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Cardiovascular disease is often a disease of aging. Considerable advances in our understanding of the biological mechanisms of aging have been made; yet, cardiovascular disease remains the leading cause of death in the United States urging a continued search for novel risk factors to target for preventing and treating disease. Mental stress (MS) is emerging as an important risk factor, and while progress has been made in understanding the link between MS and cardiovascular disease, the precise mechanisms of a putative causal relationship require greater clarification. In the current review, we (1) summarize our current understanding of the pathological effects of MS on vascular health; (2) describe important aspects of the pathobiology of vascular aging including inflammation, oxidative stress, mitochondrial dysfunction as well as novel processes such as genomic instability, epigenetic alterations, and nutrient signal pathways; (3) highlight similarities in the downstream biologic effects of aging and MS on vascular health with an emphasis on cellular and molecular processes that could be used to develop novel prognostic markers and treatment strategies for cardiovascular disease; (4) discuss lifestyle and pharmacological methods that target indicators of aging whose role could be translated into approaches managing the effects of MS; and (5) outline important future steps that should be considered in this area of research including the need for prospective clinical trials and for creating greater collaboration between preclinical aging researchers and clinical investigators managing MS.

PURPOSE CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti–CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, –1.5 to 4.4; all-pts) and 1.4% (95% CI, –1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Abstract Disclosure: M. Moazzami: Grant Recipient; Self; Rochester Epidemiology Project. S. Achenbach: None. E. Atkinson: None. I. Bancos: None. Background: Epidemiology of adrenal insufficiency (AI) is incompletely characterized with most data originating from referral centers and registries. We aimed to determine the incidence, morbidity index, risk of hospitalizations, and mortality in patients with AI living in Olmsted County, Minnesota. Methods: We assessed the standardized incidence rate, morbidity index, risk of hospitalizations and mortality of AI in residents (aged 18+) in Olmsted County, MN, USA, from Jan 1, 2005, to December 31, 2021. The data was collected using the Rochester Epidemiology Project (REP), a database of medical records for all Olmsted County residents since 1966. Incidence rates were standardized for age and sex according to the 2020 US white population. Sex- and age- matched referent subjects were selected from the REP. AI was defined based on presence of oral chronic glucocorticoid therapy (hydrocortisone, prednisone, prednisolone, or dexamethasone) defined as (1) any hydrocortisone use or (2) 6 months of consecutive use of prednisone, prednisolone, or dexamethasone or (3) two AI diagnosis codes 6+ months apart plus at least one glucocorticoid prescription within 1 year of the second diagnosis. Elixhauser morbidity index was used. Findings: Between 2005 and 2021, 5419 patients were diagnosed with AI (median age of 62 years, range 18-103), 56% women). Overall standardized incidence rates for AI increased from 206 (95% CI 174-238) in 2005 to 252 (223-280) per 100 000 person-years in 2021. At baseline, patients with AI had a higher morbidity index (median 3 vs median 1, p <0.001) and a higher history of hospitalizations within 5 years prior to baseline (57% vs 30%; p<0.001) when compared to referent subjects. When comparing patients with AI to referent subjects, and after adjusting for age, sex, morbidity index and prior history of hospitalizations, patients with AI were more likely to be hospitalized during follow-up (aHR 1.4, 95% CI 1.3-1.5). When comparing patients with AI to referent subjects, and after adjusting age, sex, and morbidity index, patients with AI had higher mortality (aHR 1.7, 95% CI 1.6-1.9). Patients with AI demonstrated a higher risk of dying from musculoskeletal disorders (aHR 4.9, 95% CI 2.2-10.8), respiratory disorders (aHR 4.7, 95% CI 3.3-6.6), neoplasms (aHR 2.4, 95% CI 2.0-2.9), and infectious disorders (aHR 2.3, 95% CI 1.2-4.3) than referent subjects. Interpretation: We demonstrate an increase in AI incidence between 2005 and 2021. Surprisingly, even after controlling for morbidity and prior hospitalizations, patients with AI were more likely to be hospitalized. In comparison to referent subjects, mortality was higher in patients with AI, even after adjustment for morbidity index. Presentation: Friday, June 16, 2023

