Citations

Abstract Disclosure: M. Salama: None. F. Pinto e Vairo: None. D. Hassan: None. S. Pittock: None. A. Lteif: None. O. Olson: None. A. Al Nofal: None. K. Leopold: None. S. Kumar: None. Objective: This study aimed to evaluate the effects of semaglutide on body mass index (BMI) and cardiometabolic profiles in adolescents with genetic variants associated with a likely high risk of monogenic obesity. Methods: A retrospective chart review was conducted for adolescents with severe obesity who underwent multigene panel testing for monogenic obesity and were treated with semaglutide. Results: Data from 27 adolescents were analyzed. At baseline, the median BMI percent of the 95th percentile (IQR) was 148 (135-189), with a mean age (SD) of 15.5 years (1.93) at treatment initiation and a median (IQR) treatment duration of 8 months (6-12). The median semaglutide dose (IQR) was 1.7 mg weekly (1.0- 2.4). Seven participants comprised the ‘’likely monogenic risk’’ group, characterized by predicted deleterious variants in dominant genes and/or carrying known dominant risk alleles. Twenty patients formed the “indetermined/negative “group, defined as harboring single rare variants in recessive genes or negative panel testing. In the likely monogenic risk group, weight loss was 8.5% with a median decrease in BMI % of the 95th %ile of 17 (95% CI 1.5- 22, p = 0.02). In the indetermined/negative group, weight loss was 7.6% with a median decrease in BMI % of the 95th %ile of 14 (95% CI 11.5- 27.5, p = <0.001). There was no statistically significant difference in median BMI % of the 95th % ile reduction between the two groups (p = 0.8) or BMI percent change (p = 0.89). Cardiometabolic changes in the likely monogenic risk group included reductions in HbA1c by 0.3% (95% CI: 0.15- 0.4, p = 0.03), total cholesterol by 15 mg/dL (95% CI: 7- 48, p = 0.03), and non-HDL cholesterol by 16.5 mg/dL (95% CI: 12- 40, p = 0.03). No significant changes were observed in fasting blood glucose, triglycerides, LDL cholesterol, HDL cholesterol, or ALT levels. The indetermined/negative group exhibited a significant reduction in HbA1c by 0.25% (95% CI 0.1 - 0.7| p = 0.009). Conclusion: Semaglutide treatment was associated with significant reductions in BMI and improvements in several cardiometabolic parameters in adolescents with likely high-risk monogenic obesity variants. These findings suggest semaglutide as a potentially effective therapeutic option for managing severe obesity in this population. Larger prospective studies are warranted to confirm and further assess these outcomes. Presentation: Monday, July 14, 2025

Abstract Disclosure: D. Hassan: None. M. Salama: None. K. Muthusamy: None. A.M. Haqq: None. S. Kumar: None. Introduction: Bardet-Biedl syndrome (BBS) is a rare genetic condition characterized by obesity and considerable clinical and genetic heterogeneity. While cardiometabolic and endocrine comorbidities are commonly associated with BBS, data on their prevalence, particularly in children, remain limited. Objective: To assess the prevalence of cardiometabolic and endocrine comorbidities among pediatric and adult patients with BBS. Methods: This is a retrospective chart review of pediatric and adult patients with BBS evaluated in the outpatient setting at Mayo clinic. The cohort included individuals aged 0-50 years with either a clinical or genetic diagnosis of BBS, identified from January 1, 2000, onward. Demographic, anthropometric, phenotypic, and biochemical data were reviewed. Results: The study comprised 34 patients, including 9 children (median age 8 years (IQR: 3.5-11)) and 25 adults (median age 33.5 years (IQR: 27-42)). Females constituted 56% of the cohort and White individuals accounted for 76%. The median age at diagnosis of BBS was 9 years (IQR: 3-16). Phenotypic characteristics included retinal dystrophy in 33% of children and 92% of adults, polydactyly in 78% of children and 52% of adults, and learning disabilities in 56% of children and 52% of adults. Obesity was prevalent in 56% of children and 80% of adults. Among children, their median maximum BMI % of the 95th percentile was 149% (IQR: 136-163%). Adults