Citations

Abstract Objectives The impact of mild autonomous cortisol secretion (MACS) on cognition is incompletely characterized. We aimed to assess cognition in patients with MACS, identify factors associated with lower cognition, and determine the impact of adrenalectomy on cognition. Methods We conducted a cross-sectional study (4/2019 to 10/2022) and a longitudinal cohort study (10/2021 to 9/2023) of adults with MACS and referent subjects. Cognition was assessed with National Institute of Health Toolbox Cognition Battery and reported as standardized T scores (adjusted for age, sex, race/ethnicity, and education) for fluid, crystallized, and total composite cognition. Participants were assessed with urine steroid profiling (liquid chromatography-tandem mass spectrometry), frailty index, Beck’s Depression Inventory (BDI), and Short Form-36 (SF-36). Results A total of 84 patients (median age 57 years, 67% women) and 201 referent subjects (median age 63 years, 58% women) were included. Patients with MACS demonstrated lower mean (SD) total composite (50.9 [9.3] vs 55.4 [8.9], P < .001) and fluid composite T score (49.3 [10.6] vs 55.2 [10.2], P < .001), but not crystallized composite T score (52.3 [8.4] vs 54.0 [8.4], P = .130) when compared with referent subjects. Multivariable analysis adjusted for age, sex, BDI, SF-36, frailty index, total glucocorticoids, and androgens demonstrated that MACS status was associated with lower cognition. When cognition was reassessed in 37 patients post-adrenalectomy and 31 referent subjects, adjusted group differences of cognition change were similar except for a higher comparative increase in attention and executive functioning in patients with MACS. Conclusion Patients with MACS demonstrate lower cognition than referent subjects. Adrenalectomy for MACS had a minor positive impact on cognition.

Abstract Motivated by studies showing an association between beta blocker (BB) use and positive bone outcomes, a pilot randomized control trial was performed at the Mayo Clinic which randomized postmenopausal women to placebo, propranolol (40 or 80 mg twice daily), atenolol (50 mg/d), or nebivolol (5 mg/d) to determine changes in bone turnover markers (BTMs) and in BMD over 20 wk. Pharmacogenetic effects and microRNA-mediated mechanisms involving beta adrenergic receptor and related genes have previously been found. We sought to validate these effects and discover new candidates in an ancillary study to the pilot clinical trial. We genotyped all participants and performed microRNA (miRNA) sequencing at baseline and at 20 wk for 24 participants from the atenolol or placebo groups. We discovered several variants in ADRB1, ADRB2, and HDAC4 which showed significant pharmacogenetic effects with BMD at multiple sites and with BTMs. Our miRNA results showed a significant treatment effect for miR-19a-3p over time with atenolol use in the low-responder group compared to placebo. Overall, the longitudinal miRNA analysis showed a large number of miRNAs which were up-regulated over the trial in the low responders but not the high responders compared to placebo, of which miR-19a-3p was one example. Finally, we compared the response to atenolol treatment for cardiovascular traits (pulse and blood pressure) with the response for the bone resorption marker, C-terminal telopeptide, and found a largely independent effect. Our results have implications for personalized therapy and for understanding mechanisms of BB treatment effect on bone.

