Citations

Abstract Disclosure: N. Lanka: None. S. Palakodeti: None. O. Oluwasolabomi: None. R. Nalam: None. G. Rangari: None. Introduction: PCOS is a complex condition with multifactorial etiology. GLP-1 RAs are used in insulin-resistant disorders like PCOS for their effects on weight and glycemic control. Recent studies suggest they may also improve follicular growth, endometrial health, ovulation, and fertility, independent of weight loss. This study evaluates the effects of GLP-1 RAs on anthropometric, metabolic, and reproductive parameters in PCOS. Methods: We followed PRISMA 2020 guidelines. We searched PubMed and Cochrane Library (2015-Feb 2025) using relevant keywords. We included RCTs and cohort studies with PCOS patients (per Rotterdam criteria) receiving GLP-1 RA monotherapy compared to placebo, metformin, or other interventions, reporting anthropometric, metabolic, or reproductive outcomes. Statistical analysis was performed using RevMan 5.4 with random-effects models, and heterogeneity was assessed using the I2 coefficient (p<0.05 considered significant). Results: We identified 73 studies, with 10 RCTs included (730 participants). Of these, 50.13% received GLP-1 RAs (49.5% liraglutide, 41% exenatide, 9.56% dulaglutide, 2.73% semaglutide), and 45.9% were controls (42.2% metformin, 20.3% placebo, others combination therapy). The meta-analysis findings are as follows: Anthropometric Outcomes: GLP-1 RAs caused significant reductions in BMI (9 studies, MD = -1.41, 95% CI: -1.73 to -1.10, p<0.00001, I2=100%) and waist circumference (8 studies, MD = -2.69, 95% CI: -4.06 to -1.32, p=0.0001, I2=100%). 1 study showed liraglutide reduced VAT (p=0.006). Metabolic Outcomes: GLP-1 RAs had a non-significant effect on HOMA-IR (7 studies, MD = -0.03, 95% CI: -0.82 to 0.76, p=0.94, I2=100%) and LDL (7 studies, MD = -0.45, 95% CI: -1.31 to 0.40, p=0.30, I2=100%). 3 studies showed improvement in OGTT, and 1 showed a significant reduction in HbA1C (p=0.015). Reproductive Health Outcomes: GLP-1 RAs caused a significant decrease in total testosterone (10 studies, MD = -0.78, 95% CI: -1.02 to -0.55, p<0.00001, I2=99%). LH decreased non-significantly (4 studies, MD = -1.96, 95% CI: -4.18 to 0.26, p=0.08, I2=99%), while FSH increased non-significantly (4 studies, MD = 0.29, 95% CI: -0.69 to 1.27, p=0.56, I2=99%). Two studies showed significant improvements in menstrual regularity with liraglutide and exenatide (p=0.0001 and <0.001, respectively). Conclusion: Our findings suggest GLP-1 RAs could become key therapies for managing this condition. However, heterogeneity among studies—due to differences in design, drug used, control, and dosing—requires further studies to explore optimal dosages, durations, combination therapies, and their impact on ovulation and fertility. Presentation: Monday, July 14, 2025