had a a median maximum BMI of 50 kg/m² (IQR: 43-55). There was insufficient data to determine the onset of hyperphagia; however, the median age of obesity onset for the cohort was 7 years (IQR: 4-11). No cases of diabetes or prediabetes were identified among children, whereas 40% of adults were diagnosed with type 2 diabetes. Cardiometabolic characteristics included hypertension in 11% of children and 48% of adults, kidney dysfunction in 33% of children and 56% of adults. Dyslipidemia was noted in 22% of children and 44% of adults, with median triglyceride levels 133 mg/dL (IQR: 93-153) in children and 142 mg/dL (IQR: 120-200) in adults. No cases of cardiovascular disease were identified in children, whereas 8% of adults were diagnosed with the condition. Endocrine characteristics included hypothyroidism in 11% of children and in 24% of adults. Of the 34 patients, genotype data were available for 28 individuals (82%). The most prevalent genotype was BBS1, comprising 27% of the cases. This was followed by BBS2 and BBS10, which each accounted for 15% of the cohort. Genotypes BBS4, BBS6 (MKKS2), IFT172, and SCLT1 were each observed in 3% of the cohort. Conclusion: This study highlights the significant clinical, cardiometabolic, and endocrine burden associated with BBS across children and adults. These findings underscore the importance of early and comprehensive multidisciplinary management of BBS. Keywords: Bardet-Biedl syndrome, obesity, cardiometabolic, endocrine comorbidities. Presentation: Monday, July 14, 2025

Abstract Disclosure: H.M. Heshmati: None. H.S. Abu-Lebdeh: None. Background: Growth differentiation factor 15 (GDF15) is a peptide hormone produced by the placenta during pregnancy and by several other organs (e.g., prostate, bladder, kidney, pancreas, and endometrium). It is a member of the transforming growth factor-β superfamily. The gene encoding for GDF15 is located on chromosome 19. The mature GDF15 has 112 amino acids and binds to glial cell-derived neurotrophic factor family receptor alpha-like. GDF15 is involved in the maintenance of homeostasis and contributes to the pathogenesis of several medical conditions. This literature analysis provides an update on the relevance of GDF15 in health and few selected diseases. Methods: A systematic search of literature was conducted using the search terms growth differentiation factor 15, pregnancy, heart failure, anorexia, obesity, diabetes, and cancer. Results: In control subjects, the median serum GDF15 level is around 680 pg/mL and increases with aging. There is an increase in GDF15 secretion during pregnancy (third trimester serum levels > 20,000 pg/mL) and under other stressful conditions such as inflammation, myocardial ischemia, pulmonary diseases, diabetes, and cancer. GDF15 is involved in the maintenance of cell and tissue homeostasis. It has anti-inflammatory, immunomodulatory, and anorectic properties. The high serum GDF15 levels observed during pregnancy plays an important role in the feto-maternal immunotolerance. Low serum GDF15 levels have been reported in pregnancies with complications (e.g., preeclampsia and miscarriage). Serum GDF15 levels are negatively correlated with body mass index. Treatment with metformin in patients with or without type 2 diabetes stimulates GDF15 production, and this can explain, at least in part, the weight-loss property of metformin. In patients with heart failure or cancer, the increased serum GDF15 levels contribute to cachexia (anorexia and weight loss). Serum GDF15 level has the potential to be used as a biomarker for disease diagnosis and prognosis (e.g., biomarker for heart failure and pancreatic cancer). High serum GDF15 levels are associated with poor prognosis and predict all-cause mortality. Based on the GDF15 properties related to appetite and body weight control, GDF15 analogs and antagonists can be considered in the weight management of various conditions such as obesity (induction of anorexia with GDF15 analogs), and heart failure or cancer (reduction of cachexia with GDF15 antagonists). Conclusion: GDF15, a hormone synthesized by several organs including placenta, prostate, bladder, kidney, pancreas, and endometrium, has an important role in multiple physiological and pathological conditions. Its serum level can be considered as a biomarker for the diagnosis and prognosis of several diseases. GDF15 analogs and antagonists have the potential to be used in the weight management of obesity and cardiac or cancer cachexia. Presentation: Sunday, July 13, 2025

