoms and course of depressive disorder.Material and methods: according to the key words “hypercortiсism”, “depression disorder”, “cortisol”, “treatment resistant depression”, “Cushing’s syndrome”, “Сushing’s disease”, a search was conducted for publications in databases Medline/ PubMed, Scopus, Web of Science, RSCI and other resources.Conclusion: there is a high comorbidity between depressive disorders and HPA axis abnormalities, including endocrine disorders with both increased and decreased cortisol secretion. Hypercorticism related to Сushing’s disease or Cushing’s syndrome is often associated with irreversible mental disorders, especially anxiety and depressive disorders, which persist after normalization of cortisol levels. Depressive patients are characterized by persistently elevated cortisol levels and their non-supression in the 1 mg dexamethasone suppression test (DST); however, sometimes they have reduced cortisol secretion. The possible pathophysiology mechanisms of hypercorticism are discussed. Beside hypercorticism, increased level of adrenocorticotropic hormone (ACTH) and decreased secretion of ACTH after CRH stimulation are demonstrated. It has been demonstrated that elevation of cortisol levels may precede the development of depression and as such can be used as marker of increased depression risk. Hypercorticism in patients with depression may promote its increased severity and transform ation of depressive symptoms. Persistent hypercorticism and non-supression of cortisol in DST are predictors of poor outcomes. HPA dysfunction seems to play an essential role in evolvement of treatment resistant depression. There is data on the efficacy of drugs modifying HPA activity for amelioration of affective disorders and psychotic symptoms in patients with depression. Further research into HPA functioning in patients with depression are needed to clarify pathogenetic mechanisms and development of newer treatment approaches to depression.

ODP018 A Case of Cushing's Syndrome due to Primary Bilateral Macronodular Adrenal Hyperplasia

Abstract Introduction Primary bilateral macro-nodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome, characterized by a high clinical heterogeneity, both with regards to the severity of cortisol excess and the morphologic appearance of the adrenals. We present an interesting case of Cushing's syndrome caused by Primary bilateral macro-nodular adrenal hyperplasia. Case presentation A 61-year-old female with Graves’ disease status post I-131 therapy was incidentally found to have two left adrenal adenomas of sizes 2 cm and 1.9 cm on CT imaging. Her laboratory workup revealed Cushing's syndrome evidenced by abnormal 1 mg dexamethasone suppression test (DST) with cortisol of 7.8 mcg/dl (8-19 mcg/dl), 24-hour urinary cortisol (UFC) of 50 mcg/24hr (0-50 mcg/24hr) with ACTH 6.2 pg/ml (7.2 -63 pg/ml) and DHEAS 79.8 mcg/dl (29.4-215 mcg/dl). Her MRI brain revealed meningioma and she underwent gamma knife therapy. Over time she developed uncontrolled hypertension, pre-diabetes, weight gain and easy bruising. On examination she has a plethoric face, ruddy complexion, and central obesity. Her repeat blood work showed 1 mg DST cortisol of 6.7 mcg/dl (8-19 mcg/dl), UFC 76 mcg/dl (6-42 mcg/dl) and normal late night salivary cortisol 0. 071, 0. 067 mcg/dl (&amp;lt;0. 010-0. 090 mcg/dl). Her repeat CT abdomen showed bilateral adrenal nodules with larger nodule on the left side measuring 2.4 cm. She underwent adrenal vein sampling using epinephrine as control which showed bilateral cortisol secretion. She did not tolerate medical therapy with Mifepristone. Testing for aberrant receptors was negative. She eventually underwent left adrenalectomy which improved her clinical co-morbidities and normalized cortisol levels. Her postoperative DST cortisol is 1.5 mcg/dl (8-19 mcg/dl) and UFC is 8 mcg/24hr (6-42 mcg/24hr). Her genetic testing is still pending. Discussion The conventional treatment of PBMAH is adrenalectomy. Unilateral adrenalectomy of larger adrenal gland is now considered a reasonable alternative to bilateral adrenalectomy in selected patients due to risk of adrenal insufficiency and lifetime steroid dependency with bilateral surgery (1). Cortisol secretion in PBMAH can be regulated by aberrant adrenal expression of receptors and all patients should be evaluated for these receptors as there is potential for medical therapy in them. PMBAH is also caused by ARMC5 mutations in familial cases, and it is commonly associated with intracranial meningiomas suggesting a possibility of new syndrome which needs to be further studied. Cranial imaging should be offered to these patients to exclude a coexisting meningioma (2).