Abstract Disclosure: R. Sandooja: None. A. Kittithaworn: None. P. Dogra: None. D. Gruppen: None. E. Atkinson: None. S. Achenbach: None. K. Yu: None. M. Connelly: None. V. Simha: None. R.P. Dullaart: None. I. Bancos: None. INTRODUCTION: Based on the spectrum of cortisol excess, adrenal adenomas are classified as adenomas with Cushing syndrome (CS), adenomas with mild autonomous cortisol secretion (MACS), and non-functioning adenomas (NFA). Patients with adrenal adenomas demonstrate a high prevalence of cardiovascular morbidity and mortality proportional to the degree of hypercortisolism. Evidence on whether dyslipidemia is a contributing cardiovascular risk factor in patients with NFA and MACS is discrepant. We aimed to characterize (apo) lipoprotein abnormalities across the spectrum of cortisol excess in patients with adenomas as compared to referent subjects. METHODS: Study Design: Single center cross sectional study between 01/2015 - 05/2021.Patients: Adults with NFA, MACS, or CS were consecutively enrolled. MACS was diagnosed based on post-dexamethasone cortisol >1.8 mcg/dL. Referent subjects were recruited from local population of patients with available abdominal imaging and no adrenal disorders. All subjects provided fasting ethylenediaminetetraacetic acid (EDTA) venous samples. Measurements: Nuclear magnetic resonance (NMR) spectroscopy measurements included total cholesterol (TC), low-density lipoprotein (LDL) and LDL particle concentrations, high-density lipoprotein (HDL) subclasses, apolipoprotein B (apo B), triglycerides (TG) and TG-rich lipoprotein concentrations. RESULTS: Participants included 101 patients with CS (median age 44 years, IQR 31-58, 85% women), 158 patients with MACS (median age 62 years, IQR 51-70, 62% women), 166 patients with NFA (median age 60 years, IQR 53--66, 63% women) and 136 referent subjects (median age 68 years, IQR 57-77, 52% women). Patients had higher BMI (32 vs 27 kg/m2), higher prevalence of hypertension (72% vs 46%) and diabetes mellitus (27% vs 9%) as compared to reference subjects. Statin therapy was used in 32% of patients and referent subjects. After adjusting for age, sex, BMI, smoking, diabetes, hypertension, and statin therapy, as compared to referent subjects, we found inconsistent increase in TC, LDL cholesterol and TG across CS, MACS and NFA and no consistent differences in LDL size, HDL variables, TG and TG-rich lipoproteins. However, when compared to referent subjects, LDL particle concentrations- CS(OR 1.78, 95% CI 1.33-2.39), MACS (OR 1.31, 95% CI 1.03-1.67), and NFA (OR 1.43, 95% CI 1.12-1.82) and Apo B levels were higher in all patient categories: CS (OR 2.26, 95% CI 1.57-3.24), MACS (OR 1.36 95% CI 1.00-1.85 ), and NFA (OR 1.54 95% CI 1.13-2.09). These differences were particularly evident in patients not on statin therapy. CONCLUSIONS: We found that LDL particle and Apo B concentrations were elevated in all patient groups, including those with MACS and NFA. In comparison to conventional lipid measurements, LDL particle and Apo B may serve as a better biomarker of the future cardiovascular risk in patients with adrenal adenomas. Presentation: Friday, June 16, 2023

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 >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

Abstract Disclosure: R.S. Douglas: Consulting Fee; Self; Horizon Therapeutics plc, Immunovant, Viridian. S. Couch: None. S.T. Wester: Advisory Board Member; Self; Horizon Therapeutics plc. Consulting Fee; Self; Immunovant, Sling. B. Fowler: Consulting Fee; Self; Horizon Therapeutics plc. C. Liu: Other; Self; Walter Kluwer Health. P. Subramanian: Consulting Fee; Self; Gensight, Horizon Therapeutics plc, Viridian. R. Tang: Consulting Fee; Self; Viridian, Alexion, Valenza. Research Investigator; Self; Viridian, Horizon Therapeutics plc, Novartis, Immunovant, Vasaragen. Speaker; Self; Serono Speaker Journal Club. Q.T. Nguyen: None. K. Hsu: Employee; Self; Horizon Therapeutics plc. Stock Owner; Self; Horizon Therapeutics plc. M. Karon: Employee; Self; Horizon