Saini, Jasmine

Abstract Context Patients with mild autonomous cortisol secretion (MACS) have higher rates of vertebral fractures compared to patients with non-functioning adrenal nodules, yet bone density is not always reduced. Objective To characterize the effect of MACS on bone density, metabolism, and microstructure as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT). Design Cross-sectional study, 2019-2022 Setting Tertiary referral center Participants Seventy-five patients with MACS and 75 age-, sex-, and gonadal status–matched referent subjects. Measurements Bone turnover markers, dual-energy x-ray absorptiometry (DXA) scan, and HR-pQCT. Outcomes Areal and volumetric bone mineral density (aBMD, vBMD), trabecular bone score (TBS), microstructural parameters including trabecular bone volume to total volume (BV/TV) ratio. Results While no differences in aBMD were observed at any skeletal site, patients with MACS had decreased TBS (1.389 vs 1.475, P < .001) and lower osteocalcin concentration (17.1 vs 19.5 ng/mL, P = .030) than referent subjects. On HR-pQCT at the tibia, patients with MACS had reduced trabecular BV/TV (0.220 vs 0.233, P = .015) compared to referent subjects. On multivariable analysis, MACS was associated with lower TBS (odds ratio [OR] per SD decrease 2.87 [1.65-5.00]), lower trabecular BV/TV at the radius (OR per SD decrease 2.58 [1.33-5.00]), and lower trabecular BV/TV at the tibia (OR per SD decrease 4.06 [2.10-7.86]). Conclusion Patients with MACS have microstructural deterioration that may not be evident on routine DXA aBMD testing.

Abstract Context Data on cognition in patients with primary aldosteronism (PA) are scarce. Mild autonomous cortisol secretion (MACS), defined based on post-dexamethasone cortisol >1.8 mcg/dL, is diagnosed in up to 30% of patients with PA. Objectives (1) Assess cognition in patients with PA vs referent subjects with hypertension and (2) determine differences in cognition between patients with PA and those with MACS. Methods A prospective, cross-sectional study, 2019-2023. Cognition was assessed by National Institute of Health Toolbox Cognition Battery and reported as T-scores corrected for age, sex, race, and education. Only subjects with hypertension were included. Results Cognitive assessment was performed in 52 patients with PA (including 11 patients with both PA and MACS, median age of 51.0 years, 30 (57.7%) women), 47 patients with MACS (median age of 57.0 years, 31 (66.0%) women), and 52 referent subjects (median age of 66.1 years, 30 (57.7%) women). When compared to referents, and after adjusting for age, smoking, systolic blood pressure, and alcohol use, patients with PA had lower total cognition (β = −5.7, P = .023), notably fluid cognition (β = −6.8, P = .017), including attention and executive function (β = −5.6, P = .012) and cognitive flexibility and executive function (β = −8.2, P = .006). When compared to patients with MACS, patients with PA had a higher processing speed (β = 9.0, P = .003). No differences in cognition were found between patients with PA with and without MACS. Conclusion Patients with PA demonstrated lower cognition compared with referents and processing speed compared with MACS. Future studies should characterize the impact of MACS on the cognition of patients with PA.

Abstract Context Evidence on the evolution of cardiometabolic comorbidities following surgical remission of hypercortisolism is scarce. Objective To determine the impact of surgical remission on cardiometabolic comorbidities in patients with endogenous hypercortisolism and to identify factors associated with cardiometabolic improvement. Methods Prospective single-center cohort study (2019-2025) of adults with Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS) with surgical remission of hypercortisolism. Outcomes included (1) changes in severity of hypertension, diabetes mellitus (DM), hyperlipidemia, and obesity between baseline, 3, and 12 months postremission and (2) factors associated with improvement in comorbidities. Results Among 357 patients (49% MACS, 36% pituitary CS, 10% adrenal CS, 5% ectopic CS; median age 53 years [interquartile range 42-62]; 81% women), 336 (94%) had hypertension, 241 (68%) had obesity, and 122 (35%) had DM. At a median of 12 months postsurgery, improvement in hypertension occurred in 70% (90/128) of patients with CS and 51% (60/117) of patients with MACS, DM in 90% (46/51) patients with CS and 37% (13/35) patients with MACS, and obesity in 79% (77/97) patients with CS and 20% (14/71) patients with MACS. In a multivariable analysis, higher baseline biochemical severity scores were associated with improvement in hypertension [odds ratio (OR) 1.3, 95% confidence interval (CI) 1.1-1.5), DM (OR 2.5, 95% CI 1.7-4.1), and obesity (OR 1.5, 95% CI 1.2-1.8) at a median of 12 months postremission of hypercortisolism. Conclusion Postsurgical improvement of cardiometabolic comorbidities was observed in both patients with CS and MACS. Higher baseline biochemical severity scores were associated with higher postremission improvement in comorbidities.