Abstract Disclosure: M. Kakakhel: None. F. Saleem: None. A. Ullah: None. K. Abdul Rehman: None. M.H. Alsaadi: None. H. Ahmad: None. A. Qadeer: None. R. Haider: None. M. Khawar: None. H. Jawad: None. J. Ikram: None. M. Filal: None. F. Ahmed: None. R.W. Kirchoff: None. Background: Thyroid disorders are common endocrine disorders including thyrotoxicosis, thyroiditis, hypothyroidism, and autoimmune thyroid diseases. Although it affects an estimated 200 million people globally, the epidemiology of this condition remains underexplored. Here we aimed to investigate mortality trends attributable to thyroid disorders in the US stratified by year, sex, race, and region. Methods: Using data from the CDC WONDER database, we calculated the crude and age-adjusted mortality rates (AAMRs) per 1,000,000 individuals (≥25 years) and used Joinpoint regression to determine annual and average annual percent change (AAPC) in the mortality trends. Results: Between 1999 and 2020, 561,089 deaths were recorded among patients with thyroid disorders in the United States, with an overall increasing trend in mortality (AAPC = 0.78). The age-adjusted mortality rate (AAMR) declined gradually from 1999 to 2018 (APC = -0.43, 95% CI: -0.65 to -0.22) before rising sharply from 2018 to 2020 (APC = 13.05, 95% CI: 6.39 to 20.12). Females had a higher AAMR (139.75) than males (81.99). Among racial and ethnic groups, Whites exhibited the highest AAMR (124.09), followed by American Indian or Alaskan Natives (121.36), Hispanics (89.13), Black or African Americans (88.44), and Asian or Pacific Islanders (59.36). Regional disparities showed the highest AAMR in the Midwest (130.45) and the lowest in the South (109.40). West Virginia (199.93) and North Dakota (198.82) reported the highest state-level AAMRs, while Nevada (60.18) and Florida (65.49) had the lowest. Non-metropolitan areas experienced higher mortality rates (141.04) than metropolitan areas (112.21), underscoring significant geographical and demographic variations in thyroid disorder-related mortality. Conclusion: Adults in the US have shown a rising trend in Thyroid-related deaths, with the highest mortality rates seen in females, Whites, and people living in the Midwest and Non-metropolitan areas. Our study also highlights the disparities across different demographics. Policy makers should focus on equitable access to healthcare to control this increasing mortality. Presentation: Monday, July 14, 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: A. Prete: HRA Pharmaceuticals, Lundbeck, Diurnal. L. Adbi: None. J.T. Bain: None. F. Shaheen: None. O. Suntornlohanakul: None. E. Deflorenne: None. A. Blanchard: None. M. Nestola: None. C. Pamporaki: None. I. Tizianel: None. E. Nowak: None. J. Bertherat: None. D.A. Vassiliadi: None. I. Bancos: None. C.M. Dennedy: None. D. Kastelan: None. M. Fassnacht: None. P. Mulatero: None. U. Ambroziak: None. A. Tabarin: None. M. Quinkler: None. S. Puglisi: None. J. Deinum: None. G.Å. Ueland: None. L. Lenzini: None. F. Beuschlein: None. M. Reincke: None. F. Ceccato: None. G. Eisenhofer: None. S.M. Corsello: None. L. Amar: None. M. Zennaro: None. N. Karavitaki: None. A.E. Taylor: None. W. Arlt: None. Introduction: Twenty-four-hour urinary free cortisol is used to diagnose Cushing’s syndrome (CS); amongst its limitations is failure to differentiate ACTH-dependent CS (AD-CS) from ACTH-independent CS (AI-CS). We tested the performance of urine steroid metabolomics (USM), the computational analysis of 24-hour urine steroid metabolome data by machine learning, for the diagnosis and differential diagnosis of CS. Given the physiological diurnal rhythm of cortisol secretion and its loss in CS, we also hypothesised that the difference in glucocorticoid excretion between CS and controls should be higher during nighttime, thereby facilitating more sensitive detection of CS. Methods: 264 subjects completed a 24-hour urine collection (40 AD-CS, 103 AI-CS due to adrenocortical adenoma or hyperplasia, 121 healthy subjects). A subset of 52 individuals (13 CS, 39 healthy) provided a nighttime urine collection and a daytime urine collection. Mass spectrometry-based multi-steroid profiling was used to quantify the urinary excretion of 27 steroid metabolites. Data were analysed by generalised matrix learning vector quantisation (a prototype-based supervised machine learning approach), multiple linear regression adjusted for age, sex, and BMI, and multiple logistic regression adjusted for age, sex, and BMI. Results: Twenty-four-hour USM demonstrated very high accuracy in differentiating CS from healthy individuals (AUC-ROC 0.99, 95%CI 0.99-0.99), reflected by higher urinary excretion of glucocorticoid and glucocorticoid precursor metabolites in CS. USM yielded high accuracy in differentiating AD-CS from AI-CS (AUC-ROC 0.91, 95%CI 0.89-0.94), with androgen metabolites being the most discriminatory. We observed significant sex differences in steroid excretion in both healthy individuals and those with CS. Women exhibited markedly lower excretion of both glucocorticoids and mineralocorticoids compared to men: average glucocorticoid excretion was reduced by 43% in healthy women and 30% in CS women, while average mineralocorticoid excretion was 29% lower in healthy women and 51% lower in CS women (results adjusted for age and BMI). Timed steroid excretion in healthy individuals reflected the diurnal pattern of adrenal steroid secretion, with lower nighttime than daytime excretion of glucocorticoid metabolites. Nighttime glucocorticoid metabolite excretion (AUC-ROC 1.00, 95%CI 0.99-1.00) performed better than daytime (AUC-ROC 0.91, 95%CI 0.77-1.00) and 24-hour excretion (AUC-ROC 0.94, 95%CI 0.86-1.00) in separating CS cases from healthy individuals. Conclusions: USM is a non-invasive, one-step candidate test for the accurate diagnosis and differential diagnosis of CS. Timed nighttime urine collection leverages cortisol circadian rhythmicity and improves the diagnostic accuracy of the current reference standard 24-hour collection. 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