Therapeutics plc. Stock Owner; Self; Horizon Therapeutics plc. M.N. Stan: Consulting Fee; Self; Immunovant, Horizon Therapeutics plc, Sling, Genentech, ArgenX. Background: Thyroid eye disease (TED) is characterized by expansion of peri- and retro-orbital fat and muscle, often resulting in disfiguring proptosis (eye-bulging) and diplopia (double vision) which may persist chronically. Teprotumumab, an inhibitor of the insulin-like growth factor-1 receptor, demonstrated improvements in proptosis, diplopia, inflammation and quality of life in clinical trials in patients with TED history of short duration (6-13 months), and active disease (clinical activity score [CAS] ≥4). In a published study of 31 patients with CAS≤3 and TED duration >2 years, teprotumumab reduced proptosis, diplopia and inflammation.1 We have undertaken the first randomized, placebo (PBO)-controlled trial to evaluate teprotumumab in patients with chronic/inactive/low CAS TED. The trial has completed randomization with results available in May 2023. Here we report characteristics of the randomized patients. Methods: The trial (NCT04583735) is being conducted in 11 centers in the United States. Key inclusion criteria were age≥18 years, TED duration ≥2 years but <10 years and CAS≤1 in both eyes, ≥3mm proptosis from baseline and/normal for sex and race, or no progression in proptosis or diplopia or new inflammatory symptoms in the preceding year. Patients must have been euthyroid or mildly hypo/hyperthyroid, and not require surgical intervention through the trial. Patients could not have received teprotumumab previously, or steroids within 3 weeks before screening. Patients were randomized 2:1 to receive 8 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) or PBO once every 3 weeks. The primary endpoint is improvement in proptosis (mm) as compared with PBO from baseline at Week 24. Other endpoints include percentage of proptosis responders (improvement of ≥2mm), diplopia responders (improvement of ≥1 grade in diplopia on the Bahn-Gorman scale, 0-3), and improvement in Graves’ Ophthalmopathy- Quality of Life (GO-QoL), all at Week 24. Adverse events (AE) and AE of special interest will be reported. Results: 62 patients were randomized. 80.6% are female, mean (SD) age was 48.7 (14.94) years. 54.8% are White, 24.2 %, Black or African American, and 12.9%, Asian. Mean (SD) TED duration was 5.2 (1.77) years. 87.1% are never/former smokers. At baseline, mean (SD) proptosis in the study eye was 24.4 (2.94) mm, and mean (SD) CAS was 0.4 (0.49). 27.4% had binocular diplopia with a mean diplopia score of 2. The mean overall GO-QoL score was 63.9 indicating similar disutility as observed in the acute trial population (previously published). Results from this 24-week trial will be presented. Conclusions: Despite a long duration of TED and low “activity”, patients enrolled in this trial have high levels of proptosis and impaired quality of life at baseline. Presentation: Saturday, June 17, 2023

Abstract Disclosure: R.S. Douglas: Consulting Fee; Self; Horizon, Immunovant, Viridian. Research Investigator; Self; Horizon. S. Couch: Research Investigator; Self; Horizon. S.T. Wester: Advisory Board Member; Self; Horizon. Consulting Fee; Self; Immunovant, Sling. Research Investigator; Self; Horizon. B.T. Fowler: Consulting Fee; Self; Horizon. Research Investigator; Self; Horizon. C. Liu: Research Investigator; Self; Horizon. Other; Self; Royalties from Wolters-Kluwer. P. Subramanian: Consulting Fee; Self; Horizon, Gensight, Viridian. Research Investigator; Self; Horizon. R. Tang: Consulting Fee; Self; Viridian, Alexion, Valenza. Research Investigator; Self; Horizon, Viridian, Novartis, Immunovant, Vasaragen. Speaker; Self; Serono Journal Club. Q.T. Nguyen: Research Investigator; Self; Horizon. R.N. Maamari: Research Investigator; Self; Horizon. K. Hsu: Employee; Self; Horizon. Stock Owner; Self; Horizon. M. Karon: Employee; Self; Horizon. Stock Owner; Self; Horizon. M. Stan: Consulting Fee; Self; Septerna Inc, Third Rock Ventures LLC, Genentech, MedicXi Ventures, ArgenX US Inc, Tourmaline Bio, Lassen Therapeutics, Ortho Clinical Diagnostics, Siemens Healthcare, Tolmar Inc, OSE, Immunotherapeutics, Roivant Sciences. Research Investigator; Self; Horizon, Immunovant, ValenzaBio, Sling Therapeutics. Background: Early inflammatory thyroid eye disease (TED) gives way to chronic disease which may lead to long-term