Abstract Disclosure: K. Yu: None. J. Saini: None. E.J. Atkinson: None. S.J. Achenbach: None. V. Fell: None. I. Bancos: None. Background: Data on cognition in patients with primary aldosteronism (PA) are scarce. Mild autonomous cortisol secretion (MACS), defined based on post-dexamethasone cortisol >1.8 mcg/dL, is diagnosed in 20-30% of patients with PA. The impact of MACS on the cognition of patients with PA is unclear. Objectives: 1) to assess cognition in patients with PA versus sex-matched referent subjects with hypertension, 2) determine the differences in cognition of patients with PA (with and without MACS) and patients with MACS. Methods: A cross-sectional study, 2019-2023. Cognition was assessed by National Institute of Health Toolbox Cognition Battery and reported as T-score corrected for age, sex, race, and education. Only subjects with hypertension were included. Results: Cognitive assessment was performed in 52 patients with PA (including 11 patients with both PA and MACS, median age of 51 yrs, 30, 58% women), 47 patients with MACS (median age of 57 yrs, 31, 66% women), and 52 referent subjects (median age of 66 yrs, 30, 58% women). When compared to referents, and after age adjustment, patients with PA had lower cognition: fluid composite cognition β of -6.3 (P=0.014) and total composite of -5.6 (P=0.016). When compared to patients with MACS, and after age and sex adjustment, patients with PA had a similar total composite cognition score (β=3.6, P=0.108) but a higher fluid composite score (β=4.7, P=0.044). No differences in cognition were found between patients with PA with and without MACS, possibly due to low sample size. Conclusion: Patients with PA demonstrate lower cognition when compared to referents with hypertension. Patients with PA had a higher fluid cognition compared to patients with MACS. Future studies should delineate the impact of hyperaldosteronism vs MACS on cognition of patients with PA. Presentation: Monday, July 14, 2025

Abstract Disclosure: S.R. Chacko: None. J. Saini: None. S. Sharma Sharma: None. S. Ahmadian: None. S.J. Achenbach: None. E. Atkinson: None. V. Fell: None. J.J. Van Gompel: None. W.F. Young, Jr.: None. I. Bancos: None. Context: Evidence on the duration of postoperative adrenal insufficiency (AI) in patients with endogenous hypercortisolism is scarce. Objective: To determine the duration of postoperative AI and to identify factors associated with the duration of AI in patients undergoing surgery for endogenous hypercortisolism.Methods: We conducted a single center prospective cohort study, 2019-2024, of patients with endogenous hypercortisolism [Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)] treated with surgery. Associations of demographics, BMI, clinical and biochemical hypercortisolism severity, subtype of hypercortisolism, presurgical hypercortisolism duration and glucocorticoid type in relation to duration of AI were investigated. Results: The 110 patients [36% MACS, 46% pituitary CS, 15% adrenal CS, 3% ectopic CS, median age 50 years (IQR: 40-60), 82% women] who developed postsurgical AI were followed for a median duration of 26 months (IQR: 15-38). By the end of follow up, 96 patients (87%) had recovery of AI. The median time to recovery of AI was shorter in MACS vs. Overt Cushing syndrome (3.0 months (95% CI: 2.5-6.2) vs. 12.3 months (95% CI 9.0-17.3), P =0.002). Biochemical severity score (r=0.32, P=0.002) and duration of preoperative hypercortisolism symptoms (r=0.29, P=0.005), but not age, sex, BMI, clinical severity, or glucocorticoid type were associated with the duration of AI. We found no differences in the duration of AI between patients with ACTH-dependent vs ACTH-independent CS (12.3 months (95% CI: 6.0-17.2) vs 13.9 months (95% CI: 9.0-25.5), P =0.7).Conclusion: In this interim analysis, we showed that after surgical remission of endogenous hypercortisolism, duration of postoperative AI was longer in CS compared to MACS. Additionally, higher biochemical hypercortisolism severity score and a longer duration of symptoms suggestive of hypercortisolism were associated with a longer duration of postoperative AI. Presentation: Sunday, July 13, 2025

