post-DST Cortisol Research Articles

Impact of Cortisol-Cosecretion on Adrenal Venous Sampling Results in Primary Aldosteronism: Study of 225 Cases

Background/Objectives: Mild autonomous cortisol secretion (MACS) can coexist with primary aldosteronism (PA). The purpose of our study was to evaluate whether (MACS) influences parameters analyzed during adrenal venous sampling (AVS) in patients with PA. Methods: Patients with PA from the SPAIN-ALDO Registry and the German Conn’s Registry with available 1 mg-dexamethasone suppression test (DST) and AVS were included. MACS was defined as a post-DST cortisol > 1.8 µg/dL in the absence of specific signs and symptoms of Cushing’s syndrome. Results: Two-hundred and twenty-five patients were included, 98 (43.6%) of whom had concomitant MACS. The mean age was 54 ± 10 years and 37.3% were women. AVS was performed by simultaneous catheterization of both adrenal veins and analysis of basal samples in 157 patients (69.8%), with both basal and post-ACTH samples in 15 patients (6.7%), and during continuous ACTH infusion in 53 patients (23.6%). AVS was considered technically unsuccessful in 40 cases (17.8%), suggesting unilateral secretion in 106 (47.1%) and bilateral secretion in 79 (35.1%). We did not find significant differences in the percentage of unilateral and bilateral results, cortisol, corrected aldosterone, or selectivity indices in the dominant and non-dominant veins, nor in the lateralization index or the contralateral suppression index between patients with and without MACS. They also had similar rates of surgical treatment and biochemical and clinical response. Conclusions: Although pathophysiological reasoning suggests that MACS could hinder AVS identification of unilateral forms of PA, our data suggest that such interference, if it exists, is of moderate clinical relevance.

6419 Cushing’s Syndrome due to Metastatic Pancreatic Neuroendocrine Neoplasm With Incidental Pituitary Microadenoma

Abstract Disclosure: A. Ibrahim: None. L. Esper: None. R. Jain: None. N. El Asmar: None. Introduction: Pancreatic neuroendocrine neoplasms (PNENs) are rare with a reported incidence of 1-2/100,000. While the majority are non-functional, insulinomas and gastrinomas are the most common functional PNENs. Our case of ACTH-producing PNENs is extremely rare. Case presentation: A previously healthy 47-year-old female was hospitalized for worsening dyspnea. Her symptoms included rapid weight gain, skin hyperpigmentation, and lower extremity edema. Her exam was notable for elevated blood pressure of 181/120 mmHg, moon facies, purple abdominal striae, and proximal myopathy. Her lab analysis showed a cortisol level of 42 mcg/dL (6.2-19.4), ACTH of 254 pg/ml (7.2-63), DHEA sulfate of 171 mcg/dl (41-243), HbA1C 7%, K of 3 mmol/l and 24H urine cortisol >2100 mcg/24hrs. A post low-dose DST cortisol level was 42.7 mcg/dl. CT chest demonstrated an ill-defined hypodense lesion in the region of the pancreatic head. MRI abdomen revealed a 3 x 2.3 x 2.3 cm mass in the pancreatic head and many small enhancing lesions within the right lobe of the liver. Adrenal glands appeared normal. Subsequent PET CT scan with GA 68 DOTOTATE showed increased uptake in the pancreatic head mass and in the right hepatic lobe. Her pituitary MRI revealed a right pituitary gland 6 mm hypointense lesion, possibly a microadenoma. A high dose DST resulted in a cortisol level of 80 mcg/dl mostly consistent with ectopic ACTH secretion. EUS-guided biopsy of the pancreatic mass showed a well-differentiated neuroendocrine tumor that stained positive for ACTH, chromogranin, synaptophysin, and CD56. Treatment with Ketoconazole 600mg q6h and Octreotide 50mg q6h was started 3 days before surgery to control acute hypercortisolism as she developed acute psychosis. The patient subsequently underwent a Whipple procedure with successful resection of the pancreatic mass. Post-op, her ACTH levels dropped to 19 pg/ml with a cortisol level of 6 mcg/dl. Final pathology showed a well-differentiated grade 3 neuroendocrine tumor with a KI-67 labeling index greater than 20%. After surgery, the patient received a short course of stress dose hydrocortisone which was tapered off over the following 2 months. The patient is being followed for planning further intervention given the aggressive grade of the tumor and hepatic metastases. Conclusion: Ectopic ACTH-producing PNENs are rare. An accurate and timely diagnosis, while challenging, is key. Patients usually present with rapidly progressing symptoms that could cause life-threatening complications such as thrombosis and sepsis. We demonstrated the importance of utilizing a multidisciplinary team approach and starting cortisol-lowering medications early given the complexity of the disease, requiring rapid intervention and lifelong follow-up. Presentation: 6/3/2024

8740 Visceral Adipose Tissue Assessment in Patients With Mild Autonomous Cortisol Secretion Using Dual-Energy X-Ray Absorptiometry: A Cross-Sectional Study