disfiguring proptosis (eye-bulging). Teprotumumab, an IGF-1 receptor inhibitor, significantly improved signs and symptoms of newly diagnosed TED (6-13 months) with active disease (clinical activity score [CAS] ≥4) in prior studies. We present data from the first randomized, placebo (PBO)-controlled trial (NCT04583735) with teprotumumab in chronic/low CAS TED, where disease has not regressed. Methods: Pts met all following criteria: ≥18 yrs, TED 2-10 yrs, inactive disease or >1 yr without progression in proptosis/diplopia/new symptoms, baseline (BL) CAS≤1, increased proptosis ≥3mm before TED or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab and no steroids within 3 wks of screen. Pts received teprotumumab or PBO once every 3 wks for 21 wks. Primary endpoint was improvement in proptosis(mm) from BL at Wk 24 vs PBO. Secondarily proptosis responders (≥2mm improvement), diplopia responders (≥1 grade improvement on Gorman scale 0-3) with resolved diplopia (grade 0) and improvement in Graves’ Ophthalmopathy-QoL (GO-QoL) visual function (VF) and appearance (AP) subscales were assessed. Treatment-emergent adverse events (TEAE) and AEs of special interest are reported. Study was solely sized/powered for proptosis. Results: 62 pts were randomized 2:1 (ITT, teprotumumab:42; PBO:20), 80.6% were female, mean(SD) age was 48.7(14.94) yrs. Mean(SD) TED duration was 5.2(1.8) yrs. 87.1% were never/former smokers. At BL, mean(SD) proptosis was 24.4(2.94) mm, mean CAS was 0.4, and 29% (teprotumumab, n=14, PBO, n=4) had diplopia with a mean score ∼2. 93%(39) of teprotumumab pts completed the study. At Wk 24, proptosis improvements from BL were significantly greater in the teprotumumab group [2.41 (0.228) mm] vs PBO [0.92(0.323) mm], P<.001. Proptosis response was observed in 26/42 (62%) of teprotumumab pts vs 5/20 (25%) of PBO, P=.01. Diplopia improvement was observed in 6/14 (43%) teprotumumab pts with resolved diplopia in 4(29%) vs 2/4(50%) in PBO and 1(25%) resolved. Significantly greater improvement from BL was observed on GO-QoL-VF for teprotumumab (8.73) vs PBO (2.41), P=.03. Change from BL on AP was 10.03 vs 7.19, P= .65. TEAEs proportions were similar: 33/41(80.5%) of teprotumumab, and 16/20(80%) of PBO pts. Hyperglycemia was reported in 6(15%) vs 2(10%) and hearing impairment in 9(22%) vs 2(10%), respectively. There were two AE discontinuations: teprotumumab (left ear conductive hearing loss with congenital anomaly) and PBO (infusion related). Conclusions: For the first time in pts with longstanding TED and low CAS/inflammation, a medical therapy, teprotumumab, produced significant improvement in proptosis as compared with PBO supporting its use regardless of TED duration or activity. The safety profile was comparable to that previously reported. Presentation: Saturday, June 17, 2023

Abstract Disclosure: C.D. Zhang: None. S. Singh: None. J. Saini: None. M. Suresh: None. K. Thangamuthu: None. R. Nathani: None. A.L. Ebbehøj: None. V. Fell: None. S.J. Achenbach: None. E.J. Atkinson: None. S. Khosla: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have higher rates of fractures compared to patients with non-functioning adrenal nodules, but bone mass is typically only modestly reduced. We hypothesized that chronic exposure to mild levels of cortisol excess may lead to a deterioration in bone quality. Objective: To characterize the effect of MACS on bone metabolism and bone microarchitecture, as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods: In this cross-sectional single-center study, patients with MACS were matched by age, sex, and gonadal status to referent subjects without adrenal nodules. MACS was defined as serum cortisol concentration >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (1-mg DST), in the absence of a classic Cushingoid phenotype. Those with other known secondary causes of osteoporosis and/or on pharmacologic treatment for low bone mass were excluded. All study participants underwent a bone health interview, blood draw for bone turnover markers, dual-energy x-ray absorptiometry (DXA) scan with trabecular bone score (TBS), and HR-pQCT of the non-dominant radius and tibia. Participants with a recent fracture within 12 months were excluded from the analysis of bone turnover markers. The Kruskal-Wallis test was used to compare measurements between groups. Results: A total of 82 patients with MACS and 82 referent subjects were