Abstract Disclosure: S. Thota-Kammili: None. J.A. McNeil: None. S.J. Peres: None. M.A. Edgar: None. J.P. Reynolds: None. J. Eleazer: None. A.Y. Chang: None. Introduction: 45,X/46,X,psrY mosaicism has been reported in the context of prenatal diagnosis with few reports on the developmental phenotype through adulthood. The 45,X/46,XY karyotype is well-studied and linked to ambiguous genitalia, dysgenetic gonads, and increased gonadal tumor risk. Less is known about 45,X/46,X,psrY mosaicism, characterized by partial Y chromosome retention. Phenotypic variability with a broad spectrum of phenotypes including Turner syndrome features, delayed puberty, hypogonadism and infertility depends on the extent and functionality of preserved Y chromosome material. We present a case of 45,X/46,X,idic(Y)(q11.21) mosaicism in an individual assigned male at birth, with a nonbinary intersex gender identity who received gender affirming feminizing hormone therapy (GAHT) before orchiectomy. Clinical Case: This is a case of a 36 y.o. patient who was found to have 45,X/46,X +mar chromosomal abnormality prenatally and initially diagnosed with Turner’s syndrome. At birth, patient had male genitalia, descended testes, and only slight hypospadias. Subsequent Y-DNA studies determined the unknown marker to be the sex determining region of the Y chromosome. Early evaluations showed appropriate responses to LHRH and ACTH, and developmental milestones were met without major health or behavioral concerns aside from a delay in puberty. The patient experienced early gender incongruence and faced questioning for gender expression. Delayed puberty led to testosterone therapy, worsening distress. Parents did not share the medical history with the patient until adulthood, when they notified them about the potential for infertility. During infertility evaluation, semen analysis revealed azoospermia. Testosterone therapy was re-attempted for hypogonadism but resulted in increased distress and patient began GAHT. Patient sought a second opinion on previous diagnosis of differences of sexual development (DSD). Chromosomal analysis revealed the 45,X/46,X,idic(Y)(q11.21) mosaicism, with duplication of Yp and deletion of the Yq. Pt was referred to urology for bilateral orchiectomy to reduce gonadal tumor risk and gender dysphoria. Pathology revealed atrophic seminiferous tubules with complete absence of spermatogenesis which were populated by Sertoli cells only and surrounded by thickened basal lamina. Leydig cells were markedly depleted. These changes are seen in transgender patients treated with estrogen prior to orchiectomy. Conclusion: Our case expands the phenotypic characterization of 45,X/46,X,idic(Y)(q11.21) mosaicism by detailing clinical features and previously unreported testicular pathology. This patient had minimal developmental concerns, and testicular pathology reflected changes associated with GAHT, highlighting the variability in phenotypic expression of 45,X/45,X,psrY mosaicism. Presentation: Sunday, July 13, 2025

Abstract Disclosure: R. Haider: None. M. Waqas: None. S. Khan: None. A. Ullah: None. M. Khawar: None. A. Qadeer: None. M. Talha: None. A. Batool: None. A. Khan: None. M.Z. Haider: None. R.W. Kirchoff: None. Background: Hypothyroidism and heart failure (HF) contribute significantly to mortality among older adults. Understanding mortality trends, including demographic, geographic, and socio-economic disparities, is crucial to inform healthcare policies and resource allocation. Methods: This study analyzed age adjusted mortality rates (AAMRs) from 1999 to 2022 for adults aged 55-85+ years. Age adjusted mortality rates (AMRs) per 1,000,000 population were stratified by gender, race, geographic location, and urbanicity. Trends