Abstract Context Diagnosing adrenal insufficiency (AI) often requires complex testing, which can be time-consuming and expensive. Dehydroepiandrosterone sulfate (DHEAS) is a promising marker of hypothalamic-pituitary-adrenal axis function; however, its diagnostic performance has not yet been evaluated in a large-scale study. Objective Evaluate the performance of DHEAS and baseline cortisol in assessing AI. Design Single-center retrospective cohort study. Setting Referral center. Patients Adults who underwent cosyntropin stimulation testing (CST) between 2005 and 2023 and had DHEAS measured within 3 months prior to CST. Main Outcome Measures Area under receiver operating characteristic curve (AUROC) for DHEAS and baseline cortisol. Prevalence of AI based on various DHEAS and baseline cortisol concentrations. Results Among 1135 patients, 195 (17.2%) had AI. Both baseline cortisol and DHEAS independently had good diagnostic performance with AUROC 0.81 [95% confidence interval (CI) 0.77-0.84 and 0.81 (95% CI 0.78-0.85)], respectively. Time of CST performance had no significant effect on diagnostic accuracy of baseline cortisol while recent glucocorticoid use decreased diagnostic performance of DHEAS (AUROC 0.72 vs 0.83). Only 1.2% of patients with baseline cortisol ≥10 mcg/dL had AI based on CST. Among patients with baseline cortisol between 5 and 9.9 mcg/dL, only 1.3% had AI if DHEAS was ≥60 mcg/dL. Conversely, the majority (72.2%) of patients with both baseline cortisol <5 mcg/dL and DHEAS <25 mcg/dL were found to have AI. Conclusion DHEAS has good diagnostic performance in assessing AI. Measuring both baseline cortisol and DHEAS concentrations may eliminate the need for further dynamic testing in many patients.

ABSTRACTCellular senescence is a biological mechanism of aging and age‐related diseases. The aim of this study was to examine whether senescence biomarkers are associated with frailty and physical function trajectories in patients undergoing kidney transplantation (KT). We also discussed the relationship between senescence biomarkers and KT function. In this multicenter study, we prospectively assessed plasma levels of senescence biomarkers, frailty as measured by the Physical Frailty Phenotype, and physical function as measured by the Short Physical Performance Battery prior to KT. Frailty, physical function, and KT function were also measured 1 year after KT. Variable associations were assessed using Cox and relaxed least absolute shrinkage and selection operation regression. The cohort consisted of 197 participants (mean age 53 ± 13 years, 61.4% male, and 80.2% White race). Higher pre‐KT levels of macrophage‐derived chemokine (MDC/CCL22) and growth differentiation factor‐15 (GDF‐15) were independently associated with less improvement in frailty and/or physical function during the first year after KT. Higher pre‐KT levels tumor necrosis factor receptor superfamily member 6 (FAS) and MMP‐9 levels were independently associated with lower KT function one year after KT. Pre‐KT cellular senescence may contribute to frailty, physical function, and kidney function trajectories during the first year after KT.

Abstract Obesity accelerates the onset and progression of age-related conditions. In preclinical models, obesity drives cellular senescence, a cell fate that compromises tissue health and function, in part through a robust and diverse secretome. In humans, components of the secretome have been used as senescence biomarkers that are predictive of age-related disease, disability, and mortality. Here, using biospecimens and clinical data from two large and independent cohorts of older adults, we tested the hypothesis that the circulating concentrations of senescence biomarkers are influenced by body mass index. After adjusting for age, sex, and race, we observed significant increases in activin A, Fas, MDC, PAI1, PARC, TNFR1, and VEGFA, and a significant decrease in RAGE, from normal weight, to overweight, to obesity body mass index categories by linear regression in both cohorts (all p < .05). These results highlight the influence of body mass index on circulating concentrations of senescence biomarkers.