Abstract Disclosure: J. Saini: None. E. Ferreira Taveras: None. Y. Hleibiehova: None. B. Bahrani Fard: None. M. Suresh: None. R. Sandooja: None. B. Salama: None. V. Fell: None. S. Achenbach: None. E.J. Atkinson: None. I. Bancos: None. Context: Patients with endogenous hypercortisolism experience glucocorticoid withdrawal syndrome (GWS) post-surgery. Meditation may be an effective intervention to alleviate the severity of GWS. Objective: To determine the acceptability of portable, wearable EEG device for guided meditation (MUSE headband) and the impact of MUSE use on GWS and quality of life 12 weeks post-surgery. Methods: We conducted a single-center prospective cohort study of adults with endogenous hypercortisolism undergoing curative surgery, 2019-2024. Patients had baseline and post-surgical assessments over 12 weeks. The study comprised of patients using MUSE for ≥ 6 weeks (MUSE cohort) and patients matched by age, sex, BMI, hypercortisolism type, and glucocorticoid type at 1:4 ratio. Quality of life and symptoms of GWS were assessed with AddiQoL, Cushing Quality of Life, and Short Form-36 mental and physical component (SF-36 MCS and PCS) questionnaires. Results: MUSE was offered to 52 patients, and 22 (42%) used MUSE for ≥ 6 weeks within 12 weeks post-surgery. At baseline, when compared to 88 matched subjects, 22 MUSE participants demonstrated a similar prevalence of comorbidities, clinical and biochemical hypercortisolism severity, but lower AddiQoL (mean 73 vs 66, P=0.031) and SF-36 MCS (mean 39 vs 33, P=0.022). At 12 weeks, these differences in quality of life were no longer present. After adjusting for age, sex, BMI, clinical severity score, and baseline quality of life, MUSE use was an independent predictor of improved SF- 36 PCS at 12 weeks post-surgery (beta 4.2, 95% CI: 0.5-7.9, P=0.026). Conclusions: Meditation intervention post-surgery may improve symptoms of GWS and accelerate recovery. Presentation: Sunday, July 13, 2025

Abstract Disclosure: S. Sharma Sharma: None. J. Saini: None. S.R. Chacko: None. S. Ahmadian: None. V. Fell: None. S.J. Achenbach: None. E.J. Atkinson: None. W.F. Young: None. I. Bancos: None. Context: The impact of active hypercortisolism on sleep is incompletely characterized. Several studies report impaired sleep in patients with Cushing syndrome (CS). Patients with mild autonomous cortisol secretion (MACS) demonstrate an abnormal circadian cortisol secretion with mild nocturnal hypercortisolism that could also impact sleep. Objectives: To characterize sleep abnormalities and to identify factors associated with impaired sleep in patients with CS and MACS. Methods: We conducted a single-center cross-sectional study of prospectively enrolled adults with active CS and MACS evaluated between August 31, 2020, and December 2, 2024. Clinical and biochemical severity scores for hypercortisolism were calculated. Quality of life (QoL) was assessed using 1) Short Form-36 (SF-36), physical (PCS) and mental (MCS) component summaries, and 2) Cushing QOL survey, with psychosocial and physical domains. Sleep quality was assessed using Pittsburgh Sleep Quality Index (PSQI), a global score of ≥5 was considered abnormal. Pearson correlations and linear regression models were used to explore associations with PSQI scores. Results: In 285 patients (226 [79%] women, 259 [91%] White, median age of 54 [IQR 44-64] years), MACS was diagnosed in 147 (52%) and CS in 138 (48%). Patients reported abnormal sleep (median PSQI of 12 (IQR 8-16) in CS vs 10 (IQR 7-15) in MACS (P=0.086). Most prevalent sleep abnormalities included report of “fairly bad” or “very bad” overall sleep quality (73% in CS and 54% in MACS) and report of severe day dysfunction due to sleepiness (70% in CS and 56% in MACS). In an age-, sex- and BMI- adjusted univariable analysis of patients with hypercortisolism, higher clinical hypercortisolism severity score (r=0.13, P=0.024) and worse QoL, as measured by SF-36 and Cushing QoL (P=<0.001 for all), were associated with higher PSQI scores, a reflection of poor sleep. In a multivariable analysis of patients with hypercortisolism, we found that younger age (est -0.08, P=<0.001), female sex (est 1.95, P=0.004), lower BMI (est -0.07, P=0.041), and higher clinical severity score (est 0.12, P=0.024) were associated with higher PSQI scores, indicating impaired sleep. In a multivariable analysis of only patients with MACS, female sex (est 2.17, P=0.012), lower BMI (est -0.12, P=0.017), and higher clinical severity score (est 0.24, P=0.003), but not age were associated with higher PSQI scores, indicating impaired sleep. In patients with CS, only younger age (est -0.12, P=<0.001), but not other variables were associated with higher PSQI scores. Conclusion: We found that patients with MACS have impaired sleep, possibly due to nocturnal hypercortisolism. In patients with MACS, but not CS, clinical hypercortisolism severity score was associated with more impaired sleep. Presentation: Sunday, July 13, 2025