PMON129 Pituitary Adenoma Co-Secreting GH, Prolactin and ACTH

Abstract Background Pituitary adenomas co-secreting GH, Prolactin and ACTH are rare. Clinical Case A 38-year-old male with a past medical history of depression and type 2 diabetes mellitus was seen in the endocrinology clinic for an evaluation of acromegaly. In the preceding four years, the patient had experienced an enlargement of his hands and feet, hyperhidrosis, development of an underbite, snoring, daytime somnolence, erectile dysfunction, headaches, and blurry vision. His visual fields were normal. Physical exam: BP 137/85, BMI 39 kg/m2. He had coarse facial features, acral changes of his hands and feet, and wide spacing of his teeth. There was a notable absence of facial plethora, abdominal obesity with thin extremities, proximal muscle weakness, purple abdominal striae, and galactorrhea. Initial laboratory results: GH 16.9 ng/mL (0.05-3 ng/ml), IGF-1 1,109 ng/mL (82-242 ng/mL), Prolactin (PRL) 96.9 ng/ml (5-20 ng/ml), testosterone 34 ng/dL (200-1000 ng/dL), LH 2.3 miu/ml (1.4–12 miu/ml), FSH 4.8 miu/ml (1.5-12 miu /ml), ACTH 197.6 pg/mL (7.2- 63.3 pg/mL), 0800 cortisol 16.2 ug/dL (5-29 ug/dL), 24-hour urine free cortisol 56.84 mcg (3.5-40 mcg), HS salivary cortisol 0.242 (&amp;lt;0.359 ug/dL), overnight 1 mg Dexamethasone suppression test cortisol 6.9 mcg/dL (&amp;lt; 1.8 mcg/dL), normal Free T4 and TSH, and A1c 9.7%. A pituitary MRI revealed a 3.9 cm lobulated, intra and supra-sellar mass with mass effect on the optic chiasm and 75% encasement of the left supra-clinoid internal carotid artery. Neurosurgery performed an endoscopic, endonasal partial resection of the pituitary tumor. The histology was diagnostic of an adenoma, and immunohistochemical staining was positive for GH and PRL, but not ACTH. Post-op lab results: GH 1.07 ng/ml, IGF-1 353 ng/ml, PRL 9.6 ng/ml, testosterone 41 ng/dL, ACTH 68.2 pg/ml, cortisol 4.5 ug/dL, 24-hr urine free cortisol 8 mcg, HbA1c 5.7%. Discussion The intent of this case presentation is to report the rare finding of a pituitary tumor co-secreting GH, ACTH, and Prolactin. The diagnosis of acromegaly was confirmed by significant elevations of GH and IGF-1. The diagnosis of subclinical Cushing's disease was confirmed by elevated ACTH level, 24-hr urine free cortisol, and failed dexamethasone suppression test. The elevated PRL may have been due to tumor PRL secretion or stalk effect. The reduction of these parameters after surgery corroborated the presence of pleurihormonal secretion. This patient's findings support screening for co-secretion of multiple pituitary hormones in patients with acromegaly. Reference Pleurihormonal ACTH-GH Adenoma: Case Report and Systematic Literature Review World Neurosurg 2018 114: 158-164 Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP061 When cortisol and catecholamines combine in a severe endocrine condition