Abstract Disclosure: J. Saini: None. B. Bahrani Fard: None. M. Suresh: None. R. Sandooja: None. Y. Hleibiehova: None. E. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Patients with endogenous hypercortisolism experience glucocorticoid withdrawal syndrome (GWS) following curative surgery. The symptoms of GWS include fatigue, weakness, muscle aches, joint pain, mood changes, and sleep disturbance. Limited interventions have been explored to alleviate the symptoms of GWS and improve patients’ quality of life. The use of meditation as an intervention has been reported to enhance postsurgical recovery in patients with other conditions and offers a promising intervention for GWS. Objective: To determine the impact of a portable, wearable, electroencephalographic device (MUSE headband device) used for guided meditation practices on the quality of life of patients in the first 12 weeks post-surgery for endogenous hypercortisolism. Methods: We conducted a single-center prospective longitudinal study of adults with endogenous hypercortisolism undergoing curative surgery between 2018 and 2024. The patients were enrolled before the surgical intervention and were followed for 2 years. Only patients who completed at least 4 weeks of follow-up were included. The study comprised of 2 groups; (1) The interventional group included consecutive patients who were offered a MUSE headband with instructions to meditate for at least 10 minutes per day for 3 months (MUSE cohort) and (2) the comparison group included age-, sex-, clinical score, hypercortisolism type, and BMI-matched 3:1 patients (Referent cohort). Quality of life and symptoms of GWS were assessed with AddiQoL and Short Form-36 (SF-36) surveys. Results: At least 4 weeks post-surgical follow-up was completed by 27 patients in the MUSE cohort and 81 referent subjects. Age (median 51 vs 47 years), women (82% vs 84%), BMI (median 31 vs 32 kg/m2), the subtype of hypercortisolism (pituitary 48% vs 52%), clinical (median 16 vs 15) and biochemical (median 6 vs 7) severity scores were similar between the two groups (P>0.05 for all). At baseline, AddiQoL score was similar in groups (median of 66 vs 70, P=0.083), though symptoms of fatigue (92.6% vs 69.1%, P=0.015) and lightheadedness (37% vs 17.3%, P=0.033) were more frequent in MUSE cohort. After 12 weeks, 20 patients using MUSE demonstrated improvement compared to 67 no muse patients in the SF-36 physical component (mean delta 3.9 (SD 11.77) vs -2.19 (SD 9.67), P=0.010). The physical functioning SF-36 subcomponent (4.94 (8.77) vs 0.92 (9.24), P=0.048) and body pain SF-36 subcomponent (2.69 (11.89) vs -3.69 (8.32), P=0.008) domains improved in the MUSE intervention group, when compared to referent cohort. No significant improvement in SF-36 mental component scores was seen in both groups. Conclusions: The use of wearable electroencephalographic device for meditation was associated with improvement in the quality of life of patients recovering from hypercortisolism, particularly in the domains of body pain and physical functioning. Presentation: 6/3/2024

Abstract Disclosure: R. Sandooja: None. J. Saini: None. R. Gregg garcia: None. C. Zhang: None. S. Achenbach: None. E. Atkinson: None. J. Van Gompel: None. W.F. Young: None. I. Bancos: None. Hydrocortisone vs Prednisone During Recovery Following Surgical Cure for Endogenous Hypercortisolism: A Longitudinal Observational Study Introduction: Glucocorticoid withdrawal syndrome (GWS) is a constellation of symptoms that occurs after successful surgery for endogenous hypercortisolism. The objective of this study is to compare hydrocortisone versus prednisone on GWS symptoms. Methods: Study design: Single-center prospective longitudinal cohort study, 2019-2023. Participants: Adults with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS) with post-operative adrenal insufficiency treated with either hydrocortisone or prednisone for glucocorticoid replacement. Measurements: Clinical and biochemical severity scores for hypercortisolism were calculated. Quality of life (QOL) was assessed using Short Form-36 (SF-36) and Cushing QOL surveys. GWS was assessed using weekly AddiQoL surveys for the first 12 weeks after surgery. Results: Of 131 patients, 91 (69%) patients were treated with hydrocortisone and 40 (31%) with prednisone. No differences in age (median age 51 vs 53 years, P=0.62), sex (84 vs 85% women, P=0.83), etiology of hypercortisolism (ACTH-dependent: 44% vs 48%, P=0.26), clinical severity of hypercortisolism (median score 13 vs 12, P=0.97), or biochemical severity of hypercortisolism (median score of 6 in both, P=0.31) were noted between groups. When assessed at 4-, 8-, and 12-weeks post-surgery, the prevalence and trajectory of symptoms (fatigue, myalgias/arthralgias, sleep, headaches, nausea, weakness) were similar in patients treated with hydrocortisone and prednisone (P>0.05 for all). However, patients treated with prednisone were less likely to report mood changes (8.5% vs 20.9%, P= 0.004) compared to those treated with hydrocortisone. When compared to the presurgical baseline, the overall Cushing QOL score 12 weeks post-surgery improved in both groups (mean delta 8.9 vs 13.0, P=0.21). No differences in the hydrocortisone vs prednisone treatment were found in the SF-36 physical component score (mean delta of -1.7 vs 0.3, P=0.23) and SF-36 mental component score (mean delta 2.3 vs 5.0, P=0.22). Using multivariable analysis, age (estimate 0.22, P= 0.005), clinical severity score (estimate -0.73, P<0.001), female sex (estimate -5.45, P= 0.046) but not glucocorticoid type (estimate -0.06, P=0.98) were associated with the overall GWS symptom burden at 12 weeks. Conclusion: Use of prednisone after curative surgery for hypercortisolism was associated with lower mood symptoms, but did not impact the overall severity or trajectory of other symptoms associated with GWS. Baseline clinical severity of hypercortisolism, age, and female sex were associated with GWS burden. Presentation: 6/1/2024