were evaluated using Average Annual Percentage Change (APC) with 95% confidence intervals (CI), examining periods of decline and increase. Results: Between 1999 and 2022, 105,008 deaths were recorded among older adults (55-85+ years) due to hypothyroidism and heart failure (HF). The age-adjusted mortality rate (AAMR) initially declined from 1999 to 2016, marked by a significant drop between 2005 and 2008 (APC = -6.0, 95% CI: -7.6 to -3.0). However, mortality trends reversed post-2016, with a sharp increase (APC = 6.7, 95% CI: 5.5 to 8.4). Age-specific trends revealed declining crude mortality rates (CMR) across all groups until 2016, followed by increases, particularly in the 65-74 and 75-84 age brackets, with APCs of 14.1 (95% CI: 7.8 to 27.8) and 8.9 (95% CI: 3.8 to 21.8), respectively. Gender disparities showed men and women had similar trends, with declines until 2015-2016 followed by surges, with APCs of 6.8 (95% CI: 5.2 to 9.1) and 6.6 (95% CI: 4.6 to 11.1), respectively. Racial disparities highlighted steady declines until 2016, followed by increases in non-Hispanic Whites (APC = 10.4, 95% CI: 5.2 to 23.2) and Hispanics (APC = 7.5, 95% CI: 6.0 to 10.1). Geographically, the Midwest exhibited the highest AAMR (71.1), while the Northeast showed the lowest (51.4). State-level disparities revealed North Dakota with the highest AAMR (129.5), contrasting with Nevada, which had the lowest (20.4). Urban-rural differences showed similar trends, with notable AAMR increases in both settings post-2016. These results underscore significant demographic and regional disparities in hypothyroidism and HF-related mortality. Conclusion: While mortality from hypothyroidism and HF among older adults declined until 2016, trends have since reversed across all demographic and geographic strata. Addressing these rising rates require targeted interventions focusing on high-risk groups and areas. Presentation: Monday, July 14, 2025

Abstract Disclosure: E.M. Lewiecki: Amgen Inc, Kyowa Kirin, Ultragenyx, Angitia, Radius Health, Inc, Ascendis. E. Kapoor: Fresenius Kabi USA Inc., Astellas Pharma, Estetra SRL, WellFound Inc., Exeltis. S. Hurtado: None. V.M. Navarro: Bayer, Inc. M. Torres: Bayer, Inc. J. Beau: Bayer, Inc. I. Gkioni: Syneos Health LLC (providing service to Bayer), AstraZeneca. K. Genga: Bayer, Inc.. Background: The neuropeptide substance-P and its receptor neurokinin-1 (SP-NK1R pathway) play a role in bone metabolism and remodelling. Pre-clinical evidence also points to a role of this pathway in energy homeostasis. NK-1R antagonists have been proposed as potential therapies in obesity and musculoskeletal disorders like osteoporosis. Elinzanetant (EZN) is a dual neurokinin-1 and -3 receptor antagonist in late-stage development for vasomotor symptoms (hot flashes) associated with menopause. This post hoc analysis evaluates potential benefits of EZN on the skeleton, body weight, and body composition in postmenopausal women. Methods: Data were gathered from exploratory endpoints of the 52-week (wk), placebo (PL)-controlled, OASIS-3 Phase 3 EZN efficacy and safety trial. Mean percentage (%) change in total bone mass (kg) (measured indirectly by bioelectrical impedance analysis at baseline (BL), wks 4, 8, 12, 18, 24, 36, 52); mean % change in bone mineral density (BMD, measured directly by dual-energy X-ray absorptiometry at BL, wks 24 and 52) in femoral neck, total hip, and lumbar spine; and mean % change in key bone turnover markers osteocalcin (OC) and procollagen 1N-terminal propeptide (P1NP) at BL, wks 4, 8, 12, 18, 24, 36, 52 were evaluated. Weight, body mass index (BMI: weight/height2), waist circumference (WC), fat mass index (FMI; fat mass/height2), lean mass index (LMI; lean mass/height2) and body water were measured to monitor body composition at BL and wks 4, 8, 12, 18, 24, 36, 52. A sub-analysis was performed based on FMI at baseline (FMI ≤9 normal fat mass; >9 excess fat mass). Descriptive statistics were used to evaluate all parameters and trends. Results: From BL to wk 52, increasing trends in bone mass were observed with EZN (mean [SD]: 2.81 [1.02] to 2.95 [1.96]) but not PL (mean [SD]: 2.87 [1.09] to 2.87 [1.13]). In parallel, lower BMD reductions were seen in EZN vs PL at all skeletal sites [EZN vs PL, mean % change from BL: femoral neck (0.00% vs -1.22%), total hip (-0.70% vs -1.37%), and lumbar spine (-0.57% vs -1.22%), with considerable variability in both groups (SD range 3.01 - 4.70)]. Lower levels of circulating OC and P1NP were consistently observed over 52 wks of EZN treatment, suggesting a lower rate of bone resorption with EZN vs PL. Trending reductions in weight, BMI, and WC, along with increases in LMI and body water were observed with EZN vs PL. Trends of higher LMI in patients with excess fat, or lower FMI in patients with normal fat at BL were observed with EZN, suggestive of a positive body re-composition with EZN. Conclusions: These data expand on EZN safety profile and further point to novel potential benefits for the skeleton and body composition of postmenopausal women. Further research is warranted to provide conclusive evidence of the benefits of EZN specifically in post-menopausal women with obesity/overweight status or osteoporosis. Sponsorship: Bayer U.S., Whippany, NJ, USA Presentation: Monday, July 14, 2025

Abstract Disclosure: S. Ahmadian: None. C.A. Villavicencio Torres: None. V.M. Fell: None. K.L. Moehnke: None. Y. Chai: None. R.L. Taylor: None. S.K. Grebe: None. A.D. Maus: None. I. Bancos: None. Background: Salivary cortisol (SalF), and cortisone (SalE) interpretation can be influenced by intra-individual variability arising from cortisol secretion cyclicity, assay performance, and sampling techniques. No studies to date have examined the impact of sampling on intra-individual variability. Methods: We conducted a single-center cross-sectional study of adults evaluated with total serum cortisol measurements as a part of the overnight dexamethasone suppression test (DST) or cosyntropin stimulation test (CST), November 2024- January 2025. Participants were provided with two cotton swabs (salivettes) and asked to collect two consecutive saliva samples immediately after the venipuncture for total cortisol. Each cotton swab was kept in the mouth for 2-2.5 minutes. Saliva was tested for SalF and SalE by mass spectrometry. Variability was examined based on cortisol tertiles. Results: A total of 78 paired saliva samples were obtained from 60 participants (45 [75%] women; median age 55 years [IQR 39-66]), who were undergoing either DST (42 [70%]) or CST (18 [30%]). A total of 10 (17%) saliva samples did not contain a sufficient sample for analysis during the first or second saliva collection (7 [12%] from DST group, and 3 [5%] from CST group).Among 53 patients undergoing DST, the median serum total cortisol was 1.3 mcg/dL [IQR 0.9-3], the median first SalF was 20 ng/dL [IQR 7-28], the median second SalF was 12 ng/dL [IQR 6-23], and the median variability was 11% [IQR 3-22%]. The median first SalE was 69 ng/dL [IQR 54-185], while the median second SalE was 63 ng/dL [IQR 56-178], with a median variability of 6% [IQR 4-10].In patients undergoing CST, peak median serum total cortisol was 20 mcg/dL [IQR 18-24], median first SalF was 809 ng/dL [IQR 536-1227], and median second SalF was 1063 ng/dL [IQR 667-1503], with the median variability of 14% [IQR 8-22]. The median first SalE was 2507 ng/dL [IQR1697-2966], while the median second SalE was 2485 ng/dL [IQR 1530-2976], with a median variability of 9% [IQR 3-12].When examining intra-individual variability of SalF, the variability was lowest in the middle tertile, corresponding to serum cortisol of 1.8-8.9 mcg/dL, at 9% [IQR 5-16]. Variability was higher in the lowest tertile (14% [IQR 0-52]) and the highest tertile (12% [IQR 6-16]). Overall, the variability of SalE was lower than that of SalF: 7% [IQR 4-13] in the lowest tertile, 5% [IQR 2-9] in the middle tertile, and 10% [IQR 4-12] in the highest tertile. Conclusion: We show that saliva sampling may impact the results, with 17% patients providing insufficient sample for analysis, and variability of 9-14% for SalF and 5-10% for SalE. Same time-point sampling-related variability should be considered in interpretation of SalF and SalE measurements. Presentation: Sunday, July 13, 2025