Abstract Introduction While the majority of ACTH dependent Cushing's Syndrome cases are the result of over secretion of ACTH from the pituitary gland, ectopic ACTH production can occur. Pheochromocytoma, a tumor originating from the adrenal chromaffin cells and classically associated with catecholamine excess, has also been very rarely shown to secrete ACTH. A 54 year old male with a history of obesity, type 2 diabetes, and resistant HTN presented to ED with a tonic clonic seizure, hypoxia and altered mental status. Labs were notable for thrombocytopenia and hypokalemia. His thrombocytopenia was treated with IVIG and solumedrol. Renin activity and renal doppler were normal. He was discharged on additional blood pressure medication, antipsychotics and Keppra. After 2 weeks he was readmitted with hypertensive urgency, anemia and worsening thrombocytopenia. Bone marrow biopsy did not elucidate the etiology of thrombocytopenia. CT abdomen showed a 5.4 cm, 54 Hounsfield unit, right adrenal mass. MRI brain showed no intracranial pathology. MRI abdomen/pelvis showed bilateral adrenal thickening. The right adrenal mass had characteristics of hematoma as well. Additional labs showed urine metanephrines 1412mcg/24Hr and normetanephrines 978mcg/24Hr, Urine free cortisol was 4494 mcg/24h, random serum cortisol was 207mg/dl, and ACTH was 1091 pg/ml. Dexamethasone suppression test cortisol was 151 ug/dL. Interesting the patient lacked cushingoid phenotypical characteristicsexcept for truncal obesity. The patient was placed on doxazosin for alpha blockadeand etomidate drip to control cortisol. The diagnosis of ACTH secreting pheochromocytoma was reaffirmed after both octreoscan and dotatate PET CT showed the presence of somatostatin receptors in the rightadrenal mass. After 14 days with controlling treatment, the patient underwent successful right adrenalectomy. Pathology was notable for a well circumscribed dark brown mass that had replaced the adrenal medulla that stained patchy positive for ACTH and was positive for synaptophysin and chromogranin. Post surgical labs demonstrated cortisol of 26.3ug/dLand ACTH of 7pg/ml. The patient was discharged 14 days after surgery. Discussion and conclusion Pheochromocytomas are rare tumors for which classical features are often absent. Symptoms of palpitations, headache and sweating are only present in 17% of patients. ACTH secreting pheochromocytomas represent 5% of ectopic ACTH syndrome with less than 100 documented cases worldwide. While obesity, hypertension and diabetes are common in our society, this patient's rapid clinical deterioration was the key clue to this rare diagnosis. This case highlights how the decisive actions of a well-coordinated, multidisciplinary team can result in a good outcome for a very challenging and critically ill patient. Presentation: No date and time listed

PSAT041 A Rare Case of Severe Cyclical Cushing Syndrome Due to Ectopic ACTH Secretion by Appendiceal Carcinoid

Abstract Cushing syndrome (CS) secondary to ectopic ACTH secretion (EAS) is rare and accounts for 10% of CS with majority being bronchial or gut neuroendocrine tumors (NETs) and squamous cell lung cancer. There are only a few case reports of EAS due to appendiceal carcinoid. A 24-year-old woman was referred to endocrinology for 60-pound weight gain, acne, hirsutism, generalized weakness, heat intolerance, and hot flashes. She had secondary amenorrhea for 6 months prior to presentation. Family history was significant for bronchial carcinoid in mother. On examination, she had moon facies, wide purple striae on abdomen, hirsutism, dorsocervical and supraclavicular fat pads. She had normal blood pressure. Her laboratory workup showed potassium 3.2 mmol/L (N, 3.5-5.3), urine free cortisol (UFC) 539 mcg/24 hours (N&amp;lt;50), ACTH 54 pg/ml (N, 6-50) and post 1-mg dexamethasone suppression test cortisol 8.8 mcg/dL. CT abdomen revealed a 3-cm enhancing appendiceal mass, enlarged periappendiceal mesenteric lymph nodes and a 4-cm enhancing right hepatic lobe lesion. Ga-68 Dotatate PET/CT confirmed increased radiotracer uptake in appendiceal mass, lymph nodes and hepatic mass. On liver biopsy, pathology showed well differentiated NET Grade 1 and positive ACTH stain. Repeat UFC was 65 mcg/24 hrs and serum cortisol went down to &amp;lt;1 mcg/dL indicating severe cyclical CS. She was referred to surgical oncology for opinion on debulking surgery. Her genetic testing was negative. She was started on Lanreotide. Given severe cyclical CS with extensive tumor burden, she underwent robotic bilateral adrenalectomy with a plan for cytoreductive surgery once she is on physiologic doses of steroids. Appendiceal NET causing Ectopic CS is exceedingly rare. In 20 years’ experience at NIH, there was only one case of appendiceal NET reported. First reported case was in 1971, when CS was cured by resection of an appendiceal carcinoid incidentally detected on laparotomy for adrenalectomy. There are 3 additional case reports in literature of appendiceal carcinoid with ectopic CS. Management can be challenging particularly in patients with metastatic disease. Medical therapy should be individualized, and adrenalectomy should be considered early in patients with uncontrolled CS due to EAS. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Sex Difference in the Association of Osteoporosis and Osteopenia Prevalence in Patients with Adrenal Adenoma and Different Degrees of Cortisol Excess.