Abstract Disclosure: J. Saini: None. C.D. Zhang: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Several studies employing computed tomography (CT) scans for body composition measurements have reported lower muscle mass and a higher proportion of visceral fat in patients with mild autonomous cortisol secretion (MACS) compared to referent subjects. While a CT scan assesses visceral adipose tissue (VAT) at a single slice level (L3), no studies have evaluated the overall VAT in patients with MACS using Dual-Energy X-ray absorptiometry (DXA). Objective: To determine the impact of MACS on VAT using DXA scan as compared to referent subjects. Methods: We conducted a single-center cross-sectional study of adults with 75 MACS and 75 referent subjects. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test in patients with adrenal adenomas and no features of overt hypercortisolism. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. All the participants underwent a full body DXA scan between 04/2019 and 07/2022. We applied the CoreScan software to estimate the (1) total lean and fat mass (2) visceral fat mass and volume (3) lean android, fat android, and android mass, and compared measurements of patients and referent subjects using linear regression models adjusted for sex and BMI. Results: A total of 75 patients with MACS (median age 57.0 years, IQR 47.8-65.6, 67% women) and 75 referent subjects (median age 57.6 years, IQR 49.1-65.8, 67% women) were included. Patients had a higher BMI compared to referent subjects (median 31.7 kg/m2, IQR 27.4-37.9 vs 28.7, IQR, 25.4-33.8, P=0.004). The median post-DST cortisol in patients was 3.1 mcg/dL (IQR, 2.2-5.2). When compared to referent subjects, and after adjustment for sex and BMI, patients had a similar total body fat (estimate=846, p-value=0.28) and lean mass (estimate=-201, p-value=0.83), similar android fat mass (estimate=59, p-value=0.64) but lower gynoid fat mass (estimate=400, 0.007). Notably, sex and BMI-adjusted analysis also showed that patients had a higher VAT fat mass (estimate= -225, p-value=0.084) and a higher VAT fat mass/total mass ratio (estimate= -0.007, p-value=0.026). Conclusions: When adjusted for BMI and sex, patients with MACS do not demonstrate differences in overall fat and lean mass. However, we showed that MACS is associated with increased visceral adiposity, a known cardiovascular risk factor. Body composition assessment by DXA could be a safer and less expensive alternative in the evaluation and follow-up of patients with MACS. Presentation: 6/2/2024

12430 Urine Steroid Profiling In Patients With Unilateral And Bilateral Mild Autonomous Cortisol Secretion

Abstract Disclosure: B. Salama: None. J. Saini: None. V. Fell: None. E.J. Atkinson: None. S.J. Achenbach: None. Background: Mildly autonomous cortisol secretion (MACS) can be unilateral in 80% of cases, or bilateral in 20% of cases, due to either bilateral adrenal adenomas or bilateral macronodular adrenal hyperplasia. Scarce evidence demonstrates the differences in plasma steroid profiling of patients with bilateral versus unilateral MACS, however, these findings have not been confirmed using a more comprehensive 24h urine steroid profiling. Objectives: To characterize 24h urine steroid metabolome in patients with unilateral and bilateral MACS. Methods: We conducted a single-center cross-sectional study between 2019-2022. Eligible participants included consecutive patients with MACS who provided a 24h urine sample. Urine was analyzed for 25 steroids with a high-resolution mass spectrometry assay. MACS was defined as cortisol >1.8 mcg/dL following the overnight administration of 1 mg dexamethasone (DST-cortisol). Partial cohort analysis is presented. Results: Of 72 patients with MACS included in the interim analysis, 36 (50%) had bilateral MACS. The two groups (unilateral vs bilateral) were similar in age (median 58 vs 58 years), sex (women 67% vs 61%), BMI (median 33 vs 32 kg/m2), and menopausal status (36% vs 39%), P>0.05 for all. Prevalence of comorbidities was also similar in both groups: hypertension (89% vs 89%), hyperlipidemia (69% vs 78%), and hyperglycemia (69% vs 61%), P >0.05 for all. While the DST-cortisol (median 3.0 vs 3.2 mcg/dL, P= 0.51) and dehydroepiandrosterone sulfate (DHEAS) (median 37.5 vs 55.0, P = 0.21) were similar between the 2 groups, patients with bilateral MACS had a lower ACTH (median 12.4 vs 8.2 pg/mL, P = 0.012) when compared to patients with unilateral MACS. Median adrenal mass size was similar in patients with both unilateral MACS (2.7 cm, IQR 1.7-3.9) and bilateral MACS (3.0 cm, IQR 2.2-3.6) P = 0.54. Of the 25 steroids measured, only tetrahydrocorticosterone was higher in patients with unilateral MACS (median 245 mcg/24h, IQR 165-416 vs median 184 mcg/24h, IQR 121 -278) P = 0.039. No differences in androgens (median 2229 vs 2036 mcg/24h), cortisol metabolites (median 6566 vs 5191 mcg/24h), cortisone metabolites (median 10300 vs 9429 mcg/24h), or glucocorticoid/androgen ratio (median 7.9 vs 8.9) was demonstrated between the unilateral vs bilateral MACS groups (P>0.05 for all). Conclusion: In this interim analysis of patients with unilateral vs bilateral MACS, we have found that patients had a similar post-DST cortisol and similar tumor bulk. Despite a lower ACTH in patients with bilateral MACS, no differences in androgens were found between the two groups. In addition to expanding steroid profiling analysis to the whole cohort, subgroup analyses will need to distinguish between patients with bilateral adenomas and macronodular adrenal hyperplasia, consider aldosterone co-secretion, and employ a more accurate measurement of adrenal tumor bulk. Presentation: 6/3/2024