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

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

Abstract Disclosure: E.Y. Ferreira: None. J. Saini: None. J. Larson: None. E. Atkinson: None. C. Powell: None. S. Nevin: None. V. Fell: None. I. Bancos: Grant Recipient; Self; HRA Pharmaceuticals. Research Investigator; Self; HRA Pharmaceuticals. Context: Mild autonomous cortisol secretion (MACS) is the most prevalent hormonal abnormality demonstrated in 20-45% of patients with adrenal adenomas. MACS is associated with increased prevalence and incidence of cardiovascular morbidity, frailty, fragility fractures, psychiatric and sleep disorders, as well as increased mortality. Bilateral MACS due to bilateral adrenal adenomas or macronodular adrenal hyperplasia is seen in around 20% of patients with MACS. Management of patients with unilateral MACS who are not surgical candidates or do not desire adrenalectomy, and management of patients with bilateral MACS is challenging. Safe and effective medical therapy is urgently needed in these patients. Objective: 1) assess safety and tolerability of overnight metyrapone therapy in patients with MACS, 2) evaluate the impact of overnight metyrapone on steroid profiling and circadian cortisol secretion and 3) determine the efficacy of overnight metyrapone on metabolic and bone parameters, mood, sleep, cognition, quality of life, frailty and senescence biomarkers. Methods: This open-label, phase 2 interventional single-center study using overnight metyrapone opened for enrollment in December 2023 (NTC06106295) and plans to enroll 30 patients with MACS. Eligible participants include adults with adrenal adenoma or macronodular adrenal hyperplasia and MACS, and at least one comorbidity attributed to hypercortisolism. Metyrapone is administered overnight at 250 mg to 1000 mg. Duration of the study is 6 months (main study) and up to 42 months for extension study. Primary endpoint is incidence of treatment related adverse events. Key secondary endpoints include: glucocorticoid/androgen ratio, morning/evening cortisol curve, metabolic parameters (change in blood pressure, hyperglycemia, weight), frailty index and senescence biomarkers. Results: Between December 15th 2023 and April 6th, 7 patients with MACS (4, 57% women) enrolled at a median age of 62 years (IQR 56-68). Median BMI was 29 kg/m2(IQR 25-34). Post-dexamethasone cortisol was 3.1 mcg/dL (IQR 2.4-6.2), corticotropin (ACTH) was 7.3 pg/mL (IQR 5-20), and dehydroepiandrosterone-sulfate (DHEAS) was 73 mcg/dL (IQR 59-86). Median hypercortisolism clinical severity score was 9 (IQR 2-11) and biochemical severity score was 3.5 (IQR 2-5). Prevalence of hypertension (57%), dysglycemia (67%), dyslipidemia (86%), depression (57%), anxiety (43%), and bone disease (70%) was high. In 7 participants, median frailty index was 0.2 (IQR 0.2-0.4), and 3 (43%) were considered frail (frailty index >0.25). As of April 6th, 2024, no major treatment-related adverse events were reported, and no patient discontinued therapy. Conclusion: Results of this study will characterize safety and tolerability of overnight metyrapone in patients with MACS and evaluate the impact of overnight metyrapone on MACS-associated comorbidities. Presentation: 6/1/2024