Objective Osteoporosis and osteopenia (OS/OP) are frequent in patients with adrenal adenomas associated with cortisol excess (CE). However, the relationship between OS/OP and CE severity considering sex differences is unknown. Design A cross-sectional observational study from January 2006 to December 2015. Patients. 237 patients with adrenal adenoma associated with CE, including Cushing's syndrome and mild autonomous cortisol secretion (MACS), diagnosed in 10 referral centers in Japan. MACS was defined by 1 mg overnight dexamethasone suppression test (DST) cortisol level >1.8 μg/dL. Measurements. Prevalence of fragility fractures, medication for osteoporosis, and bone mineral density. Results In total, 112 of 237 patients, who were predominantly female (P < 0.001) and had lower BMI (P=0.013), had OS/OP. Patients with OS/OP was significantly affected by CE (P < 0.01) than those without. The adjusted odds ratio (OR) for predicting OS/OP was obtained in multivariate logistic regression analysis. Clinical measures of CE, 1 mg DST cortisol levels, were positively associated with OS/OP in total cases (OR 1.124, 95% CI: 1.070–1.181, P < 0.001) and the cases with MACS (OR 1.156, 95%CI: 1.046–1.278, P=0.005). A cutoff value of 1 mg DST cortisol level >5.0 μg/dL was associated with OS/OP differently between men and women. OS/OP risk in men with MACS was significantly affected only by 1 mg DST cortisol levels. However, OS/OP risk in women with MACS was significantly affected by 1 mg DST cortisol levels and age. Conclusions CE severity in adrenal adenoma is positively associated with OS/OP. However, the associated factors of OS/OP in the patients with MACS are different between men and women.

HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes

DNA methylation shifts in Hypothalamic–pituitary–adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level ≥ 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders.

Confirmation of Feasibility of Selective Glucocorticoid Replacement Following Unilateral Adrenalectomy for Hypercortisolism and Primary Aldosteronism

Background: Secondary adrenal insufficiency (AI) can develop following unilateral adrenalectomy (UA) foradrenal-dependent hypercortisolism (HC) and has been reported after UA for primaryaldosteronism (PA). An institutional study previously demonstrated that cosyntropin stimulationtesting on postoperative day 1 (POD1-CST) successfully identified patients who requiredglucocorticoid replacement (GR) following UA; 50% of HC patients required GR and no PApatients required GR. The aim of this study was to reevaluate the need for GR following UA forpatients with HC and PA in a larger cohort of patients. Methods We reviewed 108 patients from a prospectively maintained adrenal database who underwent UAfor HC (n=74), PA (n=22), and concurrent HC/PA (n=12) from 9/2014-10/2020. PA patientswithout preoperative evaluation for HC were excluded. Patients with 1mg dexamethasonesuppression test (DST) cortisol >1.8 (µg/dL) were defined as having mild HC, with ³5 defined asovert Cushing’s Syndrome (CS). All patients underwent our institutional POD1-CST protocoland GR was initiated for patients with basal cortisol £5 or stimulated cortisol £14 (<18 prior to4/2017). Results: Overall, 51 (47%) patients had an abnormal POD1-CST and were discharged on GR (44 HC, 1PA, and 6 HC/PA). Two (2%) patients with CS had a normal POD1-CST but developed AIrequiring GR at 8 and 12 weeks post UA. Of the 74 patients with HC, 44 (59%) had an abnormalPOD1-CST and were discharged on GR, including 19/28 (68%) with CS and 25/46 (54%) withmild HC. Preoperative DST cortisol was higher in HC patients who required GR compared topatients with a normal POD1-CST (4.1 vs 3.6; p=0.007). Median cortisol levels for HC patientswith an abnormal POD1-CST vs those with a normal test were: basal: 3.8 vs 15.6 (p=0.027); 30-minute: 10.1 vs 20.1 (p=0.403); and 60-minute 11.4 vs 22.2 (p=0.260). Of the 22 PA patients, 19(86%) had a normal POD1-CST. Median cortisol levels for PA patients with an abnormal POD1-CST vs those with a normal test were: basal: 0.4 vs 12.1; 30-minute: 8.8 vs 24.6; and 60-minute:12.2 vs 28.9. Of the 3 (14%) PA patients with an abnormal POD1-CST, 1 was dischargedwith GR and began tapering after 2 weeks; the other 2 did not require GR and did not developAI. Of the 12 patients with combined PA/HC, 6 (50%) were discharged on GR based on POD1-CST. GR was required by 30 (59%) patients for <3 months and 82% for <12 months; 7/9 whorequired GR >12 months had CS. Conclusions: Using a standard protocol for POD1-CST in patients who underwent unilateral adrenalectomyfor HC, PA, or combined PA/HC, this study demonstrated that routine GR is not required in 32%of patients with CS and 46% of patients with mild HC. POD1-CST safely identifies patients whowill require GR with no immediate concern for adrenal insufficiency. These data also suggestthat routine evaluation for AI in postoperative PA patients is not needed if cortisol excess hasbeen excluded preoperatively.