Abstract Disclosure: M. Salehi: None. K. Yu: None. C.A. Villavicencio Torres: None. V. Fell: None. I. Bancos: None. Context: The use of the 1 mg overnight dexamethasone suppression test (1 mg-DST) is considered the standard-of-care test for the assessment of hypercortisolism. Scarce data are available on the utility of 8 mg-DST in distinguishing adrenal from pituitary hypercortisolism. Objective: To determine the value of 8 mg-DST in diagnosing hypercortisolism subtype. Methods: We conducted a single-center retrospective cohort study (2005-2024) of consecutive adults who underwent both the 1 mg-DST and the 8 mg-DST within a 6-month period. Only patients with optimal reference standard confirming the type of hypercortisolism were included. Patients were excluded if they had an abnormal DST and dexamethasone concentration <100 ng/dL or were receiving oral estrogen therapy. Delta cortisol [(post 1 mg-DST cortisol- post 8 mg-DST cortisol) x100/post 1 mg-DST cortisol)] was calculated for each patient. Results: A total of 61 patients (50, 82% women, median age 60 years, interquartile range, IQR 47-67) underwent both 1- and 8 mg-DST at least once, with 8 (13%) patients undergoing the 1 mg-DST and 8 mg-DST twice, and 1 (1.6%) patient undergoing both tests thrice. Adrenal hypercortisolism was diagnosed in 44 (72%) patients and pituitary hypercortisolism in 17 (28%) patients. Median post 1 mg-DST cortisol was 4.6 mcg/dL (IQR 2.8-7.2) in adrenal and 13.7 mcg/dL (IQR 7.3-21.7) in pituitary hypercortisolism. Median post 8 mg-DST cortisol was 3.2 mcg/dL (IQR 2.5-6.3) in adrenal and 3.6 mcg/dL (IQR 2.2-7.5) in pituitary hypercortisolism. Median delta cortisol was higher in pituitary hypercortisolism when compared to adrenal hypercortisolism (69%, IQR 25-83 vs 5 %, IQR -20-16, P<0.001). Delta cortisol demonstrated a good discrimination in distinguishing adrenal from pituitary hypercortisolism with a median area under receiver operator of 82% (95%CI 69-92). A cut-off of 25% provided a specificity of > 85%, while a cut-off of -1% yielded a sensitivity of > 85% in diagnosing adrenal hypercortisolism. Conclusion: In this study, we show that performing 8 mg-DST in addition to 1 mg-DST in selected patients with hypercortisolism and calculating delta cortisol is a valuable in distinguishing hypercortisolism subtype. Presentation: Sunday, July 13, 2025

Abstract Disclosure: A.M. Gonzalez Gil: None. E.F. Elli: None. R.J. Singh: None. S. Peres: None. A.Y. Chang: None. Background: Treatment of hypercortisolism in primary bilateral macronodular adrenal hyperplasia (PBMAH) with mild autonomous cortisol secretion (MACS) can be challenging. Medical treatment is useful for therapeutic purposes and as a bridge for adrenalectomy. We present the case of a patient who benefited from mifepristone but developed hyperestrogenism. Clinical Case: A 64-year-old man with prediabetes, hypertension, and cardiovascular disease had incidentally discovered bilateral nodular adrenal enlargement on CT scan following coronary artery bypass surgery. A few months later, he reported increasing fatigue, brain fog, weight gain, and worsening blood pressure. Physical exam showed no features of hypercortisolism. Work-up revealed baseline AM cortisol 17.3 mcg/dL [reference range (RR) 4.8-20], ACTH 10 pg/mL (RR 7.2-63) and DHEA-S 55 mcg/dL (RR 12-227); two abnormal AM cortisols after 1 mg overnight dexamethasone (5.4 and 6.9 mcg/dL; cut-off <1.8), and a normal 24-hour urine free cortisol (23 mcg/24h, RR 3.5-45). 24-hour urine metanephrines and aldosterone/renin ratio were normal. A 2-hour 75 g oral glucose tolerance test was diagnostic for type 2 diabetes mellitus (2-hour glucose 214 mg/dL). Baseline total testosterone (TT) was 366 ng/dL (RR 264-916) with normal follicle stimulating hormone (FSH) and luteinizing hormone (LH)concentrations. After a diagnosis of MACS, adrenal vein sampling showed bilateral excess cortisol secretion (lateralization ratio 1.09). Medical management versus right adrenalectomy based on nodule burden were offered, and he started mifepristone. With initial symptom improvement, his dose was increased from 