prospectively enrolled between 1/2019 and 7/2022. The median age of study participants at the time of enrolment was 57 years (interquartile range [IQR], 47-65), and 57 (70%) were women. In the MACS cohort, the median cortisol following 1-mg DST was 3.2 mcg/dL (IQR, 2.3-6.5) with median ACTH of 8.7 pg/mL (IQR, 6.0-14.0) and median DHEA-S of 42.0 mcg/dL (IQR 23.0-68.0). While no differences in bone mineral density (BMD) were observed at any site (lumbar spine, total hip, femoral neck, or distal radius) between the two groups, patients with MACS had decreased TBS (1.374 vs 1.467, P <0.001) and lower osteocalcin concentrations (16.9 vs. 19.7 ng/mL, P = 0.005) than referent subjects without adrenal nodules. On HR-pQCT at the tibia, patients with MACS had significantly reduced trabecular volumetric BMD (151.6 vs 167.4 mg hydroxyapatite/cm3, P = 0.002), trabecular bone volume/tissue volume ratio (0.219 vs 0.237, P = 0.011), and number of trabeculae (1.428 vs 1.506 1/mm, P = 0.045), while trabecular separation (0.707 vs 0.656, P = 0.023) was increased compared to referent subjects. Conclusions: Patients with MACS have altered bone metabolism and microstructural deterioration that is not evident on routine DXA BMD testing. These changes may mediate their increased fracture risk and could serve as biomarkers of cortisol-induced changes in the bone. Presentation: Thursday, June 15, 2023

Abstract Disclosure: J. Saini: None. R. Nathani: None. S. Singh: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. S. Khosla: None. I. Bancos: None. Background: Previous studies reported that both cortisol secretion and bone metabolism biomarkers follow a circadian pattern of secretion. Patients with mild autonomous cortisol secretion (MACS) demonstrate an increased risk of fractures. As most patients with MACS do not have increased cortisol production, we hypothesized that abnormal circadian cortisol secretion is associated with impaired bone metabolism. Objective: To compare the circadian secretory pattern of bone metabolism biomarkers in relation to cortisol circadian secretion in patients with MACS versus referent subjects. Methods: We conducted a pilot cross-sectional study of patients with MACS and referent subjects. MACS was diagnosed in patients with adrenal adenomas based on an abnormal 1 mg dexamethasone suppression test (cortisol >1.8 mcg/dL). Referent subjects with available abdominal imaging within 5 years and adrenal disorder were recruited from the community. Participants were admitted to the clinical research unit for blood sampling every 2 hours over 24h period. Measurements included total and free cortisol, calcium, parathyroid hormone (PTH), osteocalcin, amino-terminal propeptide type 1 collagen (PINP), and carboxy-terminal telopeptide of type 1 collagen (CTX). Subjects with disorders or medication affecting bone metabolism were excluded. Time periods of blood draw were categorized into the morning (6 to 12 hours), afternoon (14-18 hours) and night (20-2 hours). Delta (morning measurements/afternoon measurements) was calculated. Results: Subjects included 12 patients with MACS (median age 57, IQR 48-67, 83% women) and 10 referent subjects (median age 57, IQR 50-63, 80% women). The 24-hour area under the curve for total (10342 vs 9090 mcg/dL, p=0.468) and free cortisol (437 vs 329 mcg/dL, p=0.086) was no different between patients with MACS and referent subjects. However, the mean night total (6.7 vs 4.3 mcg/dL, p=0.056) and free cortisol (0.2 vs 0.1 mcg/dL, p=0.035) was higher in MACS vs referent subjects. The area under the curve for calcium, phosphorus, CTX, osteocalcin and PINP were similar between patients and referent subjects, however, the area under the curve for PTH was higher in patients vs referent subjects (mean 64179 vs 42602 pg/mL, p=0.021). Both delta total cortisol (mean 8.6 vs 5.5, p=0.01) and delta PTH (mean -1.5 vs 4.2, p=0.051) was higher in referent subjects vs patients with MACS. Conclusion: When compared to referent subjects, patients with MACS have similar 24-hour cortisol production but demonstrate an increase in night-time cortisol secretion and a blunting of diurnal cortisol (lower morning/afternoon cortisol). Patients with MACS have higher PTH production overall, as well as an abnormal diurnal PTH secretion. Noted abnormalities in PTH may contribute to the MACS-associated impairment in bone health. Presentation: Thursday, June 15, 2023