An integrated approach to understand biological stress system dysregulation across depressive and anxiety disorders

BackgroundAffective disorders involve dysregulation of major biological stress systems (hypothalamic-pituitary-adrenal (HPA)-axis, immune system, autonomic nervous system (ANS)). Suchdysregulationshave rarely beensimultaneously examined across different stress systems. MethodsIn the Netherlands Study of Depression and Anxiety (n=2789), we investigated whether current or remitted depressive and/or anxiety disorders (based on the CIDI semi-structured interview), including specific symptom profiles, were associated with separate markers and cumulative indexes of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), immune system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period). ResultsDepressive andanxiety disorderswere significantlyassociated with changes in three biological stress systemsincluding HPA-axis hyperactivity, increased inflammatory activity, and a higher ANS tone, particularly for integrative and cumulative indexes of these stress systems (pFDR <.05) vs. controls. The strongest associations were seen with current disorders andcumulative indexes of the HPA-axis (β=.124, pFDR=.001), the immune system (β =.057, pFDR=.032), and total cumulative index across stress systems (β=.102, pFDR=.004). Atypical, energy-related depression severity was linked to immune system markers (pFDR<0.001), melancholic depression severity to HPA-axis markers (pFDR=.032), and anxiety arousal severity to both HPA-axis and immune system markers (pFDR<0.05). Findings were partially explained by poorer lifestyle, more chronic diseases,or (especially for ANS-function) antidepressant use. LimitationsCross-sectional analyses limit examination of temporal associations. ConclusionPatients withdepressive and anxiety disorders showed consistent dysregulation across biological stress systems, particularly for current episodes.To understand stress system functionality in affective disorders, an integrated approach capturing cumulative stress indices within and across biological stress systems is important.

Childhood trauma and dysregulation of multiple biological stress systems in adulthood: Results from the Netherlands Study of Depression and Anxiety (NESDA)

BackgroundChildhood trauma (CT) is a risk factor for depressive and anxiety disorders. Although dysregulated biological stress systems may underlie the enduring effect of CT, the relation between CT and separate and cumulative activity of the major stress systems, namely, the hypothalamic-pituitary-adrenal (HPA)-axis, the immune-inflammatory system, and the autonomic nervous system (ANS), remains inconclusive. MethodsIn the Netherlands Study of Depression and Anxiety (NESDA, n = 2778), we determined whether self-reported CT (as assessed by the Childhood Trauma Interview) was associated with separate and cumulative markers of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), the immune-inflammatory system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period) in adulthood. ResultsAlmost all individuals with CT (n = 1330) had either current or remitted depressive and/or anxiety disorder (88.6%). Total-sample analyses showed little evidence for CT being significantly associated with the separate or cumulative stress systems’ activity in adulthood. These findings were true for individuals with and without depressive and/or anxiety disorders. To maximize contrast, individuals with severe CT were compared to healthy controls without CT. This yielded slight, but significantly higher levels of cortisol awakening response (AUCg, β = .088, p = .007; AUCi, β = .084, p = .010), cumulative HPA-axis markers (β = .115, p = .001), C-reactive protein (β = .055, p = .032), interleukin-6 (β = .053, p = .038), cumulative inflammation (β = .060, p = .020), and cumulative markers across all systems (β = .125, p = .0003) for those with severe CT, partially explained by higher rates of smoking, body mass index, and chronic diseases. ConclusionWhile our findings do not provide conclusive evidence on CT directly dysregulating stress systems, individuals with severe CT showed slight indications of dysregulations, partially explained by an unhealthy lifestyle and poorer health.

MON-169 Diagnostic Utility of Free Cortisol in Dexamethasone Suppression Test. A Prospective Study in Healthy Subjects