300 mg to 300 mg alternating with 600 mg daily. When he developed increased blood pressure and hypokalemia, eplerenone was added. After 6 months of mifepristone and 5 months eplerenone 50 mg daily, he developed tender gynecomastia with elevated estradiol (106 pg/mL, RR ≤39), low TT (112 ng/dL) and undetectable FSH and LH. As expected with mifepristone, 17-hydroxyprogesterone was high (933 ng/dL, RR 51-190), but androstenedione and DHEA-S were normal. Reduction in mifepristone and eplerenone decreased estradiol levels (56 pg/mL) but gonadotrophins remained undetectable and TT decreased to 72 ng/dL. Despite discontinuation of eplerenone for 1 month, estradiol again increased (91 pg/mL), TT remained low (77 ng/dL), and mastalgia persisted. A decision to stop mifepristone and proceed with right adrenalectomy was made. Conclusion: This is a previously unreported incident of symptomatic estradiol-induced secondary hypogonadism on mifepristone therapy. Hyperestrogenism with gynecomastia and secondary hypogonadism with mifepristone suggests that some individuals may convert cortisol precursors to estradiol. Presentation: Saturday, July 12, 2025

Abstract Disclosure: J. Arguinchona: None. N. Allen: None. M. Vahidi Rad: None. K. Doshi: None. Background: Thyrotoxic periodic paralysis (TPP) is a distinct disorder characterized by episodic, generalized muscle weakness due to hypokalemia, occurring predominantly in young adult males (20-40 years) with hyperthyroidism, particularly Graves' disease. TPP is common in East Asian populations, affecting approximately 2% of individuals with hyperthyroidism, but is rare in Western populations (0.1-0.2%) and often underrecognized in the United States. Herein, we present three cases of TPP in young Hispanic and Caucasian males with Graves’ disease, underscoring the importance of diagnostic vigilance. Clinical Cases: Case 1: A 21 y.o. Hispanic male presented to endocrine clinic following multiple hospitalizations for severe hypokalemia and myopathy. During admission, labs showed a potassium (K) 1.2 mmol/L (3.6-5.2), undetectable thyroid stimulating hormone (TSH), and free thyroxine (FT4) 2.8 ng/dL (0.9-1.7). K was replaced and Graves’s disease was confirmed by positive TSH receptor antibodies. He was started on methimazole and subsequently underwent radioactive iodine (I-131) therapy. Following development of hypothyroidism, he was placed on levothyroxine replacement, with no further recurrence of paralysis. Case 2: An 18 y.o. Caucasian male with a history of Graves’ disease presented after multiple hospitalizations for hypokalemia and lower extremity weakness. Hospitalization labs showed a suppressed TSH, FT4 2.2 ng/dL, free triiodothyronine (FT3) 7.9 pg/mL (2.3-4.1), and K 2.8 mmol/L. His weakness improved with K replacement. Methimazole was initiated and the patient subsequently opted for total thyroidectomy for definitive therapy. No recurrence of TPP was observed after thyroidectomy. Case 3: A 29 y.o. Hispanic male with Graves’ disease, non-adherent to methimazole was hospitalized due to symptoms of diffuse upper and lower extremity weakness. Labs showed K 1.6 mmol/L, undetectable TSH, and T4 >7.7 ng/dL. Symptoms resolved with K replacement. He was restarted on methimazole as well as atenolol and advised on medical adherence. Unfortunately, he was lost to follow up, and re-hospitalized 7 months later with similar symptoms and labs, again due to nonadherence with thionamide medication. After aggressive K replacement and methimazole resumption, he was discharged with urgent endocrine follow-up for definitive management of Graves’ disease. Conclusion: These cases highlight the under recognition of TPP in non-Asian populations in the United States, leading to delayed diagnosis and recurrent hospitalizations. Clinicians should maintain a high index of suspicion for TPP in young males with hypokalemia, and generalized weakness, particularly in the setting of undiagnosed or untreated hyperthyroidism. Prompt recognition and definitive treatment of hyperthyroidism is critical to preventing recurrent episodes and associated morbidity. Presentation: Saturday, July 12, 2025