12376 Comparison Of 1 Mg Versus 2 Mg Dexamethasone Suppression In Obesity

Abstract Disclosure: H. Babu: None. A. Nawaz: None. A.J. Spiro: None. T.D. Hoang: None. M.K. Shakir: None. The overnight 1 mg dexamethasone suppression test (DST) is widely used to screen for Cushing’s Syndrome (CS), especially due to its low incidence of false negative results. Serum cortisol concentrations <1.8 µg/dL suggests adequate HPA axis suppression and usually excludes CS. Concentrations >1.8 µg/dL should be verified with a second test. However, the lack of suppression on DST has been documented previously in 1.46% to 15% of obese patients without CS. Previous studies have suggested simultaneous measurements of serum cortisol, ACTH, and dexamethasone levels after DST to ensure adequate suppression. In this retrospective analysis, we compared the plasma levels of ACTH, dexamethasone, and cortisol levels after 1 mg and 2 mg DST in healthy obese (class III) subjects. The study involved 6 subjects (2 males, 4 females, age 37.5 ± 8.79 years, BMI 43.65 ± 3.12 (kg/m2) who were referred for evaluation of abnormal weight gain. Exclusion criteria for these subjects included diabetes mellitus, pregnancy, history of CS, psychiatric disorders, chronic liver disease, chronic renal failure, malabsorption disorders and nephrotic syndrome. The exclusion of CS was done by history and physical examination showing the lack of specific clinical features of CS. Additionally, none of the subjects were taking drugs that interfered with CYP3A4 or oral contraceptives within 3 months preceding the study. None of the participants reported alcohol consumption of more than 30 g per day. Screening tests for CS involved 1 mg, 2 mg DST, LNSC and 24-hour urine cortisol levels. Results: Following 1 mg DST in 5 subjects, the mean serum cortisol levels were 1.35 ± 0.13 mcg/dL and the mean serum dexamethasone levels, and ACTH levels were 282 ± 44 ng/dL and 5.92 ± 1.56 pg/mL, respectively. However, in one subject (BMI 43.5) the post-DST cortisol level was 2.96 mcg/dL with corresponding dexamethasone level of 138 ng/dL and ACTH level of 21 pg/mL. However, following 2 mg DST in all 6 subjects the serum cortisol levels were less than 1.8 mcg/dL (1.21± 0.22 mcg/dL) with ACTH levels (3.87 ± 0.70 pg/mL) and dexamethasone levels of 482 ± 80 ng/dL. The LNSC levels were normal in 4 subjects (0.010 ± 0.005 mcg/dL), whereas in 2 subjects these were minimally elevated. 24-hour urine cortisol levels were normal in 5 subjects (29.4 ± 3.74 mcg) and in one subject this was mildly elevated (67 mcg). Long term follow-up of all subjects confirmed normal cortisol status. Previous studies have demonstrated that routine CS screening of patients affected by severe obesity is not indicated. However, other investigations have shown CS may occur in a small percentage of severe obese patients. In conclusion, 2 mg DST is a preferred test in obese patients suspected to have CS although 1 mg DST generally can be used as an initial screening test. Additionally, serum dexamethasone and ACTH measurements may still be useful in patients who are suspected to have a false-positive DST. Presentation: 6/1/2024

Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone

IntroductionEven with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies...

Effect of intermittent theta-burst stimulation on the thyroid and adrenal systems in resistant depressed patients

IntroductionDisturbances in the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axes have been frequently reported in treatment resistant depressed patients (TRDs). So far, the effects of intermittent theta-burst stimulation (iTBS) treatment—a form of repetitive transcranial magnetic stimulation (rTMS) technique—on the activity of the HPT and HPA axes are poorly understood.ObjectivesThe present study aimed to evaluate the effects of iTBS sessions, applied to the left dorsolateral prefrontal cortex, in TRDs with abnormal chronobiological HPT functioning at baseline (BL) possibly associated with hypercortisolemia.MethodsThe ∆∆TSH test (i.e., the difference between the thyrotropin response to protirelin tests [∆TSH] performed at 8 AM and 11 PM on the same day) and the dexamethasone suppression test (DST) were performed in 12 TRDs and 14 healthy hospitalized control subjects (HCs). To be enrolled in this study, patients had to show at BL reduced ∆∆TSH values (i.e., < 2.5 mU/L) and a score of 18 or greater on the 17-item Hamilton Rating Scale for Depression (HAMD-17). Post-DST cortisol maximum (CORmax) serum level in excess of 120 nmol/L defined DST non-suppression (i.e., hypercortisolemia)—6 TRDs were DST non-suppressors at BL. After 10 and 20 iTBS sessions the ∆∆TSH test and the DST were repeated in all inpatients. A positive clinical response was defined by a final HAMD-17 score ≤ 8.ResultsCompared to HCs, ∆∆TSH values were lower in TRDs at BL (p < 0.00001), and remained reduced after 10 and 20 iTBS sessions (p < 0.001 and p < 0.02 respectively). Post-DST CORmax levels were higher in TRDs than in HCs at BL (p < 0.01), but were comparable to those of HCs after 10 and 20 iTBS sessions. Responders (n = 5) were characterized by 1) a normalization of their ∆∆TSH values after 20 iTBS sessions (whereas after 10 iTBS sessions ∆∆TSH values were still reduced compared to HCs [p < 0.05]), and 2) a normality of post-DST CORmax levels at BL—while after 10 and 20 iTBS sessions post-DST CORmax levels were decreased compared to HCs (p < 0.006 and p < 0.03 respectively). Non-responders (n = 7) showed 1) no significant change in their ∆∆TSH values which remained lower than those of HCs at each assessment (all p < 0.001), 2) while increased post-DST CORmax levels found at BL (p < 0.0008 vs. HCs) normalized from the 10th iTBS session.ConclusionsThe present pilot study suggests that successful iTBS treatment can restore the chronobiological activity of the HPT axis. Although iTBS may increase glucocorticoid receptor signaling, baseline hypercortisolemia could negatively impact subsequent response to iTBS treatment.Disclosure of InterestNone Declared