OBJECTIVE: Low dose dexamethasone suppression testing (DST) is standard of care in patients with adrenal incidentalomas or suspected endogenous hypercortisolism. False positive total serum cortisol (TC) results occur due to poor absorption, rapid metabolism or estrogen use. Free serum cortisol (FC) measurement is an alternative, but optimal cut-offs are unknown. We aimed to establish the optimal serum dexamethasone concentrations (DEXA) to interpret TC and FC results and identify reasons for discrepancies between TC and FC values in healthy male and female (with and without oral contraceptive therapy, OCT) subjects. METHODS: Single center prospective study of healthy subjects >17 years old undergoing assessment with DST between 2016 and 2019. Measurement of FC and DEXA was performed by tandem mass spectrometry and TC by immune-enzymatic assay at 8 AM following overnight administration of 1 mg dexamethasone at 11pm. Subjects were excluded if they had a known adrenal adenoma, any form of endogenous cortisol excess, or exogenous steroid use. RESULTS: DST was performed in 165 healthy volunteers, median age of 29.5 (18-74) years; 53 men (32%) and 112 (67%) women, median BMI 25 (18-42) kg/m2, 47 (42%) of which were taking OCT (median daily ethinyl-estradiol dose of 30 (20-35) mcg). The median DEXA was 0.34 (0.09-1.12) mcg/dl, median TC was 0.8 (0.25-15.7) mcg/dl and median FC was 24 (4-714) ng/ml. TC and FC measurements were highly correlated (r2=0.89, p<0.0001). The median FC/TC was 3% (0.3-6.7), lowest in women on OCT (median 2.5% vs 3.3% in women not on OCT and men, p<0.0001). TC>1.8 mcg/dl was demonstrated in 18 (11%) healthy subjects (men: 3/53, 5.7% vs women not on OCT: 3/65, 4.6% and women on OCT: 12/47, 25.5%, p=0.0007). Excluding women on OCT, the proportion of subjects with TC>1.8 was higher when DEXA was <0.2mcg/dl (4/15, 27%) vs when DEXA was >0.2mcg/dl (2/101, 2%),(p<0.0001). After excluding 24 (14%) healthy subjects with DEXA <0.2 mcg/dl, in the remaining 142 subjects (51 (35%) men, 54 (38%) women not on OCT and 39 (27%) women on OCT), median TC was 0.75 (0.25-4.6) mcg/dl and median FC was 23 (4-103) ng/ml). Significant differences were noted in both TC and FC following DST within subgroups: men vs women not on OCT vs women on OCT, TC: 0.6 vs 0.7 vs 1.3 mcg/dl, (p<0.0001) and FC: median 20 vs 22 vs 31 ng/ml, (p<0.0001). All men and all women not on OCT demonstrated post-DST FC <50 ng/ml (97.5% cutoff of 47 and 37), while women on OCT demonstrated post-DST FC <50 in 80% and FC<75 in 95%. CONCLUSION: Post-DST TC>1.8 mcg/dl was demonstrated in 11% of all healthy subjects, of which 1 in 4 were women on OCT and 1 in 4 had DEXA<0.2 mcg/dl. Simultaneous measurement of serum DEXA during DST may be valuable when false positive results are suspected. Despite a lower FC/TC ratio in women on OCT, post-DST FC cutoffs were higher in women on OCT. Measurement of FC after DST may be helpful in some but not all women on OCT.

Serum cortisol level after low dose dexamethasone suppression test may be predictive for diabetes mellitus and hypertension presence in obese patients: A retrospective study

AimsObesity, a remarkably increased healthcare problem, accompanies with morbidities including type 2 diabetes mellitus (DM), hypertension, and cardiovascular diseases. Hypothalamic-pituitary-adrenal (HPA) axis alteration is thought to be effective on the background of obesity, even concomitant with DM and hypertension. We aimed to evaluate the negative feedback mechanism of the HPA axis via overnight 1 mg dexamethasone suppression test (DST) and the association of post-1 mg DST cortisol level with DM and hypertension presence in obesity. MethodsThis study consisted of 402 obese patients who provide suppression after DST. Post-1 mg DST cortisol level and its association with other variables including anthropometric measurements, laboratory test results, hypertension, prediabetes, and DM presence were evaluated. Predictivity of post-1 mg DST for hypertension and DM was investigated. ResultsWe established a significant difference in post-1 mg DST cortisol level when compared patients with and without DM, patients without DM and with prediabetes, patients with prediabetes and DM (p < 0.001 vs. p = 0.003 vs. p = 0.022 respectively). Post-1 mg DST cortisol level was significantly higher in hypertensive patients (p < 0.001). Post-1 mg DST cortisol level had positive correlation with age (r = 0.319, p < 0.001), fasting plasma glucose (r = 0.168, p = 0.001), and HbA1c (r = 0.278, p < 0.001) levels. Logistic regression analyses demonstrated that post-1 mg DST cortisol level is an independent predictor of DM and hypertension presence. ConclusionCortisol negative feedback mechanism may be altered in obese patients who are complicated with hypertension and DM. Therefore, post-1 mg DST cortisol level can be predictive for hypertension and DM presence in obesity.