Abstract Disclosure: S. Sharma Sharma: None. J. Saini: None. S.R. Chacko: None. S. Ahmadian: None. V. Fell: None. S. Achenbach: None. A. Peersen: None. E. Atkinson: None. W.F. Young: None. I. Bancos: None. Context: Patients with MACS demonstrate an abnormal circadian cortisol secretion with mild nocturnal hypercortisolism that could impact sleep. Objectives: 1) To characterize sleep abnormalities and to identify factors associated with impaired sleep in patients with MACS. 2) To compare sleep abnormalities between patients with MACS and referent subjects. Methods: We conducted a single-center cross-sectional study of prospectively enrolled adults with MACS evaluated between August 31, 2020, and April 03, 2025. In parallel, we conducted a referent subject study between May 15, 2019, and May 02, 2023. Referent subjects were eligible if they had abdominal cross-sectional imaging without evidence of an adrenal mass. For patients with MACS, clinical and biochemical severity scores for hypercortisolism were calculated. In both groups, quality of life was assessed using Short Form-36 (SF-36), physical (PCS) and mental (MCS) component summaries. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), a global score of ≥5 was considered abnormal. Pearson correlations and linear regression models were used to explore associations with PSQI scores. Results: The total cohort included 167 patients with MACS and 89 referent subjects. No differences in age (median 60 vs 56 years, P= 0.122) and sex (71% vs 67% females, P= 0.523) were observed between patients with MACS and referents. However, median BMI was higher in patients with MACS (32 28 kg/m2 [IQR 28-38] vs 28 kg/m2 [IQR 24-32], P= < 0.001). Patients with MACS had more impaired sleep than referent subjects (median PSQI 11 [IQR 7-15] vs 5 [IQR 3-7], P= <0.001). In an age-, sex- and BMI- adjusted univariable analysis, lower PCS and MCS scores were associated with poor sleep in both referents (r= -0.45, P= <0.001 and r= -0.29, P= 0.008) and patients with MACS (r= -0.36 and -0.38, P= <0.001), however, the presence of obstructive sleep apnea (OSA) was not. In patients with MACS, both higher clinical and biochemical severity scores were associated with poor sleep (r=0.20, P=0.012) and (r= 0.15, P= 0.050). Multivariable analysis of age, sex, BMI, clinical severity and OSA demonstrated that women (est 2.35, P= 0.004), lower BMI (est -0.13, P= 0.014) and higher clinical severity score (est 0.17, P=0.026), but not OSA were associated with impaired sleep in patients with MACS. All PSQI subcomponents were higher in patients with MACS vs referents, indicating poor sleep-most significantly, sleep quality score (OR 3.93, 95% CI: 2.58-6.29), sleep disturbance score (OR 3.73, 95% CI: 2.28-6.37) and daytime dysfunction score (OR 4.74, 95% CI: 2.29-10.75). Conclusion: Patients with MACS report impaired sleep, and women with lower BMI and higher clinical hypercortisolism severity scores are more affected. Reversing abnormal nocturnal hypercortisolism may improve sleep. Presentation: Saturday, July 12, 2025

Abstract Disclosure: B. Salama: None. M. Bassiony: None. J. Saini: None. P. Dogra: None. E. Atkinson: None. J. Larson: None. I. Vodanovic: None. D. Kastelan: None. D.A. Delivanis: None. J. Hubska: None. U. Ambroziak: None. I. Bancos: None. Background: Frailty is a clinical syndrome characterized by diminished physiological reserve and increased vulnerability to stressors. Patients with Mild Autonomous Cortisol Secretion (MACS) demonstrate a high prevalence of frailty, however, no data are available on the impact of management on frailty progression. Objectives: To determine the impact of conservative vs surgical management on and the progression of frailty in patients with MACS. Methods: We conducted a multicenter prospective cohort study of patients with (MACS), primary aldosteronism (PA), or non-functioning adrenal adenomas (NFA) between June 2020 and April 2025. Participants completed standardized frailty assessment (frailty index) at baseline and annually. Results: A total of 691 patients were included: 253 with MACS (median age 62 years, 73% women, 230 with NFA (median age 62 years, 67% women), and 208 with PA (median age 54 years, 50% women). At baseline, prevalence of frailty was highest patients with MACS (39%), followed by patients with PA (31%) and NFA (24%). Frailty was reassessed at 1 year post baseline in 189 patients with NFA (22% frail, median frailty index of 0.17) and 116 patients with MACS (27% frail, median frailty index of 0.16) managed conservatively, as well as in 108 patients with MACS treated with adrenalectomy (49% frail, median frailty score of 0.24). Conservatively treated patients with MACS and those treated with adrenalectomy had similar post-dexamethasone cortisol (median 2.9 mcg/dL vs 3.1 mcg/dL, p=0.396), but were older (median age 65 years vs 58 years, p=0.001) At one year follow up, patients with MACS treated with adrenalectomy demonstrated an improvement in frailty when compared to conservative management (delta frailty index: Est of −0.044, p = 0.004), after adjusting for age and sex. In contrast, when compared to conservatively managed patients with NFA, conservatively managed patients with MACS demonstrated worse frailty at 1 year follow up (delta frailty index: Est of 0.028, p = 0.013). Conclusion: In comparison to patients with NFA, conservatively managed patients with MACS demonstrated worse frailty at 1 year follow up. In contrast, adrenalectomy in patients with MACS led to improvement of frailty. Frailty index could be valuable to identify patients most likely to benefit from adrenalectomy. Patients with higher baseline frailty scores were more likely to undergo adrenalectomy, Presentation: Sunday, July 13, 2025

Abstract Disclosure: S.R. Chacko: None. C. Powell: None. B. Ndovu: None. E.Y. Ferreira: None. R. Rosenberg: None. J. Saini: None. S. Nevin: None. K. Yu: None. V. Fell: None. J.J. Larson: None. E. Atkinson: None. I. Bancos: Funding for investigator-initiated research from Esteve. Context: Mild autonomous cortisol secretion (MACS), found in about 50% of patients with adrenal incidentalomas, is associated with increased cardiovascular morbidity. While adrenalectomy improves outcomes in unilateral MACS, safe and effective medical therapy is needed for bilateral MACS. Objectives: To evaluate the tolerability and safety of overnight metyrapone in adults with MACS. Methods: Study design: Open-Label, Phase 2, Clinical Trial (NCT06106295) Participants: Patients >18-years-old with MACS and benign adrenal imaging phenotype were prospectively enrolled between December 2023 and January 2025. MACS was diagnosed based on 1 mg post-dexamethasone suppression test serum cortisol >1.8 mcg/dL. Eligibility required at least one MACS-associated comorbidity (obesity, dysglycemia, dyslipidemia, hypertension, osteopenia or osteoporosis). Intervention: Metyrapone was administered at an initial dose of 250 mg each evening with up titration in 250 mg increments every 2-4 weeks based on tolerance, to a maximum of 1000 mg. Outcomes: The primary endpoint was assessment of treatment-related adverse events (AE), categorized by CTCAE grade. Adrenal insufficiency (AI) was considered an AE, assessed on biochemistry and AddiQoL survey. Sample size: 30 patients projected Results: Twenty-six patients with MACS [median age 66 years (IQR 61-68), 69% women] were enrolled. At the time of analysis, median metyrapone dose was 1000 mg (IQR 750-1000). At median follow-up of 3 months (IQR 2-6), 22 patients (85%) developed at least one AE. None were serious, aside from one patient with an acute kidney injury (AKI), unlikely related to metyrapone. All other AEs were CTCAE Grade 1-2, including dizziness 12%, nausea 6% and fatigue 5%. Of all 90 AEs, 12 (13%) occurred at a dose of 250 mg, 10 (11%) at 500 mg, 20 (22%) at 750 mg and 48 (53%) at 1000 mg. One (1%) was definitely related to metyrapone (hypokalemia), 16 (18%) probably related, 20 (22%) possibly related, 35 (39%) unlikely to be related, and 18 (20%) unrelated to metyrapone. Dose was reduced in 5 patients (19%) due to an AE. Two discontinued metyrapone, one because of AKI, while the other withdrew from the study. Morning serum cortisol was not significantly changed between baseline [11.5 (IQR 9.2-14.8)], 3 months [12.0 (IQR 11.0-15.0)], and 6 months [9.7 (IQR 7.9-12.5)] (normal: 4.8-20 mcg/dL). No patient developed AI (morning serum cortisol <10 mcg/dL and ACTH >60 pg/ml), but plasma ACTH significantly increased from baseline to 3 months [8.0 (IQR 5.4-20.8) vs. 18.0 (IQR 14.0-28.0), P=0.021] (normal: 10-60 pg/ml). Between 3 and 6 months, no significant change occurred in ACTH. AddiQol survey scores did not change significantly between baseline, 3 and 6 months. Conclusion: Metyrapone therapy in patients with MACS demonstrated a favorable safety profile with no occurrence of AI. Further investigation into efficacy and MACS-associated outcomes is warranted. Presentation: Sunday, July 13, 2025