Hypothalamic-pituitary-adrenal axis hyperactivity is normalized after successful intermittent theta-burst stimulation in resistant depressed patients

The present pilot study assessed the effects of multi-session intermittent theta-burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex in 17 treatment resistant depressed inpatients (TRDs) showing cortisol non-suppression to the overnight dexamethasone suppression test (DST) at baseline (i.e., maximum post-DST cortisol [CORmax] level > 130 nmol/L). After 20 iTBS sessions, the DST was repeated in all TRDs. At baseline, post-DST CORmax levels were higher in TRDs compared to healthy control subjects (HCs; n = 17) (p < 0.0001). After 20 iTBS sessions, post-DST CORmax levels decreased from baseline (p < 0.03) and were comparable to HCs. Decreases in post-DST CORmax levels were related to decreases in 17-item Hamilton Depression Rating Scale (HAMD-17) scores (ρ = 0.53; p < 0.03). At endpoint, 10 TRDs showed DST normalization (among them 7 were responders [i.e., HAMD-17 total score > 50% decrease from baseline]), and 7 did not normalize their DST (among them 6 were non-responders) (p < 0.05). Our results suggest that successful iTBS treatment may restore normal glucocorticoid receptor feedback inhibition at the pituitary level.

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

FRI184 Impact Of Adrenalectomy On Cognition In Patients With Mild Autonomous Cortisol Secretion

Abstract Disclosure: J. Saini: None. R. Nathani: None. C. Zhang: None. M. Suresh: None. K. Thangamuthu: None. S. Singh: None. V. Fell: None. E.J. Atkinson: None. S. Achenbach: None. N.H. Stricker: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have impaired cognition compared to patients with non-functioning adrenal adenomas. However, the impact of adrenalectomy on cognitive function in patients with MACS is unclear. Objective: To determine the impact of adrenalectomy on cognitive function in patients with MACS. Methods: Single-center prospective longitudinal study of adults with MACS. MACS was defined as serum cortisol &amp;gt;1.8 mcg/dL after the 1 mg dexamethasone suppression test (DST) in patients with adrenal adenomas without any overt features of hypercortisolism. Patients underwent cognitive evaluation using the standardized National Institute of Health (NIH) Toolbox Cognition Battery (7 tests of attention, episodic and working memory, language, executive function, cognitive flexibility, and processing speed) prior to adrenalectomy and at follow-up at least 10 months post-surgery. Fully corrected T-scores for age, sex, education, and race were compared using a paired t-test before and after adrenalectomy. A T-score of 50 is average performance (SD of 10). Total cognition is composite of fluid cognition (executive function, episodic memory, cognitive flexibility, working memory and processing speed) and crystallized cognition (language and vocabulary). Results: A total of 27 patients with MACS (median age 59.7 years, IQR 51.4-66.9, 17, 63% women) underwent cognitive evaluation prior to and at a median of 1.5 years (IQR, 1.1- 2.0) after adrenalectomy. Before surgery, median post-DST cortisol was 3.8 mcg/dL (IQR, 2.7-6.4) mcg/dL. Of the 27 patients, 21 (78%) patients developed post-operative adrenal insufficiency with 6 (21%) patients still requiring still requiring glucocorticoid replacement at the time of the last follow-up. At baseline, the mean total composite T-score was 50.7 (9.3), with fluid composite T-score of 49.9 (9.4) and crystallized composite T-score of 51.3 (8.7). Following adrenalectomy, all three composite T-scores improved compared to baseline. The crystallized composite T-score (composed of language and vocabulary) increased by a mean of 3.7 (5.5), P=0.001, the fluid composite T-score (composed of episodic, executive, working memory, cognitive flexibility, and processing speed) increased by a mean of 3.1 (8.3), P=0.068, and the total composite T-score improved by a mean of 3.9 (6.2), P=0.004. Conclusion: We showed that adrenalectomy in patients with MACS is associated with improvement in cognition. However, as test results may improve with practice (i.e., improvement due to taking the test the second time), to determine whether the improvements observed represent a reliable change in cognition, the next step is to evaluate for cognition score changes in referent subjects. Presentation: Friday, June 16, 2023

Management of Adrenal Cortical Adenomas: Assessment of Bone Status in Patients with (Non-Functioning) Adrenal Incidentalomas