SUN-379 Transformation of Adrenal Adenoma into Adrenocortical Carcinoma in a Cushing Syndrome Patient after Surgery

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with annual incidence of 0.5-2.0 cases/million. More unusual is transformation of benign adrenal adenoma to ACC after complete resection. Clinical case: A 72 year old woman with prior history of presumed nonfunctional left (L) adrenal adenoma presented with Cushing’s Syndrome (CS) in 2016. Imaging showed increase in size of her L adrenal adenoma from 1.5 cm in 2007 to 3.7 cm in 2016. On CT, it had a 1.6 X1.3 cm internal hypodense component, -15 Hounsfield units (HU), and surrounding solid component 78 HU on portal venous phase with 42% relative washout. Biochemical testing suggested ACTH-independent CS: elevated cortisol 33.79 ug/dL (4.30-22.40ug/dL), abnormal 1 mg dexamethasone suppression test (DST) cortisol 33.59 ug/dL (4.30-22.40ug/dL), ACTH undetectable <5 pg/mL (7.2-63 pg/mL), low-dose 48hr DST cortisol 37.21 ug/dL (4.30-22.40 ug/dL), normal metanephrine < 0.20 nmol/L (<0.50 nmol/L), normal normetanephrine 0.41 nmol/L (<0.90 nmol/L), aldosterone < 4.0 ng/dL (n < 21 ng/dL). She underwent uncomplicated robotic resection of the adenoma. Surgical pathology was consistent with benign adenoma, Weiss Score = 2 - mitotic rate 12/50 HPF; more than 33% diffuse architecture. She recovered well and weaned off hydrocortisone. In February 2018 she developed recurrent symptoms of CS. Repeat tests showed midnight salivary cortisol 1250 ng/dL (n <100 ng/dL), AM cortisol 39.7 ug/dL (4.30-22.40ug/dL), DHEA-S 205 (<15 - 157 mcg/dL), ACTH <5 pg/mL (7.2-63 pg/mL). Repeat MRI showed large lobulated heterogeneous L adrenal mass increased in size compared to prior despite interval resection- overall size 6.8 x 4.1 x 5.9 cm, with new scattered enhancing nodules superior & posterior to L kidney. She was again referred for surgical resection with high suspicion of conversion to ACC. She had repeat robotic resection with conversion to open L adrenalectomy and L nephrectomy, splenectomy, partial pancreatectomy, and resection of a small piece of the diaphragm. Repeat surgical pathology showed metastatic ACC with metastases to the diaphragm, omentum, perinephric and perisplenic adipose tissue, and positive margins. Post-operatively she has been treated with mitotane, cisplatin, etoposide, and doxorubicin. She is currently on mitotane therapy alone due to cardiotoxicity from her chemotherapy. Conclusion: This is an uncommon case of transformation of benign adrenal adenoma to metastatic ACC. This highlights the uncertainties regarding postoperative follow-up of adrenal adenomas and the potential need for continued surveillance post-resection. Reference: Fareau GG, et al. Diagnostic challenges in adrenocortical carcinoma: recommendations for surveillance after surgical resection of selected adrenal nodules. Endocr Pract. 2007, Oct; 13(6):636-41

Which type 2 diabetes mellitus patients should be screened for subclinical Cushing's syndrome?

Diabetes or impaired glucose tolerance are common in patients with Cushing's syndrome (CS). In this study we investigated the incidence of subclinical Cushing's syndrome (SCS) in type 2 diabetic patients with poor and good metabolic control and the relationship between blood glucose and cortisol levels. A total of 400 type 2 diabetes mellitus (T2DM) patients (Group A, HbA1c ≥8%, n=250; Group B, HbA1c ≤6.5%, n=150) were included in the study. Biochemical tests followed by the 1 mg dexamethasone suppression test (DST) were performed. If post-DST cortisol levels were above 1.8 μg/dl (non-suppressed group), the 2 mg DST test was performed for 2 days. Among the patients, post-DST cortisol of at least 1.8 μg/dL and midnight serum cortisol levels of at least 7.5 μg/dL confirmed the diagnosis of CS. While SCS was observed in 5 patients (2%) in Group A, no case was observed in group B. There was a statistically significant difference between groups for basal cortisol and post-DST cortisol results (p<0.001 and p<0.001, respectively). Microvascular complication rates were higher in the non-suppressed group (p=0.007). Post-DST cortisol levels had a positive correlation with the number of complications and HbA1c levels (respectively r=0.213, p<0.001, and r=0.191, p<0.001). Multivariate regression analysis revealed that durations of DM, HbA1c level, and post 1 mg DST cortisol levels were associated with the number of complications. This study shows the presence of SCS in a notable number in T2DM patients having poor metabolic control. Screening with 1 mg and 2 mg DST of T2DM patients with poor metabolic control who are also obese and hypertensive and have microvascular complications may be an appropriate method for detection of SCS.

Comparison of efficacy between the serum cortisol and 24 hour urine free cortisol in combined dexamethasone suppression test in the diagnosis of Cushing syndrome

To compare the sensitivity and specificity between the 24 hour urine free cortisol (24 h UFC) and serum cortisol in dexamethasone suppression test (DST) in the diagnosis of Cushing syndrome (CS). Combined low dose DST (LDDST) and high dose DST (HDDST) were carried out in 67 cases of CS with surgically confirmed cases in recent 3 years(from January 2011 to November 2015). The serum cortisol and 24 h UFC were collected simultaneously for each subject and the sensitivity and specificity of serum cortisol and 24 h UFC were compared. There were Cushing disease (CD) group (n=53), ectopic adrenocorticotropic hormone (ACTH) syndrome group (n=7) and ACTH-independent Cushing syndrome group (n=7) according to the etiology of hypercorticordism.There were no significant differences among 3 groups in gender and age.The sensitivity of serum cortisol of different cut off points(50, 110, 140 nmol/L and 50% of control)after LDDST was 97.01%, 86.57%, 83.58% and 70.15% respectively.Meanwhile, the sensitivity of cutoff point of 24 h UFC <32 nmol in combined LDDST was 92.54% in the diagnosis of Cushing syndrome.There was no significant differences in two groups between serum cortisol <110 nmol/L and 24 h UFC <32 nmol.However, the sensitivity of serum cortisol <50 nmol/L was significantly higher than 24 h UFC<32 nmol (P<0.05). Furthermore, in combined HDDST, if the suppression rate was ≥50%, the sensitivity of serum cortisol and 24 h UFC in differentiating the etiology of Cushing disease was 60.38% and 90.57%, and the specificity was 91.43% and 96.00% respectively.There were significant differences between serum cortisol and 24 h UFC in both of sensitivity and specificity (both P<0.05). In addition, if the suppression rate of 24 h UFC in HDDST was adjusted to 60.85% according to receiver operating characteristic (ROC) curve, it could have the best levels of sensitivity (92.6%) with the specificity of 85.7%. If the suppression rate of serum cortisol was adjusted to 61.53% in HDDST according to ROC curve, it could have the best sensitivity (64.8%) with the specificity of 78.6% accordingly. In combined LDDST, the serum cortisol <50 nmol/L had a higher sensitivity than the 24 h UFC<32 nmol when they were used as the criteria in determining the diagnosis of CS.In HDDST, the sensitivity and specificity of suppression rate of 24 h UFC ≥50% were better than serum cortisol to differentiate the etiology of CS.

Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors

Intergenerational effects of trauma have been observed clinically in a wide range of populations, and parental PTSD has been associated with an increased risk for psychopathology in offspring. In studies of Holocaust survivor offspring, parental PTSD, and particularly maternal PTSD, has been associated with increased risk for PTSD, low basal urinary cortisol excretion and enhanced cortisol suppression in response to dexamethasone. Such findings implicate maternally derived glucocorticoid programming in the intergenerational transmission of trauma-related consequences, potentially resulting from in utero influences or early life experiences. This study investigated the relative influence of Holocaust exposure and PTSD in mothers and fathers on glucocorticoid sensitivity in offspring. Eighty Holocaust offspring and 15 offspring of non-exposed Jewish parents completed evaluations and provided blood and urine samples. Glucocorticoid sensitivity was evaluated using the lysozyme suppression test (LST), an in vitro measure of glucocorticoid receptor sensitivity in a peripheral tissue, the dexamethasone suppression test (DST), and 24-h urinary cortisol excretion. Maternal PTSD was associated with greater glucocorticoid sensitivity in offspring across all three measures of glucocorticoid function. An interaction of maternal and paternal PTSD on the DST and 24-h urinary cortisol showed an effect of decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. Although indirect, these findings are consistent with the hypothesis that epigenetic programming may be involved in the intergenerational transmission of trauma-related effects on glucocorticoid regulation.