Background: Adolescents and young adults (15–39 years of age at time of diagnosis: AYA) with sarcoma are a unique patient population. The objective of this review is to examine the literature outlining the benefits of proton beam therapy (PBT) for treatment of AYA sarcoma patients, barriers to PBT, evaluation of AYA-specific considerations and challenges, and exploration of future opportunities for improvements in care. Methods: An electronic search was conducted using databases and online search engines, primarily PubMed. The search criteria included studies and reviews completed from 2015 to 2025. Results: 57 articles were reviewed and categorized into sections: PBT for the treatment of the AYA patient, barriers to PBT, AYA-specific considerations and challenges, and future directions for the care of an AYA patient. Conclusions: Through this review, PBT can be deemed necessary when treating AYA sarcoma patients with radiation therapy to decrease long-term therapy-related toxicities. Furthermore, considerations for caring for an AYA sarcoma patient must extend beyond evidence-based treatment plans and must embrace the patient as a whole person through acknowledgement of the challenging impact on physical, mental, and social well-being from symptoms to diagnosis, diagnosis to treatment, and treatment to survivorship.

INTRODUCTION: We conducted a retrospective cohort study comparing the safety of advanced therapies in patients with ulcerative colitis (UC). METHODS: Using an administrative claims database (OptumLabs Data Warehouse), we identified patients with UC who initiated treatment with tumor necrosis factor-α (TNF) antagonists, anti-integrin agents, anti-interleukin, Janus kinase inhibitors (JAK), or sphingosine-1 phosphate receptor modulators between 2016 and 2022 and had followed up for at least 1 year before and after treatment initiation. We compared the risk of serious infections, venous thromboembolism, and major adverse cardiovascular events through multinomial propensity score-based inverse probability weighting, with propensity scores estimated through generalized boosted models that accounted for disease characteristics, healthcare utilization, comorbidities, and previous and concomitant medications, and the competing risk of mortality. We calculated cause-specific hazard ratios (HR) and 95% confidence intervals for multiple treatment comparisons. RESULTS: We included 9,430 patients with UC treated with TNF antagonists (n = 4,111), anti-integrins (n = 3,165), anti-ILs (n = 1,342), JAK inhibitors (n = 701), or sphingosine-1 phosphate receptor modulators (n = 111), followed over median 27 months. After adjusting for confounding variables, anti-ILs were associated with a lower risk of serious infections compared with TNF antagonists (HR, 0.66 [95% confidence interval, 0.51–0.87]) and anti-integrins (HR, 0.75 [0.57–0.98]). JAK inhibitors were associated with a lower risk of serious infections compared with TNF antagonists (HR, 0.66 [0.46–0.94]). The incidence of venous thromboembolism (incidence rate, 1.4–2.0 per 100 py) and major adverse cardiovascular event (0.5–1.0 per 100 py) was very low, without any significant differences across agents. DISCUSSION: In a real-world cohort of patients with UC, anti-ILs and JAK inhibitors were associated with a lower risk of serious infections and may offer net benefit, especially in patients with previous TNF antagonist exposure.

Abstract » The coronal plane alignment of the knee (CPAK) classification is a practical and straightforward framework to define a patient’s constitutional coronal knee limb alignment and joint line obliquity. » Patients are assigned to one of nine phenotypes using two straightforward calculations; the arithmetic hip-knee-ankle angle (aHKA) and the arithmetic joint line obliquity (aJLO). » CPAK allows clear understanding of the geographical and gender variations in knee alignment, as well as the differing outcomes of knee reconstructive surgery, based on phenotype. » CPAK enables surgeons to tailor their alignment strategy to best fit a patient’s constitutional phenotype and avoid the drawbacks of a “one-size fits all” approach.