Our aim is to analyse the bone profile in adults with (non-functioning) adrenal incidentalomas (AIs), specifically addressing the impact of autonomous cortisol secretion (ACS). This narrative review, based on a PubMed search from inception to February 2023 (case reports, non-ACS, and other secondary causes of osteoporosis were excluded), included 40 original studies, a total of 3046 patients with female prevalence (female:male ratio of 1921:1125), aged between 20.5 and 95.5 years old. This three decade-based analysis showed that 37 studies provided dual-energy X-ray absorptiometry (DXA) information; another five studies reports results on bone micro-architecture, including trabecular bone score (TBS), spinal deformity index, and high-resolution peripheral quantitative computed tomography; 20 cohorts included data on bone turnover markers (BTMs), while four longitudinal studies followed subjects between 1 and 10.5 years old (surgical versus non-adrenalectomy arms). Post-dexamethasone suppression test (DST) cortisol was inversely associated with bone mineral density (BMD). TBS predicted incidental vertebral fractures (VFx) regardless of BMD, being associated with post-DST cortisol independently of age and BMD. Low BTMs were identified in ACS, but not all studies agreed. An increased prevalence of ACS-related osteoporosis was confirmed in most studies (highest prevalence of 87.5%), as well as of VFx, including in pre-menopause (42.5%), post-menopause (78.6%), and male patients (72.7%) depending on the study, with a 10-fold increased incidental VFx risk up to a 12-fold increased risk after a 2-year follow-up. No specific medication against osteoporosis is indicated in ACS, but adrenalectomy (according to four studies) should be part of the long-term strategy. This bone profile case sample-based study (to our knowledge, one of the largest of its kind) showed that AIs, including the subgroup designated as having ACS, embraces a large panel of osseous complications. The level of evidence remains far from generous; there are still no homogenous results defining ACS and identifying skeletal involvement, which might be a consequence of different investigation clusters underling adrenal and bone assessments over time. However, bone status evaluations and associated therapy decisions remain an essential element of the management of adults with AIs-ACS.

Is the 1mg-dexamethasone suppression test a precise marker of glucocorticoid excess and cardiometabolic risk in patients with adrenal incidentalomas?

To analyze if the 1mg-dexamethasone suppression test (DST) is a reliable marker of glucocorticoid excess and cardiometabolic risk in patients with adrenal incidentalomas (AIs). Cross-sectional study of patients with nonfunctioning adrenal incidentalomas (NFAIs, defined by cortisol post-DST ≤ 1.8 µg/dL) and patients with autonomous cortisol secretion (ACS, defined by cortisol post-DST > 1.8 µg/Dl). The urinary steroid profile (USP) was determined by gas chromatography coupled to mass spectrometry. Both groups were matched by sex, age and body mass index. Forty-nine patients with AIs (25 with ACS and 24 with NFAI) were included. As a whole, AIs showed a high excretion of β-cortolone, tetrahydro-11-deoxycortisol (THS), α-cortolone, α-cortol, tetrahydrocortisol (THF) and tetrahydrocortisone (THE). A positive yet modest correlation between post-DST cortisol and total excretion of glucocorticoid metabolites (r = 0.401, P = 0.004) was observed, with the stronger being observed with total THS (r = 0.548, P < 0.001) and THF (r = 0.441, P = 0.002). Some of the metabolites that were elevated in patients with AIs, were higher in patients with ACS-related comorbidities than in those without comorbidities. Post-DST cortisol showed a fair diagnostic accuracy for the prediction of ACS-related comorbidities (AUC 0.767 [95% CI 0.634-0.882]). However, post-DST diagnostic accuracy improved when combined with urinary cortisone, α-cortol, THS and serum DHEAS (0.853 [0.712‒0.954]). The DST has a positive, but modest, correlation with urinary glucocorticoid excretion. Similarly, the diagnostic accuracy of the DST for the prediction of ACS-related comorbidities is only fair, but it may be improved if combined with the results of the USP and serum DHEAS. This is the first study aimed to evaluate if 1mg-dexamethasone suppression test (DST) is a reliable marker of glucocorticoid excess and cardiometabolic risk in patients with adrenal incidentalomas (AIs) and if urinary steroid profile was measured by GS-MS could improve such a prediction. We found a positive yet modest correlation between post-DST cortisol and total excretion of glucocorticoid metabolites, with the stronger being observed with total tetrahydro-11-deoxycortisol (THS) and tetrahydrocortisol. Post-DST cortisol showed a fair diagnostic accuracy for the prediction of ACS-related comorbidities (AUC 0.767). However, post-DST diagnostic accuracy improved when combined with urinary cortisone, α-cortol, THS and serum DHEAS (0.853).

LBSAT141 Bone Health In Patients With Adrenal Disorders

Abstract Introduction Limited data suggest low bone density in patients with adrenal adenomas. However, most studies are retrospective, single-center, and none were conducted in the United States. We aimed to determine the impact of cortisol and aldosterone excess on bone density. Methods We conducted a preliminary analysis of data from our multicenter, prospective observational study of adult patients with adrenocortical hormone excess and referent subjects without adrenal disorders (January 2019 - March 2022). Patients were diagnosed with non-functioning adenomas (NFA), adenomas with mild autonomous cortisol secretion, MACS (defined as cortisol following an overnight 1-mg dexamethasone suppression test (DST)&amp;gt;1.8 mcg/dL), adrenal or pituitary Cushing syndrome (CS), primary aldosteronism (PA), and concomitant PA-MACS. Referent subjects were patients undergoing cross-sectional imaging for reasons other than adrenal disease. All participants were interviewed about their bone health, and had bone density measurements at the spine, hips, and/or radius. Bone disease was defined as osteopenia (T-score -1.1 to -2.4), or osteoporosis (T-score &amp;lt; -2.5). Results A total of 417 participants included 156 referent subjects (88, 56% women, median age 65, range 2-95 years) and 261 patients (190, 73% women, median age 59, range 21-88 years). Patients were diagnosed with NFA (51, 19%), PA (46, 17%), MACS (122, 47%), PA-MACS (12, 5%), and CS (30,12%). When compared to referent subjects, sex- and age-adjusted analysis demonstrated an increased prevalence of bone disease only in patients with CS (OR 4.8, 95%CI 1.7-13), but not in other adrenal disorders. After excluding patients with CS, those with post-DST cortisol &amp;gt;5 mcg/dL demonstrated a higher prevalence of bone disease when compared to patients with post-DST cortisol between 1.8-5 mcg/dL (OR 2.8, 95%CI 1.2-6.5) and those with post-DST cortisol &amp;lt;1.8 mcg/dL (OR 2.7, 95% CI 1.1-6.7). Patients with MACS and post-DST cortisol between 1.8-5 mcg/dL did not demonstrate increased sex and age-adjusted prevalence of bone disease compared to those with post-DST &amp;lt;1.8 mcg/dL or referent subjects. However, using post-DST cortisol as a continuous variable, we found that after adjusting for sex and age, the risk of bone disease in patients increased by 13% (OR 1.13, 95%CI 1.6-1.2) for every 1 mcg/dL increase in post-DST cortisol. Conclusions The prevalence of osteopenia and osteoporosis increases proportional to the increase in post-DST cortisol concentrations. Patients with CS, and those with MACS and post-DST cortisol &amp;gt; 5mcg/dL have the highest prevalence of bone disease. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT008 Pheochromocytoma Management: Considerations for Cardiac Stress Testing

Abstract Introduction Pheochromocytomas, though rare, can have dire consequences and should be treated with timely surgical resection. Left untreated, there is high risk for developing cardiomyopathy, hemorrhagic stroke, pulmonary edema, etc. However, the resection itself has a high risk for hemodynamic instability and cardiac complications. We present a case of pheochromocytoma in a patient with multiple comorbidities who required pre-op cardiac clearance and discuss the considerations for appropriate stress test selection. Case A 60-year-old male with PMH of HTN, T2DM, CKD, OSA, and PAD s/p bilateral LE amputations was incidentally found to have a 6×5×5cm left adrenal mass on CT A/P done after a motor vehicle accident. MRI confirmed 6.6cm left adrenal mass. Lab testing showed elevated plasma fractionated catecholamines with free metanephrines 2246 (&amp;lt;57 pg/mL), free normetanephrines 1014 (&amp;lt;148 pg/mL), total metanephrines 3260 (&amp;lt;4-fold ULN of MN+NMN), aldosterone 11 (&amp;lt;28 ng/dL), plasma renin activity 0.28 (0.25-5.82 ng/mL/h), post-DST cortisol 2.7 (&amp;lt;2.0 ng/dL; 2-10 is equivocal), and chromogranin A 1449 (&amp;lt;311 ng/mL). 24-hour urine showed metanephrines 4114 (90-315 mcg/24H), normetanephrines 1174 (122-676 mcg/24H), and total metanephrines 5288 (224-832 mcg/24H). I-123 MIBG scan confirmed suspicion for pheochromocytoma. BP was elevated despite doxazosin 4mg BID, lisinopril 20mg daily, amlodipine 10mg daily, and carvedilol 37.5mg BID. He was referred to urology who planned for surgical resection pending cardiac clearance. Cardiology requested stress test to assist with pre-op risk stratification given multiple cardiac risk factors. Exercise stress test was not possible due to h/o LE amputations. Dobutamine stress test was initially recommended as this is the default testing modality at our institution but after multi-disciplinary discussion, regadenoson stress test was later selected due to concern for catecholamine surge and pheochromocytoma crisis with dobutamine use. Stress test was completed without complications and showed small reversible perfusion defect. Cardiac clearance was obtained for semi-urgent surgery. Patient tolerated left adrenalectomy and pathology confirmed pheochromocytoma. BP is now well-controlled on carvedilol 25mg BID alone. Discussion Cardiac stress testing with an underlying pheochromocytoma requires thoughtful decision making. Case reports describe cardiogenic shock, hypertensive crisis, or even death after exercise or dobutamine stress testing, possibly secondary to catecholamine surge resulting in pheochromocytoma crisis. Dobutamine is a synthetic catecholamine that stimulates both β and α1 receptors to increase inotropy and chronotropy, whereas regadenoson is a selective α2a receptor agonist that increases coronary vasodilation. In pheochromocytoma patients who require pre-op cardiac clearance, it is important to consider mechanism of action of various stress test modalities to avoid potential complications or consequent fatalities related to hemodynamic instability. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

ODP650 Impaired Cognition in Patients with Mild Autonomous Cortisol Secretion

Abstract Background Limited data describe cognitive deficits in patients with Cushing syndrome (CS). The impact of mild autonomous cortisol secretion (MACS) on cognition is unknown. Objective To determine the impact of MACS on cognitive function. Methods Single-center cross-sectional study of adults with MACS and age and sex-matched volunteers. MACS was defined as cortisol &amp;gt;1.8 mcg/dL following the dexamethasone suppression test (DST) in patients with an adrenal incidentaloma and no features of CS. We measured cognitive function through the NIH toolbox cognition battery (7 standardized tests of attention, episodic and working memory, language, executive function, and processing speed). T-scores corrected for age, sex, education, and race were used for analysis. All patients completed the SF-36 questionnaire. The frailty index was calculated as previously reported (Singh S. JCEM 2020). Results Participants included 50 patients with MACS (median age 61, range 54-68) and 50 volunteers (median age 60 years, range 54-68), with 60% women in both groups. In patients with MACS, median post-DST morning cortisol was 3.6 (range, 2.4-6.2), and median corticotropin was 8.5 (range, 5.9-13) pg/mL (normal 6-60). Patients with MACS had a higher median frailty index (median of 0.26 vs. 0. 05 in volunteers, p&amp;lt;0. 001) and lower quality of life scores on the SF-36 survey (median of 47 vs. 91, p&amp;lt;0. 001). Compared to volunteers, patients with MACS performed worse in the domains of attention and executive function (effective allocation of one's limited capabilities in an abundance of stimuli) (median T-score of 50 vs. 46, p=0. 03), cognitive flexibility (tested as the capacity to plan and monitor goal-directed activities) (median T-score of 61 vs. 55, p=0. 01). The fluid composite score (includes executive function, episodic memory, working memory, and processing speed) was lower in patients with MACS (mean of 53.2 vs. 48.9, p=0. 03). The total composite score was lower in patients with MACS when compared to volunteers (median T score of 50 vs. 54, p=0. 06). The total composite cognitive scores in patients of MACS were associated with the Frailty Index (R2 = 0.13, p = 0. 025) and SF-36 scores (R2 = 0. 08, p = 0. 05), but not post-DST cortisol. Conclusion Compared to volunteers, patients with MACS demonstrate cognitive impairment, particularly in the executive domain, which closely mimics changes observed with aging. These deficits do not correlate with the degree of cortisol excess. Presentation: No date and time listed

Predictive model for autonomous cortisol secretion development in non-functioning adrenal incidentalomas.

We aimed to develop a predictive model able to stratify patients with non-functioning adrenal incidentalomas (AIs), according to their risk for developing autonomous cortisol secretion (ACS) during follow-up. This was a retrospective study of patients with non-functioning AIs consecutively evaluated at a single institution between 2013 and 2019 in whom hormonal follow-up information was available for at least 1year. Clinical, biochemical, and radiological features were used to build a multivariate Cox regression model using the estimation of all possible equations. We included 331 patients with non-functioning AIs. ACS (post-dexamethasone suppression test (DST) serum cortisol > 1.8µg/dL) developed in 73 patients during a median follow-up time of 35.7months [range 12.8-165.4]. The best predictive model for ACS development during follow-up combined age, post-DST serum cortisol, and bilaterality at presentation and showed good diagnostic accuracy (AUC-ROC 0.70 [95% CI 0.65-0.75]). The lowest risk for ACS development was found among patients < 50years old with cortisol post-DST values < 0.45µg/dL and with unilateral tumors (risk 2.42%). Baseline post-DST serum cortisol levels at diagnosis were the most important factor for the development of ACS during follow-up (hazard ratio 3.56 for each µg/dL, p < 0.001). The rate of ACS development was associated with post-DST cortisol levels, being 19.2, 32.3, and 68.1 cases/10,000 person-years for patients with baseline post-DST cortisol < 0.9µg/dL, 0.9-1.3µg/dL, and > 1.3µg/dL, respectively. After ruling out malignancy, follow-up visits for patients < 50years old with unilateral non-functioning AIs and post-DST serum cortisol < 0.45µg/dL are considered unnecessary given the low risk of developing ACS during follow-up.

Cortisol-producing adenoma-related somatic mutations in unilateral primary aldosteronism with concurrent autonomous cortisol secretion: their prevalence and clinical characteristics.

Concurrent autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) is being reported more frequently. Several somatic mutations including PRKACA, GNAS, and CTNNB1 were identified in cortisol-producing adenomas (CPAs). The presence of these mutations in unilateral PA (uPA) patients concurrent with ACS (uPA/ACS) is not well known. This study aimed to investigate the prevalence of these mutations and their clinical vs pathological characteristics in uPA/ACS. This is a retrospective cohort study. Totally 98 uPA patients from the Taiwan Primary Aldosteronism Investigation registry having overnight 1-mg dexamethasone suppression test (DST) and adrenalectomy from 2016 to 2018 were enrolled. Their adrenal tumors were tested for PRKACA, GNAS, and CTNNB1 mutations. 11 patients had CPA-related mutations (7 PRKACA and 4 GNAS). The patients carrying these mutations had higher post-DST cortisol (5.6 vs 2.6 μg/dL, P = 0.003) and larger adenoma (2.2 ± 0.3 vs 1.9 ± 0.7 cm, P = 0.025). Adenomas with these mutations had a higher prevalence of non-classical uPA (72.7% vs 26.3%, P = 0.014). Numerically, slightly more complete clinical success of uPA patients with these mutations was noticed after adrenalectomy, although it was statistically non-significant. Post-DST cortisol levels, adenoma size >1.9 cm, and the interaction of adenoma size >1.9 cm with potassium level were found to be associated with the presence of these mutations. Our study showed that CPA-related mutations were detected in 36.7% of uPA/ACS adenomas. The presence of these mutations was associated with higher post-DST cortisol levels, larger adenoma sizes, and a high percentage of non-classical uPA. However, these mutations did not significantly affect the clinical and biochemical outcomes after adrenalectomy of uPA/ACS patients but they showed a better trend.

Diagnostic accuracy of the different hormonal tests used for the diagnosis of autonomous cortisol secretion

To evaluate the diagnostic accuracy of the different tests commonly used in the evaluation of adrenal incidentalomas (AIs) for the identification of autonomous cortisol secretion (ACS) and comorbidities potentially related to ACS. In a retrospective study of patients with AIs ≥ 1 cm, we evaluated the diagnostic reliability and validity of the dexamethasone suppression test (DST), urinary free cortisol (UFC), ACTH, late-night salivary cortisol (LNSC), and dehydroepiandrosterone-sulphate (DHEAS) for the diagnosis of comorbidities potentially related to ACS. Diagnostic indexes were also calculated for UFC, ACTH, LNSC, and DHEAS considering DST as the gold standard test for the diagnosis of ACS, using three different post-DST cortisol thresholds (138 nmol/L, 50 nmol/L and 83 nmol/L). We included 197 patients with AIs in whom the results of the five tests abovementioned were available. At diagnosis, 85.9% of patients with one or more AIs had any comorbidity potentially related to ACS, whereas 9.6% had ACS as defined by post-DST cortisol > 138 nmol/L. The reliability of UFC, ACTH, LNSC, and DHEAS for the diagnosis of ACS was low (kappa index < 0.30). Of them, LNSC reached the highest diagnosis accuracy for ACS identification (AUC = 0.696 [95% CI 0.626–0.759]). The diagnostic performances of these tests for comorbidities potentially related to ACS was poor; of them, the DST was the most accurate (AUC = 0.661 [95% CI 0.546–0.778]) and had the strongest association with these comorbidities (OR 2.6, P = 0.045). Patients presenting with increased values of both DST and LNSC had the strongest association with hypertension (OR 7.1, P = 0.002) and with cardiovascular events (OR 3.6, P = 0.041). In conclusion, LNSC was the test showing the highest diagnosis accuracy for the identification of ACS when a positive DST was used as the gold standard for its diagnosis. The DST test showed the strongest association with comorbidities potentially related to ACS. The definition of ACS based on the combination of elevated DST and LNSC levels improved the identification of patients with increased cardiometabolic risk.

Interpretation of Abnormal Dexamethasone Suppression Test is Enhanced With Use of Synchronous Free Cortisol Assessment.

Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding. We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic workup. Cross-sectional study conducted in a tertiary medical center. Adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy [OCP], 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n = 196; 16 women on OCP). Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay). Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol. Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95% CI, 81.7-91.7); all false-positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false-positive results (21.1% vs 4.9%, P = 0.02). Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL.

Accuracy of the dexamethasone suppression test for the prediction of autonomous cortisol secretion-related comorbidities in adrenal incidentalomas.

The aim of this study was to evaluate the diagnostic accuracy of the 1mg dexamethasone suppression test (DST) for the prediction of autonomous cortisol secretion (ACS)-related comorbidities in patients with adrenal incidentalomas (AIs). This was a retrospective multicenter study. We recruited patients with AI/s ≥ 1cm, excluding those who, during the study, were found during theextensionstudy of an extra-adrenal cancer, with a known diagnosis of hereditary syndromes characterized by adrenal tumors, those presenting with overt hormonal excess syndromes, and those in whom the DST results were missing. A total of 823 patients met the inclusion criteria. Based on the 1.8, 3.0, and 5.0µg/dl post-DST cortisol thresholds, the prevalence of ACS was 33.5%, 13.7%, and 5.6%, respectively. The prevalence of hypertension (OR = 1.8, 95% CI = 1.3-2.4), diabetes (OR = 1.6, 95% CI = 1.2-2.2), and dyslipidemia (OR = 1.4, 95% CI = 1.0-1.9) was higher with cortisol post-DST ≥ 1.8µg/dl; the prevalence of hypertension (OR = 2.1, 95% CI = 1.4-3.3) and diabetes (OR = 1.7, 95% CI = 1.1-2.6) was higher with values ≥ 3.0µg/dl; and the prevalence of hypertension (OR = 2.0, 95% CI = 1.0-3.7) was higher with levels ≥ 5.0µg/dl. However, the diagnostic accuracy of the DST for the prediction of cardiometabolic comorbidities in patients with AIs was poor, with areas under the ROC curve < 0.61. The DST is a poor predictor of cardiometabolic comorbidities in patients with AIs regardless of the cortisol cut-off values applied. This finding suggests that the diagnosis of ACS should not be based solely on the results of the DST. Other clinical, metabolic, or imaging markers showing a better performance for the prediction of the development and progression of cardiometabolic comorbidities